WO 2006/135687
PCT/US2006/022326
PYRROLOBENZODIAZEPINE PYRIDINE CARBOXAMIDES AND DERIVATIVES
AS FOLLICLE-STIMULATING HORMONE RECEPTOR ANTAGONISTS
This applications claims benefit of priority to US provisional application no.
60/688,988 filed June 9,2005, which is hereby incorporated by reference in its
entirety.
BACKGROUND OF INVENTION
This invention concerns novel pyrrolobenzodiazepine pyridine carboxamides,
which act as follicle-stimulating hormone receptor antagonists, as well as
pharmaceutical compositions and methods of treatment utilizing these compounds.
Reproduction in women depends upon the dynamic interaction of several
compartments of the female reproductive system. The hypothalamic-pftuitary-
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), which is 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 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 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,"
1

WO 2006/135687

PCT/US2006/022326

B.C.J.M. Fauser, ed., Vol. 6 (London: Parthenon Publishing Group), 1997, and A.J.
Hsueh et. a!., 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 et al., 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 et al., Clin. Lab.
Med., 36, 664,1998). Therefore, 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 that is exclusively expressed in the
ovary, thus, leading to activation of the adenyl cyclase system and elevation of
intracellular levels of the second messenger cAMP (A. Mukherjee et al.,
Endocrinology, 137, 3234 1996).
Recently suramin, a sulfonic acid anticancer agent with a wide variety of
activities, was shown to inhibit FHS binding to its receptor (R.L. Daugherty et al., J.
Urol., 147,727 (1992). Administration of suramin causes a decrease in testosterone
production in rats and humans (R. Danesi et al., J. Clin. Endocrinol. Metab. 81, 2238-
2246,1996). Recently, other more selective sulfonic acid-based FSH receptor
antagonists were reported by B.J. Arey et al. (The Endocrine Society, 82nd Annual
Meeting, Toronto, Canada June 21-24, 2000, and Endocrinology 143 (10), 3822,
2002). An additional class of stilbene (bis)sulfonic acid competitive inhibitors of FSH
2

WO 2006/135687

PCT/US2006/022326

at its receptor has also been reported by J. Wrobel et al. {Bioorg. Med. Chem. 10,
639-656, 2002).
Thiazolidinone FSH-R agonists and antagonists have been disclosed by R.
Scheuerman et al. in WO 02/09705 and WO 02/09706 (2002) and in US Patent No.
6,426,357 (2002), respectively. Cyclic and acyclic alpha- and beta-
aminocarboxamides as FSH-R agonists are disclosed by El Tayer et al. in WO
00/08015 (2000). Substituted aminoalkylamide derivative FSH-R antagonists have
been disclosed by Coats et al. in WO 01/47875 (2001). Aryl sulfonic acids and
derivatives FSH-R antagonists have been disclosed by Wrobel et al. in US Patent
Nos. 6,200,963 (2001) and 6,355,633 (2002). Tetrahydroquinoline derivatives have
been disclosed as FSH-R modulators to control fertility by Van Straten et al. in WO
03/004028 (2003). Bisaryl derivatives with FSH-R modulatory activity have been
disclosed by T. Guo et al. in WO 02/070493A1. T. Guo et al. also have reported
encoded combinatorial and parallel synthesis approaches to bisaryl FSH-R agonists;
see Bioorg. Med. Chem. Lett. 14, 1713-1716, 2004 and 1717-1720, 2004,
respectively. Failli et al. in WO 02/083683 (2002) have disclosed a subset of
pyrrolobenzodiazepines as tocolytic oxytocin receptor binding antagonists.
It can be seen that there is a great need for FSH receptor binding antagonists
that can be used for contraception. This invention is directed to these, as well as
other, important ends.
SUMMARY OF THE INVENTION
The present invention relates to pyrrolobenzodiazepine pyridine
carboxamides and derivatives having antagonist activity on the FSH receptor, and to
their use as contraceptives.
In accordance with this invention are novel compounds represented by the
structure of Formula I:
3

WO 2006/135687 PCT/US2006/022326

wherein
Ri and R2 are selected independently from hydrogen, (CrC6) alkyl, halogen
trifluoromethyl, hydroxyl, (CrC6) alkoxy, OCF3l carboxy, -CONHt(CrC6)
alkyl], or -CON[(CrC6) alkyl]2, amino, (CrC6) alkylamino, -NHCO[(CrC6)
alkyl];
R3 is selected from the group consisting of hydrogen, (CrC6) alkyl, (CrC6)
alkoxy, hydroxyl, amino, (Ci-C6) alkylamino, C(0)-(CrC6) alkyl, and haloger
A is selected from the group consisting of C=0, CH2, and S02;
Bis

wherein R5, Re, R7, Rs, Rg, R10, R100, R101. and Ri02are selected independently
from the group consisting of hydrogen, alkyl, alkoxy, trihalomethyl, halogen, -
C(O) alkyl, hydroxy, hydroxyalkyl, alkyloxyalkyl, -CH(OH)alkyl, -
CH(alkoxy)alkyl, formyl, nitro, thioalkyl, - S02alkyl, -S02NHRn, -S02N(Rn)2, -
(CH2)PCN , -(CH2)pCOOR12, -(CH2)pNR13Ri4, -(CH2)pCONR13R14, -CH=NOH, -
CH=NO-alkyl, and -C(0)aryl optionally substituted by
alkyl;
Rn and Ri2are each independently hydrogen or alkyl;
R13 and R14 are each independently hydrogen or alkyl; or can be taken
together with the nitrogen to which they are attached to form a 4-6
4

WO 2006/135687 PCT/US2006/022326
membered saturated ring optionally containing one or more additional
O, S or N atoms;
p is 0 or 1;

wherein
R15 is hydrogen or alkyl;
X is selected independently from the group consisting of

wherein
Ri6 is hydrogen or alkyl;
R17 is one to three substituents selected from the group consisting of
hydrogen, alkyl, halogen, hydroxy, aryloxy, and hydroxyalkyl;
Risis 5 or 6-membered saturated heterocycle containing one nitrogen
atom;
m is an integer from 1 to 4;
q is an integer from 1 to 2; and
r is 0 or 1;
provided that:
if A is C=0, m is 1 or 2, r is 0, R7is methyl or methoxy and R5, Re, Rs,
Rg, Rio> Ri7, Rioo, and R10i are hydrogen, then Ri02 is not
methyl or methoxy;
if A is C=0, m is 2, r is 0, R6 is methoxy and R5, R7, Rg, Rio, R17, R100,
R10r, and R102 are hydrogen, then R8 is not methoxy;
if A is C=0, m is 1 or 2, r is 0, RB is methyl or methoxy, and R5, R7, Re,
R10, Ri7, Rioo, Rioi> and R102 are hydrogen, then R9 is not
methoxy;
if A is C=0, m is 2, r is 0, R6 is chlorine, R10o is methoxy, then R10i is
not methoxy wherein R5, R7, R8, Rg, R10, R17. and R102 are
hydrogen, or R102 is not methyl wherein R5, R7, R8, Rg, R10, R17.
and R101 are hydrogen;
5

WO 2006/135687

PCT/US2006/022326

if A is C=0, m is 1 or 2, r is 0 or 1, R7 is methyl, and R5, R6, R9, R10, R17l
R100, Rioi> and R102 are hydrogen, then R8 is not trifluoromethyl;
if A is C=0, m is 1, r is 0, R7 is methoxy, R5, R6, R9, R10, R17, RiQ0, and
R102 are hydrogen then R8 is not chlorine wherein R10i is
hydrogen or R10i is not methoxy wherein R8 is hydrogen;
if A is C=0, m is 1, r is 0, R5 is methoxy, R7 is chlorine, and R6, Rio,
R17, Rioo, R101, and Ri02 are hydrogen, then Ra is not
trifluoromethyl, chlorine, or methyl wherein R9 is hydrogen, or
R9 is not methoxy wherein R8 is hydrogen;
if A is C=0, m is 2, r is 0, R7is methyl, and R5, R6, R9, Rio, R17, Rioo,
R101, and R102 are hydrogen, then R8 is not methoxy;
if A is C=0, m is 1 or 2, r is 0 or 1, R6 is chlorine, R100 is methoxy, and
Rs, R7, R9> R10, Ri7 are hydrogen, then R8 is not ethoxy wherein
R101 and R102 are hydrogen, or R10i is not methyl wherein R8
and Rio2are hydrogen, or R102 is not fluorine, trifluoromethyl, or
methyl wherein R8 and R101 are hydrogen;
if A is C=0, m is 1 or 2, r is 0, R7 is methyl, and R5, R6, R8, R9, R10, R17,
R10o, and R102 are hydrogen, then R101 is not methoxy;
if A is C=0, m is 1, r is 0 or 1, R6 is methoxy, R102 is trifluoromethyl,
and R5, R7, R8, R9, R10, R17, and R101 are hydrogen, then R10o is
not hydrogen or methoxy;
if A is C=Ot m is 1 or 2, r is 0, R8 is methyl, and R5, R7, R9, R10, R17,
R100, R101 and R102 are hydrogen, then R6 is not hydrogen or
methyl; and
if A is C=0, m is 1 or 2, r is 0, and Rs, R6, R7, R9, R10, Ri7, R100, R101
and R102 are hydrogen, then R8 is not methoxy; or
a pharmaceutically acceptable salt thereof.
In accordance with this invention, there is also provided a group of
compounds represented by the Formula II:
6

WO 2006/135687 PCT/US2006/022326

wherein
Ri and R2 are as defined hereinbefore;
R3 is as defined hereinbefore;
A is as defined hereinbefore;
C is selected from the group consisting of

wherein
R19 and R2o are selected independently from the group consisting of
hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, -COOR21,
dialkylamino, nitro, cyano, aryloxy, aroyl, naphthyl and -CH2NHC(0)0-alkyl;
or R19 and R20 can be taken together with the phenyl moiety to which they are
attached to form a structure of the formula -0(-CH2)n-0- wherein n is 1 or 2,

R21 is hydrogen or alkyl;
Y is selected from the group consisting of alkyl, cycloalkyl, naphthyl,
7

WO 2006/135687 PCT/US2006/022326

wherein
R22 is selected from the group consisting of hydrogen, alkyl,
halogen, aralkyloxy-, alkylamino, hydroxyalkylamino, cycloalkylamino,
N-alkyl piperazino, (pyridinoalkyl) amino, (N-alkyl) aralkyl amino and
aralkyl amino wherein the aryl is optionally substituted with alkoxy;
R23 and R24 are each independently hydrogen or halogen;
R25 and R30 are each independently hydrogen or alkyl;
R26, R27, R28, and R29 are selected independently from the
group consisting of hydrogen, alkyl and halogen;
R31 is hydrogen, alkyl, halogen or aryl; and
R32 is each independently H, OH or taken together with the
carbon to which they are attached form -C=0;
Z consists of the moiety D-E, wherein
D is an aryl optionally substituted by one or more substituents
selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, nitro, -
SO2NH2, and trifluoromethyl; and
E is selected from the group consisting of
8

WO 2006/135687 PCT/US2006/022326

wherein R33 is hydrogen or alkyl; and

wherein
R150 is hydrogen or alkyl;
X is selected independently from the group consisting of

wherein
R160 is hydrogen or alkyl;
R170 is one to three substituents selected from the group
consisting of hydrogen, alkyl, halogen, hydroxy, aryloxy, and
hydroxyalkyl;
Risois 5 or 6-membered saturated cycloalkylamine;
m' is an integer from 1 to 4;
q' is an integer from 1 to 2;
r' is 0 or 1; or
a pharmaceutical acceptable salt thereof.
In some embodiments, when either R19 or R20 is naphthyl, then A is not C=0.
The compounds of the present invention are useful for inhibiting the fertility of
a mammal. The compounds are useful also for preventing conception and for
blocking follicular development that is mediated by follicle-stimulating hormone in a
mammal.
The present invention also provides methods of inhibiting the fertility,
preventing conception and blocking follicular development mediated by follicle-
9

WO 2006/135687 PCT/US2006/022326

wherein
Ri, R2, R3, A, and R' are as defined hereinbefore;
B' is selected independently from the group consisting of

stimulating hormone in a mamman with a compound having the struction of Formula
111:
wherein
R5, Re, R7, R8> R9 and R10 are as defined hereinbefore; or
a pharmaceutical acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses novel, non-peptidic, low molecular weight
FSH receptor binding antagonists of unique structure. None of the aforementioned
compounds are disclosed to be follicle-stimulating hormone receptor (FSH-R)
antagonists or contraceptive agents. The compounds of the present invention differ
from these previously described compounds in that they contain the optimal
substitution in the biphenyl moiety, are active as FSH-R antagonists and useful as
contraceptive agents.
In accordance with this invention are novel compounds represented by the
structure of Formula I:
10

WO 2006/135687 PCT/US2006/022326

wherein
Ri and R2 are selected independently from hydrogen, (CrC6) alkyl, halogen,
trifluoromethyl, hydroxyl, (CrC6) alkoxy, OCF3, carboxy, -CONHKCrCs)
alkyl], -CON[(CrC6) alkyl]2, amino, (CrC6) alkylamino, or -NHCO[(CrC6)
alkyl];
R3 is selected from the group consisting of hydrogen, (CrC6) alkyl, (CrC6)
alkoxy, hydroxyl, amino, (CrC6) alkylamino, C(0)-(CrC6) alkyl, and halogen;
A is selected from the group consisting of C=0, CH2, and S02;
Bis

wherein R5, R6, R7, Ra, R9, Rio> Rioo> R101. and R102are selected independently
from the group consisting of hydrogen, alkyl, alkoxy, trihalomethyl, halogen, -
C(O) alkyl, hydroxy, hydroxyalkyl, alkyloxyalkyl, -CH(OH)alkyl, -
CH(a!koxy)alkyl, formyl, nitro, thioalkyl, - S02alkyl, -S02NHRn, -S02N(Rn)2, -
(CH2)PCN , -(CH2)pCOOR12, -(CH2)PNR13R,4, -(CH2)pCONR13Ri4, -CH=NOH, -

alkyl;
Rn and R12are each independently hydrogen or alkyl;
R13 and RM are each independently hydrogen or alkyl; or can be
taken together with the nitrogen to which they are attached to form a
11

WO 2006/135687 PCT/US2006/022326
4-6 membered saturated ring optionally containing one or more
additional 0, S or N atoms;
p is 0 or 1;

wherein
R15 is hydrogen or alkyl;
X is selected independently from the group consisting of

wherein
Rie is hydrogen or alkyl;
R17 is one to three substituents selected from the group consisting of
hydrogen, alkyl, halogen, hydroxy, aryloxy, and hydroxyalkyl;
Ris is 5 or 6-membered saturated heterocycle containing one nitrogen
atom;
m is an integer from 1 to 4;
q is an integer from 1 to 2; and
r is 0 or 1;
provided that:
if A is C=0, m is 1 or 2, r is 0, R7 is methyl or methoxy and R5, R6, Rs.
Rs, Rio, R17, R100. and R10i are hydrogen, then R102 is not
methyl or methoxy;
if A is C=0, m is 2, r is 0, R6 is methoxy and R5, R7, Rg> R10, R17, R100,
R10i, and R102 are hydrogen, then R8 is not methoxy; .
if A is C=0, m is 1 or 2, r is 0, R6 is methyl or methoxy, and R5, R7, Rs,
Rio, R17. R100, Rioi.and R102 are hydrogen, then R9 is not
methoxy;
if A is C=0, m is 2, r is 0, R6is chlorine, R100is methoxy, then R10i is
not methoxy wherein R5, R7, Ra, R9, R10, Ri7> and R102 are
hydrogen, or R102 is not methyl wherein R5, R7, Ra, Rg, R10, R17.
and Riot are hydrogen;
12

WO 2006/135687

PCT/US2006/022326

if A is C=0, m is 1 or 2, r is 0 or 1, R7 is methyl, and R5, R6) R9, R10, R17,
Rioo, R101, and R102 are hydrogen, then Ra is not trifluoromethyl;
if A is C=0, m is 1, r is 0, R7 is methoxy, R5, Ra, R9, Rio, R17, Rioo, and
R102 are hydrogen then R8 is not chlorine wherein R10i is
hydrogen or Ri01 is not methoxy wherein R8 is hydrogen;
if A is C=0, m is 1, r is 0, R5 is methoxy, R7 is chlorine, and R6, Rio,
R17, Rwo, Rioi.and Ri02 are hydrogen, then Rais not
trifluoromethyl, chlorine, or methyl wherein R9 is hydrogen, or
R9 is not methoxy wherein R8 is hydrogen;
if A is C=0, m is 2, r is 0, R7is methyl, and R5, R6, R9, R10, Ri7, Rioo,
R101, and Ri02 are hydrogen, then R8 is not methoxy;
if A is C=0, m is 1 or 2, r is 0 or 1, R6 is chlorine, R100 is methoxy, and
Rs, R7, Rs, R10, R17 are hydrogen, then R8 is not ethoxy wherein
R10i and R102 are hydrogen, or R10i is not methyl wherein R8
and R102 are hydrogen, or R102 is not fluorine, trifluoromethyl, or
methyl wherein R8 and Ri01 are hydrogen;
if A is C=0, m is 1 or 2, r is 0, R7 is methyl, and R5, R6, R8, R9, R10, R17,
R100, and Ri02 are hydrogen, then R101 is not methoxy;
if A is C=0, m is 1, r is 0 or 1, R6 is methoxy, R102 is trifluoromethyl,
and R5, R7, R8, R9, R10, R17, and R10i are hydrogen, then R10ois
not hydrogen or methoxy;
if A is C=0, m is 1 or 2, r is 0, R8 is methyl, and R5, R7) R9, R10, R17,
R100, R101 and R102 are hydrogen, then R6 is not hydrogen or
methyl; and
if A is C=0, m is 1 or 2, r is 0, and Rs, R6, R7, R9, R10, R17, R100, R101
and R102 are hydrogen, then R8 is not methoxy; or
a pharmaceutical acceptable salt thereof.
In some embodiments of the invention, R1, R2, and R3 are each hydrogen and
R15 is hydrogen or methyl. In some such embodiments, Ri6 is hydrogen, m is 1 and r
is 0, and R17 has at least one substituent that is not hydrogen or none that are
hydrogen. In some such embodiments, Ri6and Ri7are hydrogen, q is 1 and r is 0,
and R13 is a 5-membered saturated cycloalkylamine. In some such embodiments,
R16and R17 are hydrogen, m is 1, r is 0 and R6is methyl, or R7is methyl or methoxy,
13

WO 2006/135687 PCT/US2006/022326
or R7 is methyl and R8 is methyl. In some such embodiments, R16 and R17 are
hydrogen, m is 1, r is 0, and R8 is selected from the group consisting of methyl,
chlorine, hydroxy, methoxy, -COCH3, -CHO, -CH(OH)CH2CH3, -CH2OH, -CN, -
CH(CH3)2, -CO(phenyl), -CH2OCH3, -CH2COOCH3l -OCH2CH3, -CH2CN, -SCH3, -
CH2COOH, -CH(OH)CH3, -COCH(CH3)2, -S02CH3, -COOCH3, -COOC(CH3)3, -
COOH, -CH2CONH2, -CH2CONHCH3> -CH2CON(CH3)2, -CH2CONH(CH2CH3), -
CH2CON(CH2CH3)2, -CH(OH)CH(CH3)2, -CON(CH3)2, -CH2N(CH3)2, -CH2NHCH3l -
CH2C(NH2)=NOH, -CH2NH2, -S02NH2, -CONHCH3, and 4-6 membered saturated
ring optionally containing one or more O, S or N atoms; or further still, R8 is selected
from the group consisting of -CH2OH, -CH2OCH3, -CH2COOCH3, -CH(OH)CH3, -
CH2CONH2, and -CH2C(NH2)=NOH.
In some embodiments, A is S02.
In some embodiments, compounds of the present invention are represented
by the structure of Formula I-2:

wherein
R6' is H or (Calkyl;
R8' is selected from the group consisting of H, (CJalkoxy, halogen, (d.
3)alkyl, (dhydroxyalkyl, -C(O)R600l CN, (C)alkoxyalkyl, CH2C(0)R6oi,CH2CN,
HC=NOH, OH, S((CM)alkyl), SCMCalkyr), CH2N(R6o2)(R603), CH2C(NH2)=NOH,
and S02NH2;
14

WO 2006/135687 PCT/US2006/022326
R9' is H, halogen or (Calkyl;
Rio' is H, halogen, (C)alkyl, or C(0)(Ci.3)alkyl;
R102 is H or (Chalky];
Ris is as defined hereinbefore;
R500 is H, OH, halogen, (C1)alkyl, or O-phenyl;
R501 and R502 are each independently H or OH; and
k is 0 or 1;
wherein
R600 is H, OH, (Calkyl, phenyl, (Calkoxy, or NR602R603;
R601 is OH, (Ci.3)alkoxy, or NR602R603; and
R602and R603are each independently H or (d)alkyl, or
R602 and R603 together form a 5-6 membered heterocycle with
up to 3 additional N or O atoms;
provided that:
when R6' is methyl, R8' is not methoxy;
when R6' is methyl, and one of R8' or R' is methyl, then either:
(a) the other of R8' or R102' is not H; or
(b) k=1;and
if R6', R9', R10', R102', R500, Rsoi> and R502 are all H, then R8 is not methyl or
methoxy.
The present invention also provides the compounds having the structure of
Formula II:

wherein
Ri and R2 are as defined hereinbefore;
R3 is as defined hereinbefore;
15

WO 2006/135687 PCT/US2006/022326
A is as defined hereinbefore;
C is selected from the group consisting of

wherein

R21 is hydrogen or alkyl;
Y is selected from the group consisting of alkyl, cycloalkyl, naphthyl,
R19 and R2o are selected independently from the group consisting of
hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, -COOR21,
dialkylamino, nitro, cyano, aryloxy, aroyl, naphthyl and -CH2NHC(0)0-alkyl;
or R19 and R20 can be taken together with the phenyl moiety to which they are
attached to form a structure of the formula -0(-CH2)n-0- wherein n is 1 or 2,

wherein
R22 is selected from the group consisting of hydrogen, alkyl,
halogen, aralkyloxy-, alkylamino, hydroxyalkylamino, cycloalkylamino,
N-alkyl piperazino, (pyridinoalkyl) amino, (N-alkyl) aralkyl amino and
aralkyl amino wherein the aryl is optionally substituted with alkoxy;
R23 and R24 are each independently hydrogen or halogen;
R25 and R30 are each independently hydrogen or alkyl;
16

WO 2006/135687 PCT/US2006/022326
R26, R27, R28, and R2g are selected independently from the
group consisting of hydrogen, alkyl and halogen;
R31 is hydrogen, alkyl, halogen or aryl; and
R32 is each independently H, OH or taken together with the
carbon to which they are attached form -C=0;
Z consists of the moiety D-E, wherein
D is an aryl optionally substituted by one or more substituents
selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, nitro, -
S02NH2, and trifluoromethyl; and
E is selected from the group consisting of

wherein R33 is hydrogen or alkyl; and

wherein
R150 is hydrogen or alkyl;
X is selected independently from the group consisting of

wherein
R160 is hydrogen or alkyl;
17

WO 2006/135687 PCT/US2006/022326
R170 is one to three substituents selected from the group
consisting of hydrogen, alkyl, halogen, hydroxy, aryloxy, and
hydroxyalkyl;
Riaois 5 or 6-membered saturated cycloalkylamine;
m' is an integer from 1 to 4;
q' is an integer from 1 to 2;
r' is 0 or 1.
In some such embodiments, R19and R2oare each selected independently
from the group consisting of hydrogen, alkyl and halogen; or from the group
consisting of hydrogen, methyl, methoxy, fluorine, chlorine, trifluoromethyl, aroyl, -
OCF3, -C(CH3)3, -(CH2)2CH3, -COOCH3l -COOH, -CN, -N(CH3)2, -N(0)=0, -
N(CH2CH3)2, - CH2NHCOOC(CH3)3, and -O-phenyl.
18
In some such embodiments, D is an unsubstituted aryl and E is selected from
the group consisting of


WO 2006/135687

PCT/US2006/022326

phenyl and R32 is each independently H; or from the group consisting of 3,3-
dimethylbutane, cyclohexyl, isobutane, 1-naphthyl, or 2-naphthyl.
In some embodiments, the present invention provides the compounds 10-{[2'-
(1-Hydroxyethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide; 10-{[2'-(Hydroxymethyl)-1,1'-
biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide; 10-{[2'-{Methoxymethyl)-1,1'-biphenyl-4-
yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide; methyl (4'-{[3-{[(pyridin-3-
ylmethyl)amino]carbonyl}-5H-pyrroIo[2,1-c][1,4] benzodiazepin-10(11 H)-yl]carbonyl}-
1,1'-biphenyl-2-yl)acetate; (-)-10-({2'-[1-Hydroxyethyl]-1,1'-biphenyI-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide; 10-{[2'-{2-Amino-2-oxoethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide; and
10-({2'-[2-Amino-2-(hydroxyimino)ethyl]-1,1 '-biphenyl-4-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide.
In further embodiments, the present invention provides the compounds
described as Examples 1-150, hereinbelow.
Also provided in accordance with the invention are compositions comprising a
pharmaceutically effective amount of a compound according to the invention, and a
pharmaceutically acceptable carrier or excipient.
The present invention also provides methods for using the compounds
disclosed herein. In some such embodiments, the invention provides methods of
inhibiting fertility comprising administering to a mammal, e.g., a human, an effective
amount of a compound of the invention. In some such embodiments, the invention
provides methods for preventing conception, which comprises administering to a
mammal an effective amount of a compound of the invention. In further
embodiments, the methods of inhibiting fertility and preventing conception comprises
administering a compound of Formula III:
19



WO 2006/135687 PCT/US2006/022326
wherein R1( R2, R3, A, and R' are as defined hereinbefore; B' is selected
independently from the group consisting of
wherein R5, R6, R7, Re, Rg and R10 are as defined hereinbefore. In some such
embodiments of the methods of the invention, the mammal can be a female; in other
embodiments, the mammal is male. When the mammal of such method is female,
the onset of pregnancy is prevented in the female mammal, while when the mammal
is male, onset of pregnancy is prevented in a second mammal that is female.
In further embodiments of the methods of the invention, FSH-mediated
follicular development is blocked by the administration to a mammal of an effective
amount of a compound of the invention. In further embodiments, the methods of
blocking FSH-mediated follicular development comprises administering a compound
of Formula III, as described hereinbefore.
In some embodiments, the present invention provides methods of inhibiting
fertility. In some embodiments, the methods include administering to a mammal an
effective amount of at least one compound as described herein, or a
pharmaceutically acceptable salt thereof. In some embodiments, the methods further
comprise identifying a mammal in need of contraception.
In some embodiments, the methods include administering an effective
amount of a combination of two or more of the compounds described herein, or salts
20

WO 2006/135687

PCT/US2006/022326

thereof. It is specifically intended that the phrases "combination of two or more of the
compounds described herein, or salts thereof," or "at least one compound as
described herein, or a pharmaceutically acceptable salt thereof," or similar language
describing specific compounds, includes the administration of such compounds in
any proportion and combination of salt or free acid forms; i.e., includes the
administration of such compounds each in the acid form, or each in the salt form, or
one or more in the acid form and one or more in the salt form, in any proportion of the
compounds and/or salts.
The invention is to be understood as embracing all simultaneous, sequential
or separate use of any combination of the compounds of the invention with any
pharmaceutical composition useful in the methods described herein.
As used herein, the term "effective amount" when applied to a compound of
the invention, is intended to denote an amount sufficient to cause the intended
biological effect. In some embodiments, the methods of the invention provide for
administration of combinations of compounds. In such instances, the "effective
amount" is the amount of the combination sufficient to cause the intended biological
effect.
The term "alkyl", employed alone or as part of a group, is defined herein,
unless otherwise stated, as either a straight-chain or branched saturated
hydrocarbon of 1 to 10 carbon atoms. In some embodiments, the alkyl moiety
contains 1 to 10,1 to 8,1 to 6,1 to 4,1 to 3 or 1 carbon atoms. Where the term
"alkyl" appears herein without a carbon atom range it means a range of CrC10.
Examples of saturated hydrocarbon alkyl moieties include, but are not limited to,
chemical groups such as methyl, ethyl, n-propyl, isopropyl, /7-butyl, terf-butyl,
isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
The term "alkoxy", employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as -O-alkyl. Examples of alkoxy moieties
include, but are not limited to, chemical groups such as methoxy, ethoxy, isopropoxy,
sec-butoxy, tert-butoxy, and homologs, isomers, and the like.
The term "cycloalkyl," employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as a cyclized alkyl group having from 3 to 8
ring carbon atoms.
21

WO 2006/135687

PCT/US2006/022326

The terms "halo" or "halogen", employed alone or in combination with other
terms, is defined herein, unless otherwise stated, as fluoro, chloro, bromo, or iodo.
The term "aryl", employed alone or in combination with other terms, is defined
herein, unless otherwise stated, as an aromatic hydrocarbon of up to 14 carbon
atoms, which can be a single ring (monocyclic) or multiple rings (bicyclic, up to three
rings) fused together or linked covalently. Any suitable ring position of the aryl moiety
can be covalently linked to the defined chemical structure. Examples of aryl moieties
include, but are not limited to, chemical groups such as phenyl, 1-naphthyl, 2-
naphthyl, and the like.
The term "aryloxy" employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as a group of formula -O-aryl, where the
term "aryl" has the definition as previously described herein.
The term "arylalkyl" or "aralkyl" employed alone or in combination with other
terms, is defined herein, unless otherwise stated, as an alkyl, as herein before
defined, substituted with an aryl moiety. Examples of arylalkyl moieties include, but
are not limited to, chemical groups such as benzyl, 1-phenylethyl, 2-phenylethyl,
diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and homologs,
isomers, and the like.
The term "acyl" employed alone or in combination with other terms, is defined
herein, unless otherwise stated, as groups of formula -C(0)-alkyl of 2 to 7 carbon
atoms.
The term "alkoxyalkyl" employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as -alkyl-alkoxy wherein the terms "alkyl"
and "alkoxy" have the definitions as previously described herein.
The term "carbalkoxy" employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as alkoxycarbonyl, e.g., -COOCH3.
The term "aminoalkyl" employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as -alkyl-amino, wherein the term "alkyl" has
the definition as previously described herein and the term "amino" is -NH2 or -NH-.
The term "alkylamino" employed alone or in combination with other terms, is
defined herein, unless otherwise stated, as -NH-alkyl, wherein the term "alkyl" has
the definition as previously described herein.
22

WO 2006/135687

PCTYUS2006/022326

The terms "inhibit," "inhibiting," "block," or "blocking" as used herein mean to
retard, arrest, restrain, impede or obstruct the progress of a system, condition or
state.
The terms "prevent" or "preventing" as used herein mean to keep from
happening or existing.
The term "administering" as used herein means either directly administering
the compounds of the present invention, or administering a prodrug, derivative or
analog of the compounds of the present invention that will form an effective amount
of the compounds of the present invention within a mammal.
The compositions of the present invention may be adapted to any mode of
administration, including intravenous administration such as subcutaneous,
intraperitoneal, or intramuscular, bolus and infusion, and oral administration.
The compounds of the present invention can be used in the form of salts
derived from non toxic pharmaceutical acceptable acids or bases. These salts
include without limitation the following: salts with inorganic acids, e.g., hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids
such as acetic acid, oxalic acid, citric acid, tartaric acid, succinic acid, maleic acid,
benzoic acid, benzene sulfonic acid, fumaric acid, malic acid, methane sulfonic acid,
pamoic acid, and para-toluene sulfonic acid. Other salts include salts with alkali
metals or alkaline earth metals, e.g., sodium, potassium, calcium or magnesium, or
with organic bases, including quaternary ammonium salts.
The compounds of the present invention also can be used in the form of
esters, carbamates and other conventional prodrug forms, which generally will be
functional derivatives of the compounds of this invention that are readily converted to
the active moiety in vivo. Also included are metabolites of the compounds of the
present invention defined as active species produced upon introduction of these
compounds into a biological system.
When the compounds of this invention are employed as described above,
they may be combined with one or more pharmaceutically acceptable excjpients or
carriers, e.g. solvents, diluents and the like. Such pharmaceutical preparations may
be administered orally in such forms as tablets, capsules (including time release and
sustained release formulations), pills, dispersible powders, granules, or suspensions
containing, for example, from 0.05 to 5% of suspending agent, syrups containing, for
23

WO 2006/135687

PCT/US2006/022326

example, from about 10 to 50% of sugar, and elixirs and the like, or parenterally in
the form of sterile injectable solutions, suspensions or emulsions containing from
about 0.05 to 5% suspending agent in an isotonic medium. Such preparations may
contain, for example, from about 25 to about 90% of the active ingredient in
combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredients employed may vary depending on
the particular compound or salt employed, the mode of administration, age, weight,
sex and medical condition of the patient, and the severity of the condition being
treated. The selection of the appropriate administration and dosage forms for an
individual mammal will be apparent to those skilled in the art. Such determinations
are routine to a physician, veterinarian or clinician of ordinary skill in the art (see for
example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci
et al., 14m ed., published by McGraw Hill). Further, the dosage regimen may be
adjusted to provide the optimal therapeutic response. For example, several divided
doses may be administered daily or the dose may be proportionally reduced as
indicated by the needs of the therapeutic situation.
These active compounds of the present invention may be administered orally
as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers such
as starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and
kaolin, liquid carriers such as sterile water, polyethylene glycols, glycerol, non-ionic
surfactants, and edible oils such as corn, peanut and sesame oils, may be employed
as are appropriate to the nature of the active ingredient and the particular form of
administration desired. Adjuvants customarily employed in the preparation of
pharmaceutical compositions advantageously may be included, such as flavoring
agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E,
ascorbic acid, BHT and BHA.
These active compounds also may be administered parenterally or
intraperitoneally. Solutions or suspensions of these active compounds as a free
base or pharmacologically acceptable salt can be prepared in water suitably mixed
with a surfactant such as hydroxypropylcellulose. Dispersions also can be prepared
in glycerol, liquid polyethylene glycols and mixtures thereof in oils. These
preparations shall contain a preservative to prevent the growth of microorganisms
under ordinary conditions of storage and use.
24

WO 2006/135687

PCT/US2006/022326

The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous preparation of
sterile injectable solutions or dispersions. In all cases, the form must be sterile and
must be fluid to the extent that easy injectability exists. It must be stable under
conditions of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi. The carrier can
be a solvent or dispersion medium containing, for example, water, ethanol, polyol
(e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable-mixtures
thereof, and vegetable oil.
Furthermore, active compounds of the present invention can be administered
intranasally using vehicles suitable for intranasal delivery, or transdermal, for
example, by using transdermal skin patches known to those ordinarily skilled in the
art. Transdermal administration further includes all administrations across the surface
of the body and the inner linings of bodily passages, including epithelial and mucosal
tissues, using carrier systems such as lotions, creams, foams, patches, suspensions,
solutions, and suppositories (rectal and vaginal). When using a transdermal delivery
system, the dosage administration will be continuous rather than in a single or
divided daily doses. The compounds of the present invention can also be
administered in the form of liposome delivery system wherein the liposomal lipid
bilayer are formed from a variety of phospholipids.
Compounds of the present invention may be delivered by the use of carriers
such as monoclonal antibodies to which the active compounds are coupled. The
compounds of the present invention also may be coupled to soluble polymers as
drug carriers or to biodegradable polymers that are useful in achieving controlled
release of the active agent.
It is understood by those practicing the art that some of the compounds of this
invention depending on the definition of R, R', R-,, R2, R3, B, B' and C may contain
one or more asymmetric centers, and thus may 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 pharmaceutical
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,
25

WO 2006/135687

PCT/US2006/022326

and include, but are not limited to, diastereomeric salt formation, kinetic resolution,
and asymmetric synthesis. It is also understood that this invention encompasses all
possible regioisomers, E-Z isomers, endo-exo isomers, and mixtures thereof that
possess the indicated activity. Such isomers can be obtained in pure form by
standard procedures known to those skilled in the art, and include, but are not limited
to, column chromatography, thin-layer chromatography, and high-performance liquid
chromatography. It is understood by those practicing the art that some of the
compounds of this invention depending on the definition of B and C 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.
Also according to the present invention there are'provided processes for
producing the compounds of the present invention.
PROCESS OF THE INVENTION
The compounds of the present invention may be prepared according to one of
the genera] processes outlined below. The compounds of Formula III may be
prepared as describe in PCT Application No. WO 2002/083683, filed April 11, 2002,
which is incorporated herein in its entirety.
The compounds of general formula (I) where A is -C=0 and B is as defined
hereinbefore, and compounds of general formula (II) where A is -C=0 and C is as
defined hereinbefore, can be conveniently prepared as shown in Scheme I.
26

WO 2006/135687

PCT/US2006/022326

Scheme I

According to the above preferred process, a tricyclic diazepine of formula (1),
where R R2, R3 and B (or C) are defined hereinbefore, is reacted with a
perhaloalkanoyl halide such as trichloroacetyl chloride, in the presence of an organic
base such as N,N-diisopropylethyl amine (Hunig's base), in an aprotic organic
solvent such as dichloromethane or 1,4-dioxane, at temperatures ranging from -10
°C to ambient, to provide the desired trichloroacetyl intermediate of formula (2).
Subsequent reaction of (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 as triethylamine in a solvent such as
acetonitrile, at temperatures ranging from ambient to the refluxing temperature of the
solvent, yields the desired compounds of formula (l) or (II) where R R2, R3, B (or C)
are as defined hereinbefore. When the amine (3) is a pyridylamine the compounds
of formula (I) or (II) can be further converted to their N-oxides by treatment with an
oxidizing agent such as a peracid or other pyridine oxidizing agents known in the
literature at temperatures ranging from -40 °C to ambient temperature.
27

WO 2006/135687 PCT/XJS2006/022326
Another preferred process is shown in Scheme II below.
Scheme li

According to the above process the trichloroacetyl intermediate of formula (2)
is hydrolyzed with aqueous base such as sodium hydroxide, in an organic solvent
such as tetrahydrofuran or acetone, at temperatures ranging from -10 °C to 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, (4) can be converted to an acyl halide
such as a chloride or bromide of formula (5, J=COCl or COBr) by reaction with thionyl
28

WO 2006/135687

PCT/US2006/022326

chloride (bromide) or oxalyl chloride (bromide) or similar reagents known in the art,
either neat or in the presence of an inorganic base such as potassium carbonate, or
in the presence of an organic base such as pyridine, 4-(dimethylamino)pyridine, or a
tertiary amine such as triethylamine in an aprotic solvent such as dichloromethane,
N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from -5 °C to 50
CC, to yield the intermediate acylated derivative (5). Subsequent coupling of the acyl
chloride (bromide) (5, J= COCI or COBr) with an appropriately substituted primary or
secondary amine of formula (3) in the presence of a stoichiometric amount of Hilnig's
base, in an aprotic solvent such as dichloromethane, N,N-dimethylformarnide or
tetrahydrofuran, at temperatures ranging from ambient to the reflux temperature of
the solvent, provides the desired compounds of formula (I) or (II) where R R2, R3
and B (or C) are as defined hereinbefore.
Alternatively, the acylating species can be a mixed anhydride of the
corresponding carboxylic acid, such as that prepared by treating the acid of formula
(4) with 2,4,6-trichlorobenzoyl chloride in an aprotic organic solvent such as
dichloromethane according to the procedure of lnanaga 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 dichloromethane, at temperatures ranging from ambient to the reflux
temperature of the solvent, provides the desired compounds of formula (I) or (II)
where R1t R2, R3 and B (or C) are as defined hereinbefore.
Alternatively, amidation of the carboxylic acids of formula (4) can be
effectively carried out by treatment of the acid with triphosgene in an aprotic solvent
such as 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 Hunig's base at temperatures ranging from -10 °C to
ambient.
Another process for the preparation of the compounds of the present
invention of formula (I) or (II), where Ri, R2, R3 and B (or C) are as defined
hereinbefore, consists of treating the acid of formula (4) with an activating reagent
such as 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
29

WO 2006/135687

PCT/US2006/022326

primary or secondary amine of formula (3), optionally in the presence of an organic
base such as Hunig's base and a catalytic amount of 4-(dimethylamino)pyridine, in
an aprotic solvent such as dichloromethane, N,N-dimethyiformamide or
tetrahydrofuran at temperatures ranging from -10 °C to ambient.
In another preferred process, the acid (4) can be activated by treatment with
other activating agents such as N,N'-carbonyldiimidazole in an aprotic solvent such
as dichloromethane or tetrahydrofuran, at temperatures ranging from -10 °C to the
reflux temperature of the solvent. Subsequent reaction of the intermediate activated
imidazolide with an appropriately substituted primary or secondary amine of formula
(3) provides the desired compounds of formula (I) or (II) where Ri, R2, R3 and B (or
C) are as defined hereinbefore.
Alternatively, the coupling of the appropriately substituted primary or
secondary amine of formula (3) with the 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 Hunig's base and in a
solvent such as N,N-dimethylformamide, at temperatures ranging from -10 °C to
ambient, to provide in good isolated yield and purity the desired compounds of
formula (I) or (II) where R1t R2, R3 and B (orC) are as defined hereinbefore.
Related coupling reagents such as 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) or (II) where R1, R2, R3and B (or C) are as
defined hereinbefore.
The method of choice for the preparation of compounds of formula (I) or (II)
from the intermediate carboxylic acid (4) is ultimately chosen on the basis of its
compatibility with the R1, R2, R3 and B (or C) groups and its reactivity with the tricyclic
diazepine of formula (1).
Another process for the preparation of compounds of formula (I) or (II) is
shown in Scheme III. A tricyclic diazepine of formula (1) is reacted with diphosgene
in an aprotic solvent such as dichloromethane, optionally in the presence of an
organic base such as triethylamine, followed by reaction of the resulting acylated
intermediate with an appropriately substituted primary or secondary amine of formula
30

WO 2006/135687

PCT/US2006/022326

(3), to provide the desired compounds of formula (I) or (II) where R1t R2, R3 and B (or
C) are as defined hereinbefore.
Scheme 111

The tricyclic diazepines of formula (1) of Scheme I, wherein A is -C=0 and
B and C are as defined hereinbefore, can be conveniently prepared as shown in
Scheme IV.
Scheme IV

Thus, a tricyclic diazepine of formula (6) is treated with an appropriately
substituted acylating agent such as an aroyl halide, such as an appropriately
substituted acyl chloride (or bromide) of formula (7, J= COCI or COBr), where B (or
C) is ultimately chosen on the basis of its compatibility with the present reaction
scheme, in the presence of an inorganic base such as potassium carbonate, or in the
presence of an organic base such as pyridine, 4-(dimethylamino)pyridine, or a
tertiary amine such as triethylamine, N,N-diisopropylethyl amine or N,N-
dimethylaniline, in an aprotic solvent such as 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).
31

WO 2006/135687

PCTYUS2006/022326

Alternatively, the acylating species of formula (7) can be a mixed anhydride of
the corresponding carboxylic acid, such as that prepared by treating the acid with
2,4,6-trichlorobenzoyl chloride in an aprotic organic solvent such as dichloromethane
according to the procedure of Inanaga et al., Bull. Chem. Soc. Jpn., 52,1989 (1979).
Treatment of the mixed anhydride of general formula (7) with a tricyclic diazepine of
formula (6) in a solvent such as dichloromethane, and in the presence of an organic
base such as 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 acylating intermediate of formula (7) is ultimately chosen on the basis of
its compatibility with the B (or C) group and its reactivity with the tricyclic diazepine of
formula (6).
The intermediates of formula (7) of scheme IV wherein C is Y or Z 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 intermediates of formula (7) of Scheme IV where B is as defined
hereinbefore can be conveniently prepared by a process shown in Scheme V. Thus,
an appropriately substituted aryl iodide (bromide, chloride, or trifluoromethane
sulfonate) of formula (8, wherein P is a carboxylic acid protecting group, for example,
P= alkyl or benzyl, M= I, Br, CI, OTf; and R5, R6, R7 and Riooare defined
hereinbefore) is reacted with an aryl tri(alkyl)tin(IV) derivative of formula (9, T=
Sn(trialkyl)3, for example, Sn(n-Bu)3), where R8, R9, R10, Rioi> and R102 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 (10).
Subsequent unmasking of the carboxylic function by hydrolysis, hydrogenolysis or
similar methods known in the art, followed by activation of the intermediate acid (11)
provides the desired compounds of formula (7), where R5, R6, R7. Rs, R9, R10. R100,
R101, and R102 are as hereinbefore defined, suitable for coupling with the tricyclic
diazepine of formula (6).
32

WO 2006/135687 PCT/US2006/022326

Alternatively, the desired intermediates of formula (10) of Scheme V where B
is as defined hereinbefore can be prepared by coupling of the iodide (bromide,
chloride, trifluoromethane sulfonate) (8, M= I, Br, CI or OTf) and an appropriately
substituted aryl boron derivative of formula (9, preferably T=B(OH)2), in the presence
of a palladium catalyst such as palladium(ll) acetate or tetrakis(triphenylphosphine)
palladium(O) and an organic base such as triethylamine or an inorganic base such as
sodium (potassium or cesium) carbonate, with or without added tetrabutylammonium
bromide (iodide), in a mixture of solvents such as toluene-ethanol-water, acetone-
33

WO 2006/135687

PCT/US2006/022326

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 prepared similarly from the bromide (8, M= Br) and the
boronic acid (9) in a solvent such as 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, T= Br, I or OTf) with a pinacolato boronate
[boronic acid, or trialkyltin(IV)] derivative of formula (8, M= B(OH)2, or
SnBu3) yields the desired intermediate of formula (10), which is converted to (1) in
the manner of Scheme V.
The required appropriately substituted aryl halides of formula (8, M= 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 (8, P= H, alkyl or benzyl, M= 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),
respectively, or with copper(l) bromide (March, Advanced Organic Chemistry, 3rd ed.,
p.647-648, John Wiley & Sons, New York (1985)).
Alternatively, the desired intermediates of formula (11) of Scheme V where B
is as defined hereinbefore can be conveniently prepared as shown in Scheme VI by
a cross-coupling reaction of an appropriately substituted pinacolato boronate of
formula (13), where RB, R9, Rio, R101 and R102 are as hereinbefore defined, with an
aryl triflate or an aryl halide of formula (14, Q= OTf, Br, I), where R5, R6, R7 and R100
are as defined hereinbefore, according to the general procedures of Ishiyama et al.,
Tefr. Lett. 38, 3447-3450 (1997) and Giroux et al. 7efr. Lett. 38, 3841-3844 (1997),
followed by basic or acidic hydrolysis of the intermediate nitrite of formula (15) (cf.
34

WO 2006/135687 PCT/US2006/022326
March, Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York, p. 788
(1985)).
Scheme VI

Alternatively, reaction of an iodide (bromide, chloride, or trifluoromethane
sulfonate) of formula (12, L= Br, CI, I, orOTf) with a boronic acid [ortrialkyl tin(IV)]
derivative of formula (14, Q= B(OH)2, or SnBu3) yields the desired intermediate of
formula (15), which is converted to (11) in the manner of Scheme VI.
The desired phenyl boronic esters of formula (13) of Scheme VI can be
prepared conveniently by the palladium-catalyzed cross-coupling reaction of
bis(pinacolato)diboron (16) with an appropriately substituted aryl halide such as a
bromide or iodide (12, L= Br, I) or aryl triflate (12, L= OTf) according to the described
procedures of Ishiyama et a)., 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 A is -C=0 and
B is as defined hereinbefore can be alternatively prepared by a process shown in
Scheme VII.

WO 2006/135687 PCT/US2006/022326
Scheme VII

Thus, a tricyclic diazepine of formula (6) is treated with an appropriately
substituted acylating agent such as a halo aroyl halide such as an iodo (bromo) aroyl
chloride (bromide) of formula (17, J= COCI or COBr; K= I, Br), where R5, R6, R7 and
R100 are as defined hereinbefore, 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, R7 and R100 groups, and its reactivity with the tricyclic
diazepine of formula (6).
36

WO 2006/135687

PCT/US2006/022326

A Stille coupling reaction of an halide (18, K= I) with an appropriately
substituted organotin reagent such as a trialkyltin(IV) derivative, for example, a tri-n-
butyltin(IV) derivative of formula (9, T= SnBu3), where R8, R9, R10, R10i and R102 are
as hereinbefore defined, in the presence of a catalyst such as tetrakis
(triphenylphosphine) palladium (0), in an aprotic organic solvent such as toluene and
N,N-dimethylforrnamide, at temperatures ranging from ambient to 150 °C (cf. Farina
et al., J. Org. Chem, 59, 5905 (1994) and references cited therein), affords the
desired compounds of formula (1) wherein R-i, R2, R3, Rs, Re, R7, RB, R R2, R3, R5, Re, R7, Rs, R9, R10, R100, R101 and R102 are as defined hereinbefore.
The preferred substituted aroyl chlorides (bromides) of formula (17) of
Scheme VII (K= I, Br; J= COCI or COBr), where R5, R6, R7 and R100 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, T= Sn(alkyl)3; for example, alkyl= 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 of formula
(19) where R8, R9, R10, R101 and R102 are as hereinbefore defined, by first reacting
them with n-butyl lithium followed by reaction of the intermediate lithiated species
with a trialkyl (e.g., trimethyl or tri-n-butyl) tin(IV) chloride.
37

WO 2006/135687 PCT/US2006/022326

The substituted aryl boronic acids of formula (9, T= 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.
Alternatively, as shown in Scheme IX, the appropriately substituted aroyl
halides, for example, aroyl chlorides of formula (20, J= COCI), where R5, Re, R7 and
R10o are as 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 alkyi-di-tin (e.g., 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), where R8, Rg, R10, R101 and R102 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 A is -C=0 and B,
R1, R2, R3, R6, Re, R7. R8, R9, Rio, R100, R101 and R102 are as defined hereinbefore.
38

WO 2006/135687 PCT/US2006/022326

Alternatively, the desired compounds of formula (1) of Scheme IX wherein B
is as defined hereinbefore can be prepared as shown in Scheme X.
Scheme X

Thus, an appropriately substituted biphenyl of formula (24), wherein R5, R6,
R7 and R100 are defined hereinbefore, is treated with carbon monoxide in the
presence of a tricyclic diazepine of formula (6), a palladium(O) catalyst such as
PdBr2{Ph3P)2 and a tertiary amine such as n-tributylamine, in a solvent such as
anisole or dioxane, at temperatures ranging from ambient to the reflux temperature of
the solvent (cf. Schoenberg et al. J. Org. Chem. 39, 3327 (1974)) to provide the
39

WO 2006/135687 PCTYUS2006/022326
desired compounds of formula (1) wherein R1( R2| R3, R5, Re, R7. Re, Rs, R10, Rioo,
R10i and R102 are defined hereinbefore.
Another process for the preparation of the desired compounds of general
formula (I) or (II) of Scheme I, wherein A is -C=0 and B and C are as defined
hereinbefore, is shown in Scheme XI.
Scheme XI

Thus, a tricyclic diazepine of formula (25), wherein R1, R2 and R3 are defined
hereinbefore, carrying a protecting group such a fluorenylalkoxycarbonyl group, such
as a fluorenylmethyloxycarbonyl (P= Fmoc) group or an alkoxycarbonyl protecting
group such as a tert-butyloxycarbonyl (P= Boc) group is reacted with a
perhaloalkanoyl halide such as trichloroacetyl chloride, in the presence of an organic
base such as N,N-diisopropylethyl amine (Hunig's base) or a tertiary amine such as
40

WO 2006/135687

PCT/US2006/022326

triethylamine or N.N-dimethylaniline, optionally in the presence of catalytic amounts
of 4-(dimethyIamino) pyridine, in an aprotic organic solvent such as dichloromethane
at temperatures ranging from -10 °C to 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, P=Boc), which is then deprotected (intermediate 28) and acylated to the
desired product of formula I (or II). Alternatively, the conversion of (26) to (28) can
be carried out in a single step by treatment of (26, P=Fmoc) with a primary amine (3)
in the presence of dimethylsulfoxide in an aprotic solvent such as acetonitrile and at
the reflux temperature of the solvent.
Alternatively, hydrolysis of the trichloroacetate intermediate (26) with aqueous
base such as sodium hydroxide in an organic solvent such as acetone, at
temperatures ranging from -10 °C to ambient, is accompanied by simultaneous
removal of the protecting group (P= Fmoc) and yields the intermediate acid of
formula (29), as shown in Scheme XII. The required amidation of the carboxylic acid
(29) can be effectively accomplished by treating (29) with an activating reagent such
as 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) optionally in the presence of Htinig's base or a catalytic amount of 4-
(dimethylamino)pyridine, in an aprotic solvent such as dichloromethane, N,N-
dimethylformamide or tetrahydrofuran at temperatures ranging from -10 °C to
ambient. Subsequent acylation of the amide (28) under the conditions of Scheme IV
provides the desired compounds of formula (I) or (II).
41

WO 2006/135687 PCT/US2006/022326
Scheme XII

Other coupling reagents known in the literature that have been used in the
formation of amide bonds in peptide synthesis also can be used for the preparation ol
compounds of formula (28). The method of choice for the preparation of compounds
of formula (28) from the intermediate carboxylic acid (20) is ultimately chosen on the
basis of its compatibility with the R R2, and R3 groups.
Alternatively, the intermediate acids of formula (29) of Scheme XII, wherein
RL R2, and R3 are defined hereinbefore, can be obtained by reacting a tricyclic
diazepine of formula (6) with an excess of acylating agent such as trifluoroacetic
anhydride or trichloroacetyl chloride, in the presence of an inorganic base such as
potassium carbonate or an organic base such as N,N-diisopropylethylamine, in an
aprotic solvent such as N,N-dimethylformamide, followed by basic hydrolysis of the
intermediate bis-trifluoroacetyl (trichloroacetyl) intermediate of formula (30) optionally
with aqueous sodium hydroxide in a protic organic solvent such as ethanol, at
temperatures ranging from ambient to the reflux temperature of the solvent as shown
in Scheme XIII.
42

WO 2006/135687 PCT/US2006/022326
Scheme XIII

Some processes for the preparation of compounds of formula (1) of Scheme I,
wherein A is -C=0 and B, R,, R2, R3, R5, R6. R7> Rs> Rs, R10, R100, R101 and R102 are
as defined hereinbefore, also utilize acylation of the amide 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 (31, K= Br or I) with an
appropriately substituted aryl boronic acid (9, T= B(OH)2) in a mixture of solvents
such as dimethoxyethane and water or acetonitrile and water, and in the presence of
a Pd(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a Pd(ll) catalyst
such as [1.1'-bis(diphenylphosphino)ferrocene]dichloro palladium(ll), and a base
such as potassium or sodium carbonate, at temperatures ranging from ambient to
reflux, yields the desired compound (I).
43

WO 2006/135687 PCT/US2006/022326

Alternatively, some compounds of formula (I) of Scheme I, wherein A is
-C=0 and B, R1f R2, R3, Rs, Re, R7, Rs, Rs. R10, R100, R101 and , R102are as defined
hereinbefore, can be prepared, as shown in Scheme XV, by acylation of the amide
intermediate (28) of Scheme XII with an acylating agent of formula (20) of Scheme
IX.
44

WO 2006/135687 PCT/US2006/022326
Scheme XV

Alternatively, the preferred compounds of formula I of Scheme I, where A is -
C=0 and B, R R2, R3, R5, Re, R7, Rs, R9, R10, R100, R101 and R102 are as defined
hereinbefore, can be prepared by acylation of the amide intermediate (28) of Scheme
XII with an acylating agent of formula (7) of Scheme V, wherein J is as hereinbefore
defined, as shown in Scheme XVI.
Scheme XVI

Another process for the preparation of the amide intermediate (31) of Scheme
XIV is shown in Scheme XVII. A tricyclic benzodiazepine of formula (6) is acylated
with an acylating agent (17, K= Br or I) to provide the intermediate (34), which then is
45

WO 2006/135687 PCT/US2006/022326
reacted with a perhaloalkanoyl halide (e.g., trichloroacetyl chloride) under the
conditions of Scheme I to provide the trichloroacetyl intermediate of formula (35).
Subsequent reaction of (35) with an appropriate primary or secondary amine, also
under the conditions of Scheme I, provides the desired product (31).
Scheme XVII

The compounds of formula I, wherein A is S02 or CH2 and B, R1( R2, R3, R5,
R6, R7, Rs, Rs, R10, R100, R101 and R102 areas defined hereinbefore, also can be
prepared as shown in Scheme XVIII below

WO 2006/135687 PCT/US2006/022326

Acylation of (6) with either an aryl sulfonyl halide such as a sulfonyl chloride
or bromide (17, W= S02Cl or S02Br) in the presence of Hunig's base in
dichloromethane or alkylation of (6) with a benzyl halide, for example, chloride or
bromide (17, W= CH2Cl or CH2Br), in the presence of potassium carbonate in N,N-
dimethylformamide provides the intermediates (36, A'= S02 or CH2), which are
converted to (37) in the manner of Scheme XVII, and then to compounds (I) wherein
A' is S02 or CH2 in the manner of Scheme XIV.
EXAMPLES
COMPOUND EXAMPLES
The following examples are presented to illustrate rather than limit the scope
of the present invention.
EXAMPLE 1
10-[(2-METHOXY-2'-METHYL-1,r-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLOt2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Step A. Methyl 4-bromo-3-hydroxybenzoate
47

WO 2006/135687

PCT/US2006/022326

To a solution of 4-bromo-3-hydroxybenzoic acid (30 mmol) in methanol (100 mL) was
added concentrated sulfuric acid (2.6 mL). The solution was heated at reflux for 5
hours, cooled to 0 °C, and brought to pH 7 by adding saturated aqueous sodium
carbonate. The solution was evaporated to one-third the original volume. Water was
added and the product was extracted into ethyl acetate. The organic extracts were
washed with water and brine, and dried over anhydrous sodium sulfate. Evaporation
gave 6.15 g (89%) of the title compound as a white solid. This was used without
further purification.
Step B. Methyl 4-bromo-3-methoxybenzoate
A solution of 4-bromo-3-hydroxybenzoic acid of Step A (27 mmol), potassium
carbonate (33 mmol) and dimethyl sulfate (32 mmol), in acetone (40 mL) was stirred
at reflux temperature under nitrogen atmosphere for three hours. The mixture was
cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of
water was added. The product was extracted into dichloromethane. The organic
solution was dried over anhydrous magnesium sulfate, and evaporated to provide the
title compound (6.5 g; 99%) as a hard, white, crystalline solid.
Step C. 2-Methoxy-2'-methyl-1,1,-biphenyl-4-carboxylic acid methyl ester
A solution consisting of toluene (100 mL), ethanol (50 mL), and water (50 mL), was
sparged with dry nitrogen gas for 45 minutes. To the solvent mixture was added 4-
bromo-3-methoxybenzoic acid methyl ester of Step B (26.5 mmol), o-tolylboronic
acid (29.1 mmol), and sodium carbonate (112.5 mmol). The mixture was sparged
with nitrogen gas for an additional ten minutes.
Tetrakis(triphenylphosphine)palladium (0) (1 mmol) was added to the mixture which
was then heated at 105 °C for 6 hours. The mixture was cooled and the phases
separated. The organic phase was washed three times with a sequence of saturated
aqueous sodium carbonate, and brine. The organics were dried over anhydrous
sodium sulfate, and evaporated to an oil. Chromatography on silica gel using
dichloromethane and hexane (3:1) provided the title compound as a clear oil (6.7g,
99%).
Step D. 2-Methoxy-2'-methyl-1,1 '-biphenyl-4-carboxylic acid
To the ester of Step C (26 mmol) was added methanol (10 mL), tetrahydrofuran (45
mL), and 1 N sodium hydroxide (33 mL). The solution was refluxed vigorously in an
oil bath at 105 °C for one hour. The volatile solvents were evaporated and the
48

WO 2006/135687

PCT/US2006/022326

solution was chilled in ice. Hydrochloric acid (2.0 N) was added until the pH was ~1.
The product was extracted into ethyl acetate, dried with anhydrous magnesium
sulfate, filtered and evaporated to a white solid. This was recrystallized in ethyl
acetate and hexane to afford
5.5 g of the title compound (86 %).
Step E. 10-[(2-Methoxy-2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,benzodiazepine
To a solution of 2-methoxy-2'-methyl-biphenyl-4-carboxylic acid of Step D (23 mmol)
in dichloromethane (50 mL) was added a drop of N,N-dimethylformamide. Oxalyl
chloride (36 mmol) was then added dropwise to the solution. The solution was then
stirred at reflux temperature for 2 hours. The solvents were evaporated and the
resulting acid chloride was dissolved in 20 mL dichloromethane. This was added
dropwise to a stirred mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepine
(25 mmol), and triethylamine (34 mmol) in dichloromethane (30 mL) at 0 °C under
nitrogen atmosphere. After 20 hours the mixture was quenched with water and
washed with 0.5 N hydrochloric acid, 1.0 N sodium hydroxide, and brine. The
solution was dried over anhydrous sodium sulfate, and evaporated to a solid. The
product was purified by column chromatography using ethyl acetate and hexane (1:3)
to provide 8.77g (95%) of the title compound as a white solid.
StepF. 2,2,2-Trichloro-1-{10-[(2-methoxy-2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
A solution of 10-[(2-methoxy-2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine of Step E (21 mmol) and triethylamine (43 mmol) in
anhydrous dichloromethane (45 mL) was cooled in an ice bath. To the stirred solution
was added, dropwise, trichloroacetyl chloride (65 mmol). The mixture was allowed to
stir at ambient temperature for 72 hours. The solution was washed with 0.1 N
hydrochloric acid and brine and dried over anhydrous sodium sulfate. Evaporation
gave a green foam. This was crystallized by heating in ethyl acetate and chloroform
to give 10.2 g of the title compound as a white powder (85%), m.p. 221-222 °C.
MS[(+)ESI,m/z]: 553 [M+Hf
Step G. 10-[(2-Methoxy-2'-methyl-1,1 ,-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
49

WO 2006/135687

PCT/US2006/022326

A solution of 2,2,2-trichloro-1-{10-[(2-methoxy-2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step F (2 mmol),
and 3-aminomethylpyridine (4.2 mmol), in dimethylsulfoxide (7 mmol) and acetonitrile
(15 ml_) was stirred at 80 °C for 18 hours. The solvents were evaporated and the
residue was dissolved in dichloromethane, washed with water, dried over anhydrous
sodium sulfate, and evaporated. The product crystallized from ethyl acetate and
hexane (0.96g; 89%), m.p. 165-167 °C.
MS [(+)ESI, m/z]: 541 [M+H]+
EXAMPLE 2
N-{[3-HYDROXY-5-(HYDROXYMETHYL)-2-METHYLPYRIDIN-4-YL]METHYL}-10-
[(2-METHOXY-2'-METHYL-1,1'-BIPHENYL-4-YL)CARBONYL]-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared from 2,2,2-trichloro-1-{10-[(2-methoxy-2'-methyl-
1,1'-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-
yl}ethanone of Example 1, step F and pyridoxamine dihydrochloride hydrate in the
manner of Example 1, m.p. 179 °C.
MS [(+)ESI, m/z]: 603 [M+H]+
EXAMPLE 3
10-[(2,2'-DIMETHYL-1,1 '-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
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 was 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 organic phase was separated, washed with 1 M
sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium
carbonate and concentrated in vacuo to give the crude product as a dark oil (28.6 g).
Purification by flash chromatography using a solvent gradient of 2% ethyl acetate in
hexane afforded the title compound (24.7 g, 93%) as a pale yellow oil.
MS [(+)ESI, m/z]: 241 [M+H]+
50

WO 2006/135687

PCT/US2006/022326

HRMS [(+)ESI, m/z]: 241.12205 [M+H]+. Calcd forC16H1702: 241.12231
Anal. Calcd for C16H1602: 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 sodium
hydroxide (108 mL, 108 mmol) and the reaction mixture was heated at reflux for 1
hour. The cooled mixture was then concentrated in vacuo to remove organic
solvents. The resulting aqueous solution was cooled to 0 °C and 2 M 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 hour at 0 °C then filtered
to afford the title compound (22.6 g, 97%) as a white solid, m.p. 140-143 °C.
MS t(-)ESI), m/z]: 225 [M-HV
Step C. (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-dimethyiformamide (5 mL) followed by the dropwise addition of a 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), and 10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N,N-
diisbpropylethylamine (87 mL, 500 mmol). The reaction mixture stirred at room
temperature under nitrogen for 16 hours. The mixture was then washed with 1 M
hydrochloric acid (5 x 1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL),
dried over anhydrous magnesium sulfate, 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, 32%) as a pale orange solid.
Purification of the mother liquors by flash chromatography yielded additional title
compound (11.5 g, 30%) as a white solid, m.p. 145-148 °C.
MS [+)ESI, m/z]: 393 [M+H]+
51

WO 2006/135687

PCT/US2006/022326

StepD. 2,2,2-Trichloro-1-{10-[(2>2,-dimethyl-1l1,-biphenyl-4-y])carbonyG-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]ben2odiazepin-3-yl}ethanone
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-
(2,2'dimethyI-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 light
green oil. The title compound was obtained pure as a light yellow crystalline solid by
treatment with hot ethyl acetate/ hexane (3/1), mp 212-214 °C.
MS [(+)ESI, m/z]: 537 [M+H]+
Anal. Calcd for C29H23CI3N202: C, 64.76; H, 4.31; N, 5.21. Found: C, 64.70; H, 4.35;
N, 4.96.
Step E. 10-[(2,2'-Dimethyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of 2,2,2-trich!oro-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 Step D (8.0 g,
15 mmol) and dimethyl sulfoxide (5.3 mL, 75 mmol) in dry acetonitrile (90 mL) at
room temperature under nitrogen was added 3-(aminomethyl)pyridine (3.1 mL, 30
mmol) and the reaction mixture was heated to reflux for 48 hours. The cooled
mixture was concentrated in vacuo, the oily residue redissolved in ethyl acetate (400
mL), washed with 1M sodium hydroxide (100 mL) and brine (100 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to give a red foam.
Purification by flash chromatography using a solvent gradient of 50 to 100% ethyl
acetate in hexane gave a pale yellow foam. Trituration with hot diethyl ether (150
mL) afforded the title compound (5.9 g, 75%) as a pale yellow solid, m.p. 147-149 °C.
Alternatively, the title compound could be purified by HPLC (normal phase, Luna CN
bonded packing) and crystallized from ethyl acetate/hexane, m.p. 148-150 °C.
MS[(-)ESI, m/z]:525[M-Hr
HRMS [(+)ESI, m/z]: 527.24314 [M+H]+. Calcd for CsN: 527.24415
Anal. Calcd for: C, 77.54; H, 5.74; N, 10.64. Found: C, 77.20; H, 5.81; N, 10.50
EXAMPLE 4
52

WO 2006/135687

PCT/US2006/022326

10-[(2,2'-DIMETHYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-t(1-OXIDOPYRIDIN-3-
YL)METHYL]-10,11-DIHYDRO-5H-PYRROLO[2,1-CH1,4]BENZODlAZEPINE-3-
CARBOXAMIDE
Prepared in essentially the same manner as Example 56, replacing 10-{[2'-(1-
hydroxyethyO-l.l'-biphenyl-ylJcarbony-Npyridin-S-ylmethyO-IO.II-dihydro-SH-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamidewith 10-[(2,2'-dimethyl-1,1'-
biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 3. Purification by flash
chromatography using a solvent gradient of 3 to 10% methanol in dichloromethane
afforded a colorless foam that was crystallized from ethyl acetate/hexane to give the
title compound (0.0317 g, 15%) as a white crystalline solid, m.p. 170 -173 °C.
MS [(+)ESI, m/z]: 543 [M+Hf
MS [(-)ESI, m/z]: 541 [M-H]'
HRMS [[(+)ESI, m/z]: 543.23825 [M+H]+. Calcd forCsiN: 543.23907
EXAMPLE 5
10-{[2-METHYL-2'-TRIFLUOROMETHYL-[1,1'-BIPHENYL]-4-YL]CARBONYL}-N-(3-
PYRIDINYLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE •
Prepared in essentially the same manner as Example 58 Step D, replacing
phenylboronic acid with 2-trifluoromethylphenylboronic acid. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave a brown glass that was triturated with diethyl ether to afford the title compound
(0.289 g, 66%) as a tan solid.
MS [(+)ESI, m/z]: 581 [M+H]+.
MS [(-)ESI, m/z]: 579 [M-H]"
Anal. Calcd for CaFalOz: C, 70.34; H, 4.69; N, 9.65. Found: C, 70.04; H, 4.61;
N, 9.58.
EXAMPLE 6
N-[(5-BROMOPYRIDIN-3-YL)METHYLL]-10-[(2'-METHOXY-1,1'-BIPHENYL-4-
YL)CARBONYL]-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-
CARBOXAMIDE
Step A. 5-Bromonicotinic acid ethyl ester
53

WO 2006/135687

PCT/US2006/022326

A solution of 5-bromonicotinic acid (5.15 g, 25.5 mmol) in ethanol (100 ml.)
containing 1 mL of concentrated sulfuric acid was refluxed for 18 hours. The solvent
was removed under reduced pressure and the residue basified with saturated
aqueous sodium bicarbonate. The solution was then extracted three times with
ether. The organics were dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give the tittle compound (5.29 g) as an off
white solid.
Anal. Calcd for C8H8BrN02: C, 41.77; H, 3.5; N, 6.09. Found: C, 41.74; H, 3.2; N,
5.75
Step B. (5-Bromo-pyridin-3-yl)-methanol
Crushed pellets of sodium borohydride were added over 30 minutes to a solution of
5-bromonicotinic acid ethyl ester of Step A (5.0 g, 21.7 mmol) in ethanol (150 mL).
The reaction was stirred at room temperature for five days and then quenched with
water. The ethanol was removed under reduced pressure and the aqueous residue
was extracted three times with methylene chloride. The combined organics were
dried over anhydrous magnesium sulfate, and concentrated under reduced pressure
to a yellow oil. The material was purified by flash chromatography over silica gel
Marck-60 using 2:1 hexane/ethyl acetate as an eluant to give the title compound
(1.41 g) as a light yellow liquid which was used in the next step without further
purification.
Step C. (5-Bromopyridin-3-yl) methylamine
A solution of (5-bromo-pyridin-3-yl) methanol of Step B (1.26 g, 6.7 mmol) in
dichloromethane (10 mL) was added dropwise at ice bath temperature to 5 mL of
thionyl chloride. The resulting mixture was stirred at room temperature for one hour
and then cooled in an ice bath before adding ethyl ether (40 mL). The resulting
precipitate was collected by filtration, washed with ethyl ether and dried under
reduced pressure for 10 minutes. The solid was then added with stirring to an ice
cold solution of aqueous ammonia (30mL) and ethanol (40mL). The reaction stirred
at room temperature for 20 hours, the solvent was removed under reduced pressure
and the resulting residue partitioned between 2N sodium hydroxide and
dichloromethane. The organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure to a yellow solid. The solid was purified
54

WO 2006/135687

PCT/US2006/022326

by flash chromatography over silica gel Merck-60 using a gradient of methanolic
ammonia in dichloromethane to give the title compound (0.456 g).
MS [El, m/z)] 186.0 [Mf
StepD. N-[(5-Bromopyridin-3-yl)methyl]-10-[(2'-methoxy-1,1,-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A solution 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 (0.288 g, 0.534 mmol), (5-
bromopyridin-3-yl)methylamine of Step C (0.20 g, 1.07 mmol), triethylamine (0.043
g, 0.588 mmol), dimethylsulfoxide (0.190 ml_, 2.67 mmol), and acetonitrile (5 mL)
was heated for 17 hours at an oil bath temperature of 81° C. The solvent was
removed under reduced pressure and the resulting residue taken up in
dichloromethane. The organics were washed with water and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure to a yellow
solid. The solid was triturated with hexane, diethyl ether, and ethyl acetate, collected
by filtration, and dried under reduced pressure to give the title compound (0.145 g) as
an off white solid, m.p 180-184° C.
MS [(+)ESI, m/z]: 607 [M+H]+
Anal. Calcd for C33H27BrN403: C, 65.24; H, 4.48; N, 9.22. Found: C, 64.81; H, 4.66;
N, 9.02.
EXAMPLE 7
10-[(2'-METHOXY-1,r-BIPHENYL-4-YL)CARBONYL]-N-[(2-PHENOXYPYRIDIN-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 6, Step D,
from 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 (0.20 g, 0.379 mmol), 2-phenoxy-
pyridin-3-ylmethyl-ammonium chloride (0.192 g, 0.78 mmol), triethylamine (0.112 g,
0.8 mmol), dimethylsulfoxide (0.131 mL, 1.85 mmol), and acetonitrile (5 mL). The
crude material was purified by hplc using the following conditions: solvent system,
65:35 acetonitrile: water (0.1% trifluoroacetic acid); Primesphere 10 C18, 250 by 50
mm column; flow rate lOOmL/min) to provide the title compound (0.062 g) as a white
solid.
MS [(+)ESI, m/z]: 621 [M+H]+
55

WO 2006/135687

PCT/US2006/022326

Anal. Calcd for CagHszNA C, 75.47; H, 5.20; N, 9.03. Found: C, 74.96; H, 4.94; N,
8.80
EXAMPLE 8
10-[(2'-METHOXY-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared according to the procedure of Example 6, Step D,
from pyridin-3-yi-methylamine (0.515 mL, 5.057 mmol), 2,2,2-trichloro-1-{10-[(2'-
methoxy-1,1'-biphenyl-4-yl)carbonyI]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}ethanone (1.30 g, 2.41 mmol), triethylamine (0.738 mL,
5.30 mmol), dimethylsulfoxide (0.854 mL, 12.04 mmol) and acetonitrile (15 mL). The
crude material was purified by flash column chromatography on silica gel Merck-60
using 4% methanol in dichloromethane as the eluant to give a light yellow solid. The
solid was taken up in dichloromethane and precipitated by the addition of diethyl
ether and ethyl acetate. The precipitate was collected by filtration and dried under
reduced pressure to give the title compound (0.69 g, 54%) of as a white solid, m.p.
123-127° C.
MS [(+)ESI, m/z]: 527 [M-H]"
EXAMPLE 9
10-[(2'-METHOXY-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(2-PYRIDIN-3-YL-2-
PYRROLIDIN-1-YLETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared according to the procedure Example 6, Step D,
from2,2,2-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 (1.21 g, 2.25 mmol), 2-(3-pyridyl)-2-
pyrrolidinylethyl amine trihydrochloride (0.450 g, 1.5 mmol), triethylamine (5
equivalents), dimethylsulfoxide (0.540 mL) and acetonitrile (28 mL). The crude
material was was flash chromatographed over silica gel Merck-60 using a gradient of
methanol (1-5%) in dichloromethane containing 0.2% ammonium hydroxide, to
provide a brown foam. The material was further purified by preparative HPLC (40:60
acetonitrile :water containing 0.1% formic acid; Primesphere 10 C18, 250x50 mm
column; flow 90 mL/min). The solution was brought to pH 8 with concentrated
ammonium hydroxide prior to concentration to small volume in vacuo. The residue
was redissolved in dichloromethane, dried over anhydrous potassium carbonate and
56

WO 2006/135687

PCT/US2006/022326

evaporated to dryness to provide an off-white foam (0.560 g). This material was
sonicated with hexane (containing a few drops of ethyl acetate). The resulting off-
white powder was collected and dried (0.442 g).
MS [(+)ESI, m/z]: 612.25 (M+H]+
MS [(-)ESI, m/z]: 610.3 [M-HT
Anal. Calcd for C38H37N5CV 0.35 CH2CI2 : C 71.81; H 5.92; N 10.92. Found: C
71.80; H 6.22; N 10.88
EXAMPLE 10
N-(PYRIDIN-3-YLMETHYL)-10-[(2l2,l6,-TRIMETHYL-1l1,-BIPHENYL-4-
YL)CARBONYL]-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
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 mmol). 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 C17H1802: C 80.28; H 7.13. Found: C 80.37; H 7.21
Step B. 2,2',6'-Trimethyl-biphenyl-4-carboxylic 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 [(-)ESI, m/z]: 239.1 [M-HV
57

WO 2006/135687

PCT/US2006/022326

Anal. Calcd. For. Ci6H1602: C 79.97; H 6.71. Found: C 79.71; H 6.70
Step C. (5H, lOVP'.e'-Trimethyl-l.l'-biphenyM-yOcarbonyO-IO.H-dihydro-SH-
pyrrolo[2,1 -c][1,4]benzodiazepine
The 2,2',6,-trimethyl-biphenyl-4-carboxylic acid of Step B (11.4g, 47.4 mmol) was
stirred with 35 mL (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 benzodiazepine (12.23g, 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,
and concentrated. Flash chromatography of the residue on silica gel Marck-60 using
a gradient of dichloromethane in hexane (from 1:1 to 4:1) gave the pure title
compound which was recrystallized from aqueous ethanol as fine translucent plates,
m.p. 170-171 °C.
MS [(+)ESI, m/z]: 407.2 [M+H]+
Anal. Calcd for C28H26N20 0.15 H20: C 82.18, H 6.48; N 6.85. Found: C 82.28, H
6.32, N 6.76.
StepD. 2,2,2-Trichloro-1-{10-[(2,2,I6,-trimethyl-1,1,-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
To a solution of (5H, 10)-[(2,2,,6,-trimethyl-1,1,-biphenyI-4-yl)carbonyl]-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step C (7.934 g, 19.5 mmol) 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 0.1N hydrochloric acid and brine, dried over anhydrous magnesium
sulfate, and concentrated to a yellow foam.
MS [(+)ESI, m/z]: 551.1 [M+H]+
Anal. Calcd. For. C30H25CI3N2O2 H20: C 64.97, N 4.60, H, 5.05. Found: C 64.79, H
4.97, H 4.58
Step E. N-(Pyridin-3-ylmethyl)-10-P.Z.e'-trimethyl-l ,1 '-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
58

WO 2006/135687

PCT/US2006/022326

A suspension of 2,2l2-trichloro-1-{10-[(2,2,,6'-trimethyl-1,1,-biphenyl-4-yl)carbony)]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (0.610
g, 1.1 mmol) and 3-(aminomethyl)pyridine (0.119 g, 1.0 mmol) in acetonitrile.(15 mL),
was treated with dimethylsulfoxide (0.432 g, 5.5 mmol) and triethylamine (0.246 g,
2.4 mmol). The mixture was heated under nitrogen at 80 °C overnight, and then
concentrated. The residue was taken up in dichloromethane (25 mL), washed with
brine and water, dried over anhydrous magnesium sulfate and concentrated. Flash
chromatography of the residue on silica gel Merck-60 eluting with 85:10:5
ethylacetate:hexane:dichloromethane provided the title compound (0.275 g).
MS [(+)ESI, m/z]: 541.2 [M+H]+
MS [(-)ESI, m/z]: 539.2 [M-HT
EXAMPLE 11
N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H~
PYRROLO[2,1 CJI1,4]BENZODIAZEPiNE-3-CARBOXAMlDE
To a stirred solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxylic acid (0.912 g, 4 mmol) in N,N-dimethylformamide (10 mL) under nitrogen
was added N-methyl morpholine (0.440 mL) followed by 1- hydoxybenzotriazole
hydrate (1.22 g, 8 mmol) and 1~ethyl-3-(3-dimethylamino~propyl)carbodiimide
hydrochloride (0.843 g, 4.4 mmol). After 15 minutes at room temperature 3-
(aminomethyl)pyridine was added (0.432 g, 4 mmol). The mixture was stirred
overnight at room temperature, evaporated to dryness, and the residue washed with
water and dried over anhydrous magnesium sulfate. The crude product was flash
chromatographed over silica gel Merck-60 eluting with a gradient from 0.5 to 2.5% of
methanol in dichloromethane to provide the title compound as an off white solid (1.09
g).
MS [(+)ESI, m/z]: 319[M+Hf
EXAMPLE 12
lO-P'.e'-DlMETHYL-l.l'-BIPHENYLYLJCARBONYy-N-tPYRIDlN-S-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Step A. 2',6'-Dimethyl-1,1 '-biphenyl-4-carboxylic acid
A solution of 2',6'-dimethyl-1,1'-biphenyl-4-carboxylic acid methyl ester (5 g, 20.8
mmol) in tetrahydrofuran (70 mL) was treated dropwise under nitrogen with 1N
59

WO 2006/135687

PCT/US2006/022326

lithium hydroxide (45 ml_). The mixture was heated at reflux for 8 hours, filtered warm
(Celite) and concentrated in vacuo to remove organic solvents. The aqueous residue
was acidified in the cold to pH 3 with 2N hydrochloric acid. The precipitate was
collected, washed with water ad dried. The residue was dissolved in ethyl acetate,
treated with charcoal (with warming), filtered (Celite) and evaporated to yield the title
compound as an off-white crystalline solid.
MS [(-)ESI, m/z]: 225 [M-H]"
StepB. lO-'.e'-Dimethyl-l.l'-biphenyU-yOcarbonyn-Npyridin-S-ylmethyO-IO.H-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A stirred solution of 2',6'-dimethyl-1,1'-biphenyl-4-carboxylic acid of Step A (0.790 g,
3.5 mmol) in dichloromethane (15 mL) was treated under nitrogen with a catalytic
amount of N,N-dimethylformarnide followed by dropwise addition of 2N oxalyl
chloride in dichloromethane (2.8 mL). After the gas evolution ceased the mixture was
refluxed for 4 hours, cooled, and evaporated. The residue was azeotroped twice with
benzene and dried in vacuo to provide 2\6'-dimethyl-1,1'-biphenyl-4-carboxylic acid
chloride. The crude 2',6'-dimethyl-1,1'-biphenyl-4-carboxylic acid chloride (0.856 g,
3.5 mmol) was dissolved in dichloromethane (7 mL) and added dropwise to a
suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 12 (0.450 g, 1.41 mmol) in
anhydrous tetrahydrofuran 10 mL) containing N,N-diisopropylethyl amine (0.860 mL).
The mixture was stirred for 18 hours at room temperature and evaporated to dryness.
The residue was dissolved in dichloromethane, the solution washed with saturated
aqueous sodium bicarbonate and brine, dried over anhydrous potassium carbonate
and evaporated. The residue was chromatographed over silica gel Merck-60 eluting
with a gradient from 0 to 4% methanol in 1:1 hexane-ethyl acetate to provide the title
compound (0.452 g) as a white solid after trituration with hexane, m.p. 216-218 °C
(dec).
MS [(+)ESI, m/z]: 527[M+Hf
MS [(-)ESI, m/z] 525 [M-Hf
Anal. Calcd for C34H3oN402 C4H80: C 77.17, H 5.80, N 10.46. Found: C 76.91, H
5.64, N 10.46.
EXAMPLE 13
60

WO 2006/135687

PCT/US2006/022326

10-(1,1'-BIPHENYL-4-YLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 10-(1,1 '-Biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine
To a solution of 5.53 g (0.03 mol) of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepine in 50 mL of 1,4-dioxane was added 3.64 g (0.03 mol) of N,N-
dimethylaniline followed by 6.50 g. of 4-biphenylcarbonyl chloride. The reaction
solution was allowed to stand at room temperature for 2 hours and then slowly
poured into 2 L of water. On cooling the mixture a crystalline white solid was formed
which was collected and dried to provide the title compound (9.5 g). The product was
used directly in the next step.
MS [(+)ESI,m/z]: 365 [M+H]+.
Step B. 1 -[10-(1,1 '-Biphenyl-4-ylcarbonyl)-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepin-3-yI]-2,2,2-trichloroethanone
10-(1,1'-Biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1 benzodiazepine
of Step A (1.822 g; 0.005 mol) was dissolved in 50 mL of 1,4-dioxane to which was
then added 0.946 g (0.0052 mol) of trichloroacetyl chloride. The reaction solution
was heated under reflux with stirring over night, cooled to room temperature and then
poured into 250 mL of water. Recrystallization of the crude materia] from ethanol
provided a solid, m.p. 197-198 °C.
MS [(+) ESI, m/z]: 509 [M+H]+.
Anal. Calcd for C27H19CI3N202: C 63.61, H 3.76, N 5.49. Found: C 63.49, H 3.79, N
5.47.
Step C. 10-(1,1,-biphenyl-4-ylcarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A solution of 0.216 g (0.002 mol) of 3-aminomethylpyridine and 0.508 g (0.001 mol)
of 1-[10-(1,1'-biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl]-2,2,2-trichloroethanone of Step B in 25 mL of 1,4-dioxane
was heated overnight under reflux with stirring. The cooled reaction mixture was
poured into 200 mL of water. The solid was collected and dried to provide the title
compound (0.053 g).
MS [(+)ESl, m/z]: 499 [M+Hf.
61

WO 2006/135687

PCT/US2006/022326

Anal. Calcd. For C32H26N402 • H20. C 74.40, H 5.46, N 10.85. Found: C 74.82, H 5.21,
N 11.00
EXAMPLE 14
10-{[2'-(METHYLTHIO)-1,1'-BlPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE 0.67 HYDRATE
Step A. 2'-(Methylthio)-1,1 '-biphenyl-4-carboxylic acid
A stirred mixture containing 4.15 g (0.025 mole) of 2-bromothioanisole, 5.08 g.
(0.0025 mole) of 4-carboxybenzeneboronic acid, 10.36 g (0.075 mol) of potassium
carbonate and 0.45 g (0.00063 mol) of dichlorobis(triphenylphosphine) palladium(ll)
in 40 mL of water and 20 ml_ of 1,4- dioxane was heated under reflux for two hours
under nitrogen. The reacton mixture was allowed to cool to room temperature and
filtered. The dioxane was removed in vacuo, the residue was diluted with 100 mL of
water and then acidified with 20% hydrochloric acid. The crude product (6.1 g) was
recrystallized from ethanol to yield the title compound, m.p. 220-222 °C.
MS [(+)ESI, m/z]: 245 [M+H]+
Anal. Calcd. for C14H1202S: C 68.83, H 4.95. Found: C 68.66, H 4.76.
Step B. 10-{[2'-(Methylthio)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To 20 mL of thionyl chloride was added 0.244 g (0.001 mol) of 2'-(methylthio)-1,1'-
biphenyl-4-carboxylic acid of Step A. The solution was heated under reflux for 1 hour.
The excess thionyl chloride was removed in a vacuo. To the residue was added 25
mL of dry pyridine and 0.318 g (0.001 mol) of N-(pyridyl-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12. The reaction
was allowed to stand at room temperature for 1 hour and the pyridine was removed
in vacuo. The residue was collected and washed with water giving a tan solid (0.62
g), m.p. 172-175 °C.
MS [(+)ESl, m/z]: 545 [M+H]+.
Anal. Calcd. for C33H28N4O2S 0.67 H20: C 71.19, H 5.31, N 10.06. Found: C 71.46,
H 5.21, N 9.68.
EXAMPLE 15
62

WO 2006/135687

PCT/US2006/022326

lO-p'METHYLSULFONYLJ-l.r-BIPHENYL-YUCARBONYLJ-NPYRIDIN-S-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Step A. 2'-(Methylsulfonyl)-1,1'-biphenyl-4-carboxylic acid
To a solution of 0.977 g (0.004 mole) of 2'-(methylthio)-1,1'-biphenyl-4-carboxylic
acid of Example 14, Step A, in 25 ml_ of water and 75 mL of acetone was added 10
g. (0.163 mole) of oxone. The mixture was stirred overnight at room temperature.
The acetone was removed in vacuo, and the residue was collected (0.80 g) and
washed with water to provide a solid, m.p. 273-275 CC.
MS [(-)ESI, m/z]: 275 [M-H]".
Anal. Calcd. For C14H1204S: C 60.86, H 4.38. Found: C 60.67, H 4.22
Step B. 10-{[2'-(Methylsulfonyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
The title compound (0.23 g) was obtained starting with the conversion of 0.74 g
(0.0027 mol) of 2'-methylsulfonyl)-1,1'-biphenyl-4-carboxylic acid of step A to the acid
chloride and its subsequent reaction with 0.863 g (0.0027 mol) of N-(pyridinr3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of
Example 12, in 30 mL of dry pyridine according to the procedure of Example 15
StepB, m.p. 153-156 °C.
MS [(+)ESI, m/z]: 577 [M+Hf.
Anal. Calcd. for C33H28N404S 0.1 H20: C 68.52, H 4.91, N 9.69. Found: C 68.27, H
4.91, N 9.59
EXAMPLE 16
10-{[2'-(AMINOSULFONYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound (0.08 g) was obtained starting with the conversion of 0.555 g
(0.002 mol) of 2'-(aminosulfonyl)-1,1'-biphenyl-4-carboxylic acid to the acid chloride
and its subsequent reaction with 0.637 g (0.002 mol) of N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 11, in 30
mL of dry pyridine according to the procedure of Example 15 Step B, m.p. 153-156
°C.
MS [(+)ESl, m/z]: 578 [M+Hf.
63

WO 2006/135687

PCT/US2006/022326

Anal. Calcd. for CMHZTNSOAS H20: C 64.52, H 4.91, N 11.76. Found:
C 64.78, H 4.63, N 11.6.
EXAMPLE 17
10-{[2'-(CYANOMETHYL)-1,1 '-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPlNE-3-
CARBOXAMIDE
Step A. 2'-(Cyanomethyl)-1,1'-biphenyl-4-carboxylic acid
A stirred mixture containing 5.88 g (0.03 mol) of (2-bromo-phenyl)-acetonitrile, 4.978
g. (0.03 mol) of 4-carboxyphenylboronic acid, 8.29 g (0.06 mol) of potassium
carbonate and 0.52 g of dichlorobis(triphenylphosphine) palladium(ll) in 46 mL of
water and 25 mL of 1,4- dioxane was heated under reflux for two hours in an
atmosphere of nitrogen. The reaction mixture was allowed to cool to room
temperature and filtered. The dioxane was removed in vacuo and the residue diluted
with 100 mL of water and then acidified with 20% hydrochloric acid. The crude
product (1.2g) was recrystallized from ethanol to give a solid, m.p. 218-220 °C.
MS[(-)ESI,m/z]:236{M-H]-
Anal. Calcd. for C16Hu N02- 0.33 H20: C 74.08, H 4.83, N 5.76. Found: C 74.01, H
4.45, N 5.39.
Step B. 10-{[2'-(Cyanomethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrro!o[2,1-c][1,4]benzodiazepine-3-carboxamide
A mixture of 20 mL of thionyl chloride and 0.243 g (0.001 mol) of 2'-(cyanomethyl)-
1,1'-biphenyl-4-carboxylic acid of Step A was heated under reflux for 1 hour. The
excess thionyl chloride was removed in vacuo. To the residue was added 35 mL of
dry 1,4-dioxane, 0.318 g (0.001 mol) of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide and 0.122 g (0.001 mol) of N,N-
dimethylformamide. The reaction was heated under reflux for three hours, cooled
and evaporated to dryness. The residue was collected, washed with water and
triturated with ether to give 0.62 g. of a tan solid, m.p. 105-108 °C.
MS: [(+)ESI, m/z]: 538 [M+H]+.
Calcd. for C34H27N502 • 0.67H2O: C 74.29, H 5.20, N12.74. Found: C 74.57, H 4.96,
N 11.92
EXAMPLE 18
64

WO 2006/135687

PCT/US2006/022326

10-({2'-[2-AMINO-2-(HYDROXYIMINO)ETHYL]-1,1,-BIPHENYL-4-YL}CARBONYL)-
N-(PYRIDIN-3-YLMETHYL)-10,11-DlHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
A mixture of 0.806 g (0015 mol) of 10-{[2'-(cyanomethy!)-1,1'-biphenyl-4-yl]carbonyi}-
N-(pyridin-3-yimethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide of Example 17, 0.52 g (0.0075 mol) of hydroxylamine hydrochloride
and 1.03 g (0.0075 mol) of potassium carbonate in 100 mL of ethanol and 25 mL of
water was heated under reflux for 2 hours. An additional 1.04 g (0.015 mol) of
hydroxylamine hydrochloride and 2.06 g (0.015 mol) of potassium carbonate was
added to the and refluxing was allowed to continue until LC/MS indicated that all the
starting nitrile was consumed. The solvents were removed in vacuo and the residue
was washed with water and purified by chromatography to provide the title compound
(0.191 g),m.p. 131-134 °C.
MS [(+)ESI, m/z]: 571 [M+Hf
Anal. Calcd. for C34H3oN603 i H20: C 69.37, H 5.48, N 14.28. Found: C 69.11, H
5.66, N 13.83
EXAMPLE 19
N-(PYRIDIN-3-YLMETHYL)-10-{[2'-(1H-TETRAZOL-5-YLMETHYL)-1,1'-BIPHENYL-
4-YL]CARBONYL}-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3~
CARBOXAMIDE
A mixture of 0.537 g (0.001 mol) of 10-{[2'-(cyanomethyl)-1,1'-biphenyl-4-
yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 17, 0.32 g (0.005 mole) of sodium
azide and 0.26 g (0.005 mole) of ammonium chloride in 20 mL of dimethyl sulfoxide
was heated with stirring at 50 °C for three hours. The reaction mixure was poured
into 100 mL of water, and the precipitated crude product was subjected to
chromatographic purification giving 0.46 g of title compound, m.p. 164-167 °C.
MS [(+)ESI, m/z]: 581 [M+Hf.
Anal. Calcd for C34H28N802 -1.5H20: C 67.20, H 5.14, N 18.44. Found: C 67.14, H
5.13, N 18.29
EXAMPLE 20
65

WO 2006/135687

PCT/US2006/022326

10-[(2'-FLUORO-2-METHYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with 2-fluorophenylboronic acid. Purification by flash
chromatography using a solvent gradient of 2.5 to 5% methanol in dichloromethane
gave the title compound (0.288 g, 72%) as a tan foam.
MS {[(+)ESI, m/z]: 531 [M+H]+
MS [(-)ESI, m/z]: 529 [M-HT
HRMS [(-)ESI, m/z]: 529.2035 [M-H]\ Calcd for C33H2SFN402 :529.20398.
EXAMPLE 21
10-[(2'-CHLORO-2-METHYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with 2-chlorophenylboronic acid. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave the title compound (0.276 g, 67%) as a tan foam.
MS [(+)ESI, m/z]: 547/549 [M+H]+
MS [(-)ESI, m/z]: 545/547 [M-HT
HRMS [(-)ESI, m/z]:: 545.17433 [M-HT. Calcd for CsCINA,: 545.17443
EXAMPLE 22
10-[(2,4'-DIMETHYL-1,r-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with p-tolylboronic acid. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave the title compound (0.268 g, 68%) as a tan foam.
MS [(+)ESI, m/z]: 527 [M+HJ+
MS [(-)ESI, m/z]: 525 [M-HT
HRMS [(-)ESI, m/z]: 525.2286 [M-HT. Calcd for CHN: H, 525.22905
EXAMPLE 23
66

WO 2006/135687

PCT/US2006/022326

10-[(3'-CHLORO-2-METHYL-1,r-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with 3-chlorophenylboronic acid. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave the title compound (0.353 g, 86%) as a tan foam.
MS [(+)ESl, m/z]: 547/549 [M+H]+
MS [(-)ESI, m/z]: 545/547 [M-HV
HRMS [(+)ESI, m/z]: 547.18868. Calcd for C33H28CIN4O2: 547.19008
EXAMPLE 24
lO-'-CHLORO-METHYL-l.l'-BlPHENYL-YCARBONYLl-NPYRIDIN-S-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPlNE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with 4-chlorophenylboronic acid. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave the title compound (0.359 g, 88%) as a tan foam.
MS [+)ESI, m/z]: 547/549 [M+H]+
MS [(-)ESI, m/z]: 545/547 [M-HV
HRMS [(+)ESI, m/z}; 547.18916 [M+H]+: Calcd for CCIN: 547.19008
EXAMPLE 25
lO-P''-DICHLORO-METHYL-l.r-BIPHENYL-YLARBONYLl-NPYRIDIN-S-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAM1DE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with 3,4-dichlorophenylboronic acid. Purification by
flash chromatography using a solvent gradient of 1 to 4% methanol in
dichloromethane gave the title compound (0.294 g, 67%) as an off-white foam.
MS [(+)ESI, m/z]: 581/583 [M+H]+
MS [(-)ESI. m/z]: 579/581 [M-H]"
HRMS [(+)ESI, m/z]: 581.14997 [M+H]+. Calcd for C33H21C\2NAOZ 581.15111
EXAMPLE 26
67

WO 2006/135687

PCTVUS2006/022326

1(H(4,ACETYL-2-METHYL-1)1,-BIPHENYL-4-YL)CARBONYLl-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 57,
replacing phenylboronic acid with 4-acetylphenylboronic acid. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave the title compound (0.262 g, 63%) as an off-white foam.
MS [+)ESI, m/z]: 555 [M+Hf
MS [(-)ESI, m/z]: 553 [M-Hf
HRMS [(+)ESI, m/z]: 555.23803 [M+Hf. Calcd for C3sH1QN403: 555.23962
EXAMPLE 27
10-[(2'-METHYL-1,1'-BlPHENYL-3-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMlDE
Step A. 10-(3-Bromobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (5.0 g, 27 mmol)
and N.N-diisopropylethylamine (7.5 mL, 43 mmol) in dry dichloromethane (135 mL)
was added 3-bromobenzoyl chloride (2.9 mL, 22 mmol) and the reaction mixture was
stirred at room temperature under nitrogen for 16 hours. The reaction mixture was
then washed with 1 M hydrochloric acid (5 x 200 mL), 1 M sodium hydroxide (200
mL), and brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated
in vacuo to give a yellow solid (7.2 g). Recrystallization from ethyl acetate gave the
title compound (5.8 g, 72%) as a white crystalline solid.
MS [(+) ESI, m/z]: 367 [M+H]+
HRMS [(+)ESI, m/z]: 367.04375 [M+H]+. Calcd for C19H16BrN20: 367.04405
StepB. 10-[(2'-Methyl-1,1'-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine
A mixture of 10-(3-bromobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine of Step A (2.0 g, 5.4 mmol), o-tolylboronic acid (0.8 g, 5.9
mmol) and potassium carbonate (2.4 g, 17.7 mmol) in ethylene glycol dimethyl ether:
water (20 mL: 5 mL) was purged with nitrogen for 1 hour. [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium [II] (0.22 g, 0.26 mmol) was
added and the reaction mixture heated to 75 °C with vigorous stirring for 16 hours.
68

WO 2006/135687

PCT/US2006/022326

The cooled reaction mixture was then filtered through Celite and the cake washed
with dichloromethane (100 mL). The organic phase was separated, washed with 1 M
sodium hydroxide (100 mL) and brine (100 mL), dried over anhydrous potassium
carbonate and concentrated in vacuo to give the crude product (2.3 g) as a dark
brown solid. Purification by flash chromatography using a solvent gradient of 40% to
100% dichloromethane in hexane afforded the title compound (1.7 g, 85%) as a white
solid.
MS [(+)ESI, m/z]: 379 [M+H]+
HRMS [(+)ESI, m/z]: 379.18052 [M+H]+. Calcd for C26H23N20: 379.18049
StepC. 2,2,2-Trichloro-1-{10-[(2'-methyl-1,1'-biphenyl-3-yl)carbonyl]-10,11-dihydro-
5/-/-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
To a mixture of 10-[(2'-methyl-1,1'-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine of Step B (1.7 g, 4.5 mmol) and sodium carbonate
(0.95 g, 9.0 mmol) in dry tetrahydrofuran (40 mL) was added dropwise trichloroacetyl
chloride (0.75 mL, 6.7 mmol) and the reaction mixture stirred at room temperature
under nitrogen for 18 hours. The reaction mixture was then diluted with ethyl acetate
(150 mL), washed with 1 M hydrochloric acid (150 mL), water (150 mL) and brine
(150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to
give a dark foam. Purification by flash chromatography using a solvent gradient of
60% to 80% dichloromethane in hexane afforded a white solid that was recrystallized
from hot ethyl acetate to give the title compound (1.2 g, 50%) as a white needles.
MS [(+)ESI, m/z]: 523 [M+H]*
Anal. Calcd for C28H21Cl3N202: C, 64.20; H, 4.04; N, 5.35. Found: C, 64.01; H, 4.10;
N, 5.22.
Step D. 10-[(2'-Methyl-1,1 '-biphenyl-3-yl)carbonyl]-/V-(pyridin-3-ylmethyl)-10,11-
dihydro-5/-/-pyrro!o[2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of 2,2,2-trichloro-1-{10-[(2,-methyl-1,1'-biphenyl-3-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3~yl}ethanone of Step C (0.600 g, 1.1
mmol) and dimethyl sulfoxide (0.41 mL, 5.8 mmol) in dry acetonitrile (5.5 mL) at room
temperature under nitrogen was added 3-(aminomethyl)pyridine (0.23 mL, 2.2 mmol)
and the reaction mixture heated to reflux for 45 hours. The cooled reaction mixture
69

WO 2006/135687

PCT/US2006/022326

was concentrated in vacuo, the oily residue redissolved in ethyl acetate (25 ml_),
washed with 1M sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried
over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale orange
foam. Purification by flash chromatography using ethyl acetate as solvent afforded a
pale yellow foam that was recrystallized from ethyl acetate/diethyl ether/hexane to
give the title compound (0.435 g, 74%) as an off-white crystalline solid.
MS [(+)ESI, m/z]: 513[M+Hf
MS [(-)ESl, m/z]: 511 [M-H]"
HRMS [(+)ESI, m/z]: 513.22694 [M+H]+. Calcd for C33H29N4O2: 513.22850
EXAMPLE 28
10-[(2'-METHYL-1,1 '-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
A solution of 2,2,2-trichloro-1-{10-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}ethanone (1.72 mmol), and 3-
aminomethylpyridine (3.44 mmol) in dimethylsulfoxide (8.6 mmol) and acetonitrile (15
mL) was stirred at 80 °C for 18 hours. The solvent was evaporated and the residue
dissolved in dichloromethane, washed with water, dried over anhydrous sodium
sulfate, and evaporated. The material was purified by HPLC (Normal phase, Luna
CN bonded packing) and crystallized from ethyl acetate/hexane. (0.68 g; 77%), m.p.
176-177 °C.
MS[(+)ESI,m/z]:511 [M+H]+
Anal. Calcd for CN: C, 77.32; H, 5.51; N, 10.93. Found: C, 77.28; H, 5.45; N,
10.93.
EXAMPLE 29
10-[(2'-ACETYL-2-METHYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 47,
replacing 2-methoxyphenylboronic acid with 2-acetylphenylboronic acid. Purification
by flash chromatography using a solvent gradient of 1 to 5% methanol in
dichloromethane gave a yellow syrup that was crystallized from ethyl acetate/hexane
to afford the title compound (0.276 g, 58%) as a white solid, m.p. 171-172 °C.
MS [(+)ESI, m/z]: 555 [M+H]+
70

WO 2006/135687

PCT/US2006/022326

MS [(-)ESI, m/z]: 553 [M-HT
HRMS [(+)ESI, m/z]: 555.23866 [M+H]+. Caicd for C35H3iN403: 555.23907
EXAMPLE 30
-[(Z-CYANO-I.I'-BIPHENYL-YLJCARBONYLJ-NPYRIDIN-S-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C]I1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 2'-Cyano-1,1'-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanonewith2-bromobenzonitrile. The title
compound (3.3 g, 92%) was obtained as a tan solid.
MS[(-)ESI,m/z]:222[M-Hr
HRMS [(-)ESI, m/z]: 222.05607 [M-H]\ Calcd for C14H8N02: 222.05605
StepB. lO-P'-Cyano-l.r-biphenyl--yOcarbonylJ-A/pyridin-S-ylmethyO-IO.H-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-cyano-1,1'-biphenyl-4-
carboxylic acid of Step A. Purification by flash chromatography using a solvent
gradient of 1 to 3% methanol in dichloromethane gave the title compound (0.322 g,
62%) as a tan solid.
MS (+)ESI, m/z]: 524 [M+Hf
HRMS [(+)ESI, m/z]: 524.20802 [M+H]+. Calcd for CHNsC: 524.20810
EXAMPLE 31
10-[(2'-ISOPROPYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 2'-lsopropyl-1,1 '-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanone with 2-bromoisopropylbenzene. The
title compound (1.5 g, 41 %) was obtained as a tan solid.
MS [(-)ESI, m/z]: 239 [M-HT
HRMS [(+)ESI, m/z]: 241.12173 [M+H]+. Calcd for C16H1702: 241.12231
Anal. Calcd for C16H1602: C, 79.97; H, 6.71. Found: C, 79.63; H, 6.71
StepB. lO-P'-lsopropyl-l.l'-biphenyl-yOcarbonyli-yVpyridin-S-ylmethylHO.II-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
71

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-isopropyl-1,1'-biphenyl-
4-carboxylic acid of Step A. Purification by flash chromatography using a solvent
gradient of 1 to 3% methanol in dichloromethane gave the title compound (0.298 g,
55%) as a white solid.
MS [(+)ESI, m/z]: 541 [M+H]+
HRMS [(+)ESI, m/z]: 541.26016 [M+Hf. Calcd for C35H33H402: 541.25980
Anal. Calcd for C5H32N4O2: C, 77.75; H, 5.97; N, 10.36. Found: C, 77.51; H, 5.92; N,
10.13.
EXAMPLE 32
METHYL (4'-{[3-{[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYLh5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPIN-10(11H)-YL]CARBONYL}-1,r-BIPHENYL-2-YL)ACETATE
Step A. Methyl (2:-bromophenyl)acetate
A solution of 2-bromophenylacetic acid (10 g, 46 mmol) and 12 M hydrochloric acid
(1 mL, 12 mmol) in methanol (100 mL) was heated to reflux for 16 hours. The cooled
solution was then quenched with saturated aqueous sodium hydrogen carbonate (50
mL) and concentrated in vacuo to remove methanol. The aqueous phase (ca. 50
mL) was extracted with ethyl acetate (150 mL), and the organic phase washed with
water (75 mL) and brine (75 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to give the title compound (10.1 g, 96 %) as a clear, colorless
oil.
MS [(+)ESI, m/z]: 229/231 [M+H]+
Anal. Calcd for CHsBrOz: C, 47.19; H, 3.96. Found: C, 47.24; H, 3.88.
Step B. 2'-(2-Methoxy-2-oxoethyl)-1,1'-biphenyl-4-carboxylicacid
A mixture of methyl (2-bromophenyl)acetate of Step A (20.0 g, 87.3 mmol), 4-
carboxybenzeneboronic acid (14.5 g, 87.4 mmol), [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium [II] (3.6 g, 4.4 mmol) and potassium phosphate (55.6 g,
262 mmol) in dry 4-dioxane (ca. 400 mL) was heated at 100 °C with vigorous stirring
for 17 hours. The cooled mixture was then filtered through Celite and washed with
1,4-dioxane (ca. 200 mL). The filtrate was concentrated in vacuo to give a tacky
brown solid (28.0 g). Purification by flash chromatography using a solvent gradient of
320 :1 :1 to 80 :1 :1 dichloromethane / acetic acid / methanol afforded an impure
tacky orange solid (11.9 g). The solid product was dissolved in ethyl acetate (300
72

WO 2006/135687

PCT/US2006/022326

mL), filtered from insoluble material, and the filtrate washed with water (2 x 150 mL)
and brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in
vacuo to give a light orange solid (7.3 g). Recrystallization from diethyl ether
provided the title compound (5.2 g, 22%) as pale orange needles.
MS [(-)ESI, m/z]: 269 [M-H]"
HRMS [(+)ESI, m/z]: 293.07804 [M+Na]+. Calcd for C16H1404Na: 293.07843
Anal. Calcd forC16Hi404: C, 71.10; H, 5.22. Found: C, 71.30; H, 5.19.
Step C. Methyl (4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyr)-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1'-biphenyl-2-yl)acetate
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl«biphenyl-4-carboxylic acid with 2'-(2-methoxy-2-oxoethyl)-
1,1'-biphenyl-4-carboxylic acid of Step B. Purification by flash chromatography using
a solvent gradient of 0.5 to 4% methanol in dichloromethane gave a brown foam that
was crystallized from hot methanol to afford the title compound (0.730 g, 53%) as a
tan crystalline solid.
MS I(+)ESI, m/z]: 571 [M+H]+
MS [(-)ESI, m/z]: 569 [M-HT
HRMS [(+)ESl, m/z]: 571.23261 [M+H]+. Calcd forC35H3iN404: 571.23398
EXAMPLE 33
10-[(2'-ETHOXY-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 2'-Ethoxy-1,1 '-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 61,
Step A, replacing 2-methoxymethylphenylboronic acid with 2-ethoxybenzeneboronic
acid. The title compound (1.26 g, 88%) was obtained as a white solid.
MS [(+)ESI, m/z]: 243 [M+H]+
MS [(-)ESI, m/z]: 241 [M-HV
HRMS [(+)ESI, m/z]: 243.10112 [M+H]*. Calcd for C15H1503: 243.10157
Step B. 10-[(2'-Ethoxy-1,1'-biphenyl-4-yl)carbonyl]-A/-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrroIo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 61,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-ethoxy-1,1'-biphenyl-4-
carboxylic acid of Step A. Purification by flash chromatography using a solvent
73

WO 2006/135687

PCT/US2006/022326

gradient of 1 to 4% methanol in dichloromethane gave a brown foam that was
crystallized from methanol to afford the title compound (0.56 g, 51 %) as a pale yellow
solid.
MS [(+)ESI, m/z]: 543 [M+Hf
HRMS [(+)ESI, m/z]: 543.23874 [M+H]+. Calcd for C34H31N4O3: 543.23907
EXAMPLE 34
10-[(2'-HYDROXY-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a suspension of 10-[(2'-ethoxy-1,1'-biphenyl-4-yl)carbonyrj-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 33
(0.281 g, 0.518 mmol) in dry dichloromethane (2.6 mL) at 0 °C under nitrogen was
added dropwise a 1.0 M solution of boron tribromide in dichloromethane (2.6 mL, 2.6
mmol) over ca. 5 minutes. The reaction mixture was allowed to warm to room
temperature and then stirred for 5 hours. The reaction was quenched by the addition
of saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl
acetate (2 x 50 mL). The combined organic extracts were washed with brine (50
mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a
tan solid (0.210 g). Purification by flash chromatography using a solvent gradient of
1 to 4% methanol in dichloromethane gave the title compound (0.042 g, 16%) as a
white solid.
MS[(+)ESI,m/z]:515[M+Hf
MS[(-)ESI,m/z]:513[M-H]-
HRMS [(+)ESl, m/z]: 515.20677 [M+H]+. Calcd for CaaHCy. H, 515.20777
EXAMPLE 35
(4'-{[3-{[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYL}-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPIN-10(11H)-YL]CARBONYL}-1,1'-BIPHENYL-2-YL)ACETIC
ACID
To a suspension of methyl (4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1'-biphenyl-2-yl)acetateof
Example 32 (0.585 g, 1.03 mmol) in 2 :1 v/v methanol: water (12 mL) was added
lithium hydroxide monohydrate (87 mg, 2.07 mmol) and the mixture heated to reflux
for 90 minutes. The cooled reaction mixture was concentrated in vacuo to remove
methanol and then diluted with water (10 mL). The aqueous phase was washed
74

WO 2006/135687

PCT/US2006/022326

with ethyl acetate (2x10 mL) then slowly added to a mixture of 1 M aqueous
hydrochloric acid (2.2 mL) in water (20 mL) and the resulting suspension cooled to 0
°C for 1 hour. Filtration afforded the title compound (0.381 g, 66%) as a tan solid.
MS [(+)ESI, m/z]: 557 [M+H]+
MS [(-)ESI, m/z]: 555 [M-HT
HRMS [(+)ESI, m/z]: 557.21794 [M+H]+. Calcd for C34H29N4O4: 557.21833
EXAMPLE 36
10-[(2'-ISOBUTYRYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Step A. 1-(2-Bromophenyl)-2-methylpropan-1-ol
To a solution of 2-bromobenzoyl chloride (1.3 mL, 9.9 mmol) in dry tetrahydrofuran
(38 mL) at 0 °C under nitrogen was added dropwise a 2.0 M solution of
isopropylmagnesium bromide in tetrahydrofuran (12.4 mL, 24.8 mmol) over ca. 5
minutes. The reaction mixture was stirred at 0 °C for 30 minutes then at room
temperature for 27 hours. The reaction was quenched by the addition of 1 M
aqueous hydrochloric acid (30 mL) and concentrated in vacuo to remove
tetrahydrofuran. The aqueous phase was diluted to ca. 50 mL with water and
extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were
washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo to give the crude product as an orange oil
(2.1 g). Purification by flash chromatography using a solvent gradient of 1 to 4%
ethyl acetate in hexane gave the title compound (0.77 g, 33%) as a clear, pale yellow
oil.
MS [(+)ESI, m/z]: 211/213 [M+H-H20]+
Step B. 1-(2-Bromophenyl)-2-methy!propan-1-one
To a suspension of [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one]
(2.2 g, 5.19 mmol) in dichloromethane (18 mL) at room temperature under nitrogen
was added dropwise a solution of 1-(2-bromophenyl)-2-methylpropan-1-ol of Step A
(1.00 g, 4.36 mmol) in dichloromethane (18 mL) over ca. 5 minutes. After 2 hours,
additional [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (0.20 g, 0.47
mmol) was added and the reaction mixture stirred at room temperature for 4 days.
The reaction mixture was then diluted with diethyl ether (100 mL) and the resulting
75

WO 2006/135687

PCT/US2006/022326

suspension added to 1.3 M aqueous sodium hydroxide solution (40 mL) with stirring.
After 10 minutes the organic phase was separated, washed with 1.3 M sodium
hydroxide (40 mL) and water (50 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to give the title compound (0.89 g, 90%) as a clear, pale
yellow oil.
MS [(+)ESI, m/z]: 227/229 [M+H]+
HRMS [(+)ESI, m/z]: 227.00596 [M+H]+. Calcd for C10H12BrO: 227.00660
Step C. 2'-lsobutyryl-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanonewith 1-(2-bromophenyl)-2-
methylpropan-1-one of Step B. The title compound (0.59 g, 60%) was obtained as a
white solid.
MS [(-)ESI, m/z]: 267 [M-HT
StepD. 10-[(2'-lsobutyryl-1l1'-biphenyl-4-yl)carbonyl]-A/-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-isobutyryl-biphenyl-4-
carboxylic acid of Step C. Purification by flash chromatography using a solvent
gradient of 0.5 to 4% methanol in dichloromethane gave a brown oil that was
crystallized from methanol/diethyl ether to afford the title compound (0.463 g, 62%)
as white needles.
MS [(+)ESI, m/z]: 569 [M+H]+
MS [(-)ESI), m/z]: 567 [M-HT
HRMS [(+)ESI, m/z]: 569.253 [M+H]+. Calcd for C36H33N4O3: 569.25472
EXAMPLE 37
10-{[2'-(1-HYDROXY-2-METHYLPROPYL)-1,r-BIPHENYL-4-YL]CARBONYL}-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 50,
replacing 10-[(2'-acetyl-2-methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-yImethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide with 10-[(2'-
isobutyryl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
76

WO 2006/135687

PCT/US2006/022326

pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 37. Purification by
flash chromatography using a solvent gradient of 2 to 8% methanol in
dichloromethane gave title compound (0.212 g, 64%) as a yellow solid.
MS [(-)ESI, m/z]: 569 [M-HT
HRMS [(+)ESI, m/z]: 571.26906 [M+H]+. Calcd for C36H35N403: 571.27037
EXAMPLE 38
10-{[2'-(2-AMINO-2-OXOETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 68,
replacing 4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolot2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1 '-biphenyl-2-carboxylic acid with (4'-{[3-
{t(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1 -c][1,4]benzodiazepin-10(11H)-
yl]carbonyl}-1,1'-biphenyl-2-yl)acetic acid of Example 36, and dimethylamine with
ammonia. Purification by flash chromatography using a solvent gradient of 2 to 8%
methanol in dichloromethane gave the title compound (0.138 g, 58%) as a white
solid.
MS [(+)ESI, m/z]: 556 [M+H]+
MS ([(-)ESI, m/z]: 554 [M-H]-
HRMS [(+)ESI, m/z]: 556.23307 [M+H]+. Calcd for C34H3oN503: 556.23432
EXAMPLE 39
10-({2r-[2-(METHYLAMINO)-2-OXOETHYL]-1,r-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 68,
replacing 4'-{l3-{[(pyridin-3-ylmethyl)amino]carbonyi}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1'-biphenyl-2-carboxylic acid with (4'-{[3-
{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
yl]carbonyl}-1,1'-biphenyi-2-yl)acetic acid, Example 36, and dimethylamine with
methylamine. Purification by flash chromatography using a solvent gradient of 2 to
8% methanol in dichloromethane gave the title compound (0.149 g, 61%) as an off-
white solid.
MS [(+)ESI, m/z]: 570 [M+H]+
77

WO 2006/135687

PCT/US2006/022326

MS [(-)ESI, m/z]: 568 [M-H]"
HRMS [(+)ES1, m/z]: 570.24846 [M+H]+. Calcd for C35H32N5O3: 570.24997
EXAMPLE 40
10-({2'-[2-(DIMETHYLAMINO)-2-OXOETHYL]-1,r-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BEN20DIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 68,
replacing 4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1'-biphenyl-2-carboxylic acid with (4'-{[3-
{I(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
yl]carbonyl}-1,1'-biphenyl-2-yl)acetic acid of Example 36. Purification by flash
chromatography using a solvent gradient of 2 to 8% methanol in dichloromethane
gave the title compound (0.180 g, 72%) as a white solid.
MS [(+)ESI, m/z]: 584 [M+H]+
MS [(-)ESI, m/z]: 582 [M-H]"
HRMS [(+)ESI, m/z]: 584.26446 [M+H]+. Calcd for C36H34N5O3: 584.26562
EXAMPLE 41
N-(PYRIDIN-3-YLMETHYL)-10-{[2'-{PYRROLIDIN-1-YLMETHYL)-1,1'-BIPHENYL-4-
YL]CARBONYL}-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPlNE-3-
CARBOXAMIDE
To a solution of 10-[(2'-formyl-1,1'-biphenyl-4-yl)carbonyl]-N-{pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56,
Step B (0.38 mmol), and pyrrolidine (0.80 mmol) in methanol (5 mL) was added a
methanolic solution of sodium cyanoborohydride (0.2 M) and zinc chloride (0.1 M).
The mixture was stirred at ambient temperature for 20 hours. The methanol was
evaporated and the residue was taken up in chloroform and washed with 1.0 N
sodium hydoxide, dried over anhydrous sodium sulfate, and evaporated. The solid
was crystallized from ethyl acetate and hexane, m.p. 210-212 °C.
MS [(+)ESI, m/z]: 582.2 [M+H]+
EXAMPLE 42
10-({2'-[(METHYLAMINO)METHYL]-1,1'-BIPHENYL-4-YL}CARBONYL)-N-(PYRIDIN-
3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
78

WO 2006/135687

PCT/US2006/022326

The title compound was prepared from 10-[(2'-formyl-1,1'-biphenyl-4-yl)carbonyl]-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide of Example 56, Step B, and methylamine (8 M solution in ethanol) in
the manner of Example 42, m.p. 149-150 °C.
MS [(+)ESl, m/z]: 540.3 [M+Hf
EXAMPLE 43
10-{[24MORPHOLIN-4-YLMETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared from 10-[(2'-formyl-1,1'-biphenyl-4-yl)carbonyl]-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide of Example 56, Step B, and morpholine in the manner of Example 42,
m.p. 191-194 °C.
MS [(+)ESI, m/z]: 596.3 [M+Hf
EXAMPLE 44
10-{[2'-(PIPERIDIN-1-YLMETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-
3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared from 10-[(2'-formyl-1,1'-biphenyl-4-yl)carbonyl]-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide of Example 56, Step B, and piperidine, in the manner of Example 42,
m.p. 199-202 °C.
MS t(+)ESI, m/z]: 596.2 [M+H]+
EXAMPLE 45
10-({2'-[(DIMETHYLAMINO)METHYL]-1,1'-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPlNE-3-CARBOXAMIDE
The title compound was prepared from 10-[(2'-formyM,1'-biphenyl-4-yl)carbonyl]-N-
(pyridin-3-ylmethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-
carboxamide of Example 56, Step B, and dimethylamine (2.0 M solution in methanol)
in the manner of Example 42, m.p. 95-104 °C.
MS [(+)ESI, m/z]: 554.3 [M+H]+
EXAMPLE 46
79

WO 2006/135687

PCTAJS2006/022326

10-{[2'-(AMINOMETHYL)-1,1 '-BIPHENYL-4-YL]CARBONYL}-N-(PYRlDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-
CARBOXAMIDE
Step A. 10-{[2'-(Hydroxymethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11 -dihydro-5H~pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
A solution of 10-[(2'-formyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 567, Step B
(0.75 mmole), in ethanol (5 mL) at 5 °C was treated with sodium borohydride (4.5
mmole). The mixture was stirred and allowed to warm to room temperature over 6
hours. To the reaction mixture was added 2N hydrochloric acid until a pH of 8.0 was
reached. The ethanol was evaporated and the residue extracted with
dichloromethane. The organic solutions were combined, dried over anhydrous
sodium sulfate, and evaporated. The residue was purified by passing it through a
short column of silica gel to give the title compound, m.p. 119-121 °C.
MS [(+)ESI, m/z]: 529 [M+H]+
MS [(-)ESI, m/z]: 527 [M-H]"
HRMS [(+)ESI, m/z]: 529.22249 [M+H]+. Calcd for C33H29N403: 529.22342
Step B. 10-{[2'-(Azidomethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The 10-{[2'-(hydroxymethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step A
(0.495 mmole) was dissolved in tetrahydrofuran (4 mL) and cooled to 5 CC. The
soluditon was treated with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.692 mmole) and
diphenylphosphorylazide (0.692 mmole). After warming to room temperature and
stirring for 16 hours, the tetrahydrofuran was removed by evaporation and the
desired material was purified by flash chromatography on silica gel eluting with ethyl
acetate and used as such in the next step.
Step C. 10-{[2'-(Aminomethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of 10-{[2'-(azidomethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
(0.49 mmole) of Step B in tetrahydrofuran (3 mL) was added solid
triphenylphosphine (0.55 mmole). The mixture was stirred at room temperature for
80

WO 2006/135687

PCTYUS2006/022326

16 hours. Water (0.3 mL) was then added and the reaction mixture was heated to 45
°C for 3 hours. The solvent was removed by evaporation and the residue was
extracted with dichloromethane. The organic solution was dried over anhydrous
sodium sulfate, and evaporated. The residue was purified by HPLC (normal phase,
20 - 70% gradient of [20% methanol in dichloromethane] and hexane, Luna CN
bonded packing) and crystallized upon solvent evaporation, m.p. 115-120 °C.
MS [(+)ESI, m/z]: 528.4 [M+H]+
EXAMPLE 47
10-[(2'-METHOXY-2-METHYL-1,1'-BlPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DlHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
To a solution of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74, Step C (0.200
g, 0.356 mmol), and 2-methoxyphenylboronic acid (0.081 g, 0.533 mmol) in
acetonitrile (3 mL) was added a 0.4 M aqueous sodium carbonate solution (3 mL)
and the mixture purged with nitrogen for 10 minutes.
Tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.018 mmol) was then added and
the reaction mixture heated to 90 °C for 4 hours. The cooled reaction mixture was
partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The
organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50
mL) and brine (50 mL), dried over amnhydrous magnesium sulfate, and concentrated
in vacuo to give a yellow syrup (0.23 g). Purification by flash chromatography using
a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass
that was recrystallized from dichloromethane/hexane to afford the title compound
(0.181 g, 94%) as a white solid, m.p. 119-124 °C.
MS [(+)ESl, m/z]: 543 [M+H]+
Anal. Calcd for C34H30N4O3: C, 75.26; H, 5.57; N, 10.32. Found: C, 75.11; H, 5.58; N,
10.30.
EXAMPLE 48
10-[(2'-ETHOXY-2-METHYL-1,1 '-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
81

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 47,
replacing 2-methoxy phenylboronic acid with 2-ethoxyphenylboronic acid.
Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in
dichloromethane gave a colorless glass that was recrystallized from diethyl
ether/hexane to afford the title compound (0,182 g, 92%) as white solid, m.p. 139 -
143 °C.
MS [(+)ESI, m/z]: 557 [M+H]+
MS [(-)ESI, m/z]: 555 [M-H]'
Anal. Calcd for CaN: C, 75.52; H, 5.79; N, 10.06. Found: C, 75.21; H, 5.74; N,
9.83.
EXAMPLE 49
10-{[2'-(METHOXYMETHYL)-2-METHYL-1,1 '-BIPHENYL-4-YL]CARBONYL}-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 47,
replacing 2-methoxyphenylboronic acid with 2-methoxymethylphenylboronic acid.
Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in
dichloromethane gave a white foam that was crystallized from diethyl ether to afford
the title compound (0.147 g, 74%) as white solid, m.p. 163-164 °C.
MS [(+)ESI, m/z]: 557 [M+H]+
MS [(-)ESl, m/z]: 555 [M-H]"
Anal. Calcd for C35H32N403: C, 75.52; H, 5.79; N, 10.06. Found: C, 75.27; H, 5.91; N,
10.10.
EXAMPLE 50
10-{[2-(1-HYDROXYETHYL)-2-METHYL-1,1,-BIPHENYL-4-YL]CARBONYLN-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a solution of lO-KZ-acetyl-methyl-l.l'-biphenyM-yOcarbonyn-Npyridin-S-
ylmethyl)-10,11-dihydro-5H-pyrroio[2,1-c][1,4]benzodiazepine-3-carboxamide of
Example 29 (0.122 g, 0.220 mmol) in 2-propanol (5 mL) and water (1 mL) was
added sodium borohydride (0.0092 mg, 0.242 mmol) and the reaction mixture stirred
at room temperature under nitrogen for 24 hours. The reaction was quenched by the
addition of 2 M hydrochloric acid (10 mL) and then washed with diethyl ether (20 mL).
82

WO 2006/135687

PCT/US2006/022326

The aqueous phase was basified by the addition of 2 M sodium hydroxide and the
resulting milky suspension extracted with ethyl acetate (2 x 30 mL). The combined
organic extracts were washed with water (50 mL) and brine (50 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to afford a colorless syrup.
Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in
dichloromethane gave a colorless glass that was recrystallized from diethyl
ether/hexane to afford the title compound (0.061 g, 50%) as white solid.
MS [(+)ESI, m/z]: 557 [M+H]+
MS [(-)ESI, m/z]: 555 [M-HV
HRMS [(+)ESI, m/z]: 557.25391 [M+H]+. Calcd for C35H33N4O3: 557.25472
EXAMPLE 51
10-[(2'-ACETYL-1,1 '-BIPHENYL-4-YL)CARBONYL]-N-(PYRlDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 2'-Acetyl-biphenyl-4-carboxylic acid
To a suspension of 4-carboxybenzeneboronic acid (2.0 g, 12.1 mmol) and 1-(2-
bromo-phenyl)-ethanone (1.63 mL, 12.1 mmol) in dry acetonitrile (60 mL) was added
a 0.4 M aqueous sodium carbonate solution (60 mL) and the reaction mixture purged
with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.433
mmol) was then added and the reaction mixture heated to 90 °C for 22 hours. The
hot reaction mixture was filtered through celite and then concentrated in vacuo to
remove acetonitrile. The resulting aqueous suspension was diluted with water to 75
mL then washed with diethyl ether (75 mL). The aqueous phase was acidified to pH
1 by the addition of concentrated hydrochloric acid and the resulting white •
suspension cooled to 4 °C for 1 hour. The solid product was filtered, washed with
water and then dried in vacuo at 50 °C overnight to afford the title compound (2.62 g,
91%) as a white solid, m.p. 199 - 201 °C.
MS [(+)ESI, m/z]: 241 [M+H]+
Step B. 10-[(2'-Acetyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of 2'-acetyl-biphenyl-4-carboxylic acid of Step A (0.340 g, 1.41 mmol) in
dry tetrahydrofuran (30 mL) at room temperature under nitrogen was added dry N,N-
dimethylformamide (1 drop) followed by the dropwise addition of a 2.0 M solution of
oxalyl chloride in dichloromethane (1.17 mL, 2.34 mmol). The reaction mixture was
83

WO 2006/135687

PCT/US2006/022326

stirred at room temperature for 2 hours then concentrated in vacuo and the residue
redissolved in dry dichloromethane (30 mL). The solution was concentrated in vacuo
to afford the crude acid chloride as a cream solid. The acid chloride was dissolved in
tetrahydrofuran (30 mL); N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 11 (0.300 g, 0.942 mmol) was
added, followed by N N-diisopropylethylamine (0.49 mL, 2.83 mmol) and the reaction
mixture stirred at room temperature under nitrogen for 19 hours. The reaction was
quenched by the addition of 2 M sodium hydroxide (20 mL), the mixture stirred
vigorously for 5 minutes and then partitioned between ethyl acetate (100 mL) and 2
M sodium hydroxide (100 mL). The organic phase was separated, washed with 2 M
sodium hydroxide (100 mL), water (100 mL) and brine (100 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow foam.
Purification by flash chromatography using a solvent gradient of 1 to 3.5% methanol
in dichloromethane gave a cream foam that was crystallized from ethyl
acetate/hexane to afford the title compound (0.45 g, 88%) as a white solid, m.p. 149 -
150 °C.
MS [(+)ESI, m/z]: 541 [M+H]+
MS [(-)ESI, m/z]: 539 [M-HT
HRMS [(+)ESl, m/z]: : 541.22378 [M+Hf. Calcd for C34H29N4O3: 541.22342
Anal. Calcd for CHaN: C, 75.54; H, 5.22; N, 10.36. Found: C, 75.31; H, 5.29; N,
10.26.
EXAMPLE 52
10-{[2'-(1-HYDROXYETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 50,
replacing 10-[(2'-acetyl-2-methyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide with 10-[(2'-
acetyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 51. Purification by
flash chromatography using a solvent gradient of 1 to 5% methanol in
dichloromethane gave a white foam that was crystallized from ethyl acetate/hexane
to afford the title compound (0.076 g, 58%) as white solid, m.p. 122 °C (foaming).
84

WO 2006/135687

PCT/US2006/022326

MS [(+)ESI, m/z]: 543 [M+H]+
MS [(-)ESI, m/z]: 541 [M-H]"
HRMS [(-)ESI, m/z]: 541.22394 [M-H]-. Calcd for CaN: 541.22451
EXAMPLE 53
(-)-10-({2'-[1-HYDROXYETHYL]-1,1 '-BIPHENYL-4-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10l11-DIHYDRO-5H-PYRROLOt2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Racemic 10-{I2'-(1-hydroxyethyl)-1,1'-biphenyl-4-yl]carbonyl}-A/-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 52
was passed through a chiral chromatography column using 75: 25 hexane : ethyl
acetate containing 0.1% diethylamine as the eluant to afford the title compound as a
white solid, m.p. 122 -126 °C, [a]214D= -6.0" (c= 1.04, CHCI3)
MS I(+)ESI, m/z]: 543 [M+H]+
MS [(-)ESI, m/z]: 541 [M-H]"
EXAMPLE 54
(+)-10-({2'-[1-HYDROXYETHYL]-1,1'-BIPHENYL-4-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Racemic 10-{[2'-(1 -hydroxyethyl)-1,1 '-biphenyl-4-yl]carbonyl}-/V-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 52
was passed through a chiral chromatography column using 75 : 25 hexane :'ethyl
acetate containing 0.1% diethylamine as the eluant to afford the title compound as a
white solid, m.p. 118 °C (shrinking), [a]21'4D= +6.7° (c= 1.04, CHCI3)
MS[(+)ESI, m/z]: 543 [M+H]+
MS [(-)ESI, m/z]: 541 [M-H]"
EXAMPLE 55
10-{[2'-(1-HYDROXYETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-[(1-
OXIDOPYRIDIN-3-YL)METHYL]-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a solution of -{[-(l-hydroxyethyO-l.l'-biphenyM-ylJcarbonylJ-Npyridin-S-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c]t1,4]benzodiazepine-3-carboxamide of
Example 52 (0.500 g, 0.92 mmol) in dichloromethane (20 mL) was added saturated
aqueous sodium hydrogencarbonate solution (20 mL) followed by 70% 3-
85

WO 2006/135687

PCT/US2006/022326

chloroperoxybenzoic acid (909 mg, 3.69 mmol) and the triphasic mixture was stirred
vigorously for 1 hour. The reaction was quenched by the addition of 5% aqueous
sodium metabisulfite solution (20 mL), the mixture stirred vigorously for 5 minutes,
then partitioned between ethyl acetate (100 mL) and 2 M sodium hydroxide (100 mL).
The organic layer was separated, washed with 2 M sodium hydroxide (2 x 100 mL),
water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford a white solid. Purification by flash chromatography
using a solvent gradient of 3 to 10% methanol in dichloromethane gave the title
compound (31.1 mg, 6%) as a white solid, m.p. 213-215 °C.
MS t(+)ESI, m/z]: 559 [M+H]+
MS [(-)ESI, m/z]: 557 [M-H]-
HRMS [(+)ESI, m/z]: 559.23356 [M+H]+. Calcd for C34H31N4O4: 559.23398
EXAMPLE 56
10-[(2'-FORMYL-1l1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 2'-Formyl-1,1'-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanone with 2-bromobenzaldehyde. The title
compound (2.26 g, 83%) was obtained as a white solid, m.p. 215 - 219 °C.
MS [(+)ESI, m/z]: 227 [M+Hf
MS [(-)ESI, m/z]: 225 [M-H]"
StepB. 10-[(2'-Formyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-formyl-1,1'-biphenyl-4-
carboxylic acid of Step A. Purification by flash chromatography using a solvent
gradient of 1 to 5% methanol in dichloromethane gave a white foam that was
crystallized from ethyl acetate/hexane to afford the title compound (0.57 g, 92%) as a
white solid, m.p. 162-163 °C.
MS [(+)ESI, m/z]: 527 [M+Hf
MS [(-)ESI, m/z]: 525 [M-HT
HRMS [(+)ESI, m/z]: 527.20591 [M+H]+. Calcd for C33H27N4O3: 527.20777. •
EXAMPLE 57
86

WO 2006/135687

PCT/US2006/022326

10-[(2-METHYL-1,1'-BIPHENYL-4-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
A mixture of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihyclro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74 (0.300 g, 0.53
mmol), phenylboronic acid (0.098 g, 0.80 mmol) and potassium carbonate (0.221 g,
1.60 mmol) in dimethoxyethane : water (8 ml_: 2 ml_) was purged with nitrogen for 10
minutes. [1,1'-bis(Diphenylphosphino)ferrocene]dichloropalladium [II] (0.022 g,
0.0266 mmol) was then added and the reaction mixture heated to 100 °C for 4 hours.
The cooled reaction mixture was then partitioned between ethyl acetate (100 ml_)
and 1 M sodium hydroxide (100 mL). The organic phase was separated, washed
with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo to give an olive syrup (0.32 g). Purification by
flash chromatography using ethyl acetate as solvent afforded the title compound
(0.260 g, 95%) as a white foam, m.p. 108-112 °C.
MS [(+)ESI, m/]: 513[M+H]+
HRMS [(+)ESI, m/z]: 513.227 [M+H]+. Calcd for C33H29N4O2: 513.22905
EXAMPLE 58
10-{t2'-(1-HYDROXYPROPYL)-1,1'-BIPHENYL-4-YL]CARBONYLhN-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
To a solution of 10-[(2'-formyI-1,1'-biphenyl-4-yI)carbonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56
(0.132 g, 0.251 mmol) in dry tetrahydrofuran (15 mL) was added 3.0 M
ethylmagnesium bromide in diethyl ether (0.68 mL, 2.04 mmol) and the reaction
mixture stirred at room temperature under nitrogen for 17 hours. The reaction was
quenched by the addition of saturated aqueous ammonium chloride solution (20 mL)
and then the mixture partitioned between ethyl acetate (100 mL) and half saturated
aqueous ammonium chloride solution (100 mL). The organic phase was separated,
washed with brine (100 ml), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford a cream foam. Purification by flash chromatography
using a solvent gradient of 1 to 6% methanol in dichloromethane gave a colorless
glass that was triturated with diethyl ether to afford the title compound (0.039 g, 28%)
as a white solid, m.p. 111 -115 °C.
87

WO 2006/135687

PCT/US2006/022326

MS [(+)ESI, m/z]: 557 [M+H]+
MS[(-)ESI,m/z]:555[M-H]-
HRMS [(+)ESI, m/z]: 557.25449 [M+H]+. Calcd for C35H33N4O3: 557.25472
EXAMPLE 59
10-{[2'-(HYDROXYMETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 50,
replacing 10-[(2'-acetyl-2-methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide with 10-[(2'-
formyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-.
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56. Purification by
flash chromatography using a solvent gradient of 1 to 6% methanol in
dichloromethane gave a white foam that was crystallized from ethyl acetate/hexane
to afford the title compound (0.133 g, 84%) as white solid, m.p. 119-121 °C.
MS [(+)ESI, m/z]: 529 [M+H]+
MS[(-)ESI,m/z]:527[M-Hy
HRMS [(+)ESI, m/z]: 529.22249 [M+H]+. Calcd for C33H29N403: 529.22342
EXAMPLE 60
lO-KZ-BENZOYL-l.l'-BIPHENYL-YLJCARBONYLl-NPYRIDIN-S-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 2'-Benzoyl-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanonewith2-bromobenzophenone. The
title compound (3.12 g, 86%) was obtained as a white solid, m.p. 211 - 215 "C.
MS [(+)ESI, m/z]: 303 [M+H]+
MS [(-)ESI, m/z]: 301 [M-HT
StepB. 10-[(2'-Benzoyl-1,1'-biphenyl-4-yl)carbonyl]-A/-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-benzoyl-biphenyl-4-
carboxylic acid of Step A. Purification by flash chromatography using a solvent
gradient of 1 to 5% methanol in dichloromethane gave a yellow glass that crystallized
88

WO 2006/135687

PCT/US2006/022326

from ethyl acetate/hexane to afford the title compound (0.546 g, 72%) as a white
solid, m.p. 198-199 °C.
MS [(+)ESI, m/z]: 603 [M+H]+
MS [(-)ESI, m/z]: 601 [M-H]'
Anal. Calcd for C39H30N4O3: C, 77.72; H, 5.02; N, 9.30. Found: C, 77.43; H, 4.94; N,
9.16.
EXAMPLE 61
ICK'-lMETHOXYMETHYLVI.r-BIPHENYL-YLlCARBONYLl-N-CPYRIDlN-S-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
Step A. 2'-Methoxymethyl-biphenyl-4-carboxylic acid
To a suspension of 4-iodobenzoic acid (0.82 g, 3.31 mmol) and 2-
methoxymethylphenylboronic acid (0.55 g, 3.31 mmol) in dry acetonitrile (30 mL) was
added a 0.4 M aqueous sodium carbonate solution (30 mL) and the reaction mixture
purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (90
mg, 0.078 mmol) was then added and the reaction mixture heated to 90 °C for 19
hours. The hot reaction mixture was filtered through celite, concentrated in vacuo to
remove acetonitrile and the resulting aqueous suspension washed with ethyl acetate
(2 x 30 mL). The aqueous phase was acidified to pH 1 by the addition of
concentrated hydrochloric acid, the resulting white suspension cooled to 4 °C for 1
hour and the solid product filtered. Recrystallization from dichloroethane gave the
title compound (0.469 g, 59%) as a white solid, m.p. 164.5-165.5 °C.
MS I(-)ESI, m/z]: 241 [M-HT
Step B. 10-{[2'-(Methoxymethyl)-1,1 -biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-methoxymethyl-
biphenyl-4-carboxylic acid of Step A. Purification by flash chromatography using a
solvent gradient of 1 to 5% methanol in dichloromethane gave a yellow syrup that
crystallized from ethyl acetate/hexane to afford the title compound (0.338 g, 66%) as
a white solid, m.p. 156-157 °C.
MS [(+)ESI, m/z]: 543 [M+H]+
MS [(-)ESl, m/z]: 541 [M-HT
89

WO 2006/135687

PCTYUS2006/022326

Anal. Calcd for C34H30N4O3: C, 75.26; H, 5.57; N, 10.32. Found: C, 74.87; H, 5.27; N,
10.14.
EXAMPLE 62
lO-'-KEHHYDROXYIMINOJMETHYLhl.V-BIPHENYL--YLKJARBONYLJ-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a solution of 10-[(2'-formyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56
(0.500 g, 0.95 mmol) and hydroxylamine hydrochloride (0.132 g, 1.90 mmol) in
methanol (15 ml_) was added pyridine (0.155 ml_, 1.90 mmol) and the reaction
mixture heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was
then poured into 5% w/v aqueous sodium carbonate solution (100 mL) and extracted
with ethyl acetate (100 mL). The organic extract was washed with water (100 mL)
and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in
vacuo to afford a white foam. Crystallization of the crude product from
dichloromethane gave the title compound (0.458 g, 89%) as a white crystalline solid,
m.p. 165-167 °C.
MS [(+)ESI, m/z]: 542 [M+H]+
MS [(-)ESI, m/z]: 540 [M-H]"
Anal. Calcd for C33H27N503: C, 73.18; H, 5.02; N, 12.93. Found: C, 73.01; H, 4.76; N,
12.81.
EXAMPLE 63
METHYL-4'-{[3-{[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYL}-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPIN-10(11 H)-YL]CARBONYL}-1 ,f-BIPHENYL-2-
CARBOXYLATE
Step A. 2'-(Methoxycarbonyl)-1,1'-biphenyl-4-carboxylic acid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanone with methyl 2-bromobenzoate.
Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl
acetate in dichloromethane (containing 1% acetic acid) gave a white solid that was
recrystallized from dichloroethane/hexane to afford the title compound (0.26 g, 9%)
as a white solid, m.p. 151 -152 "C.
MS [(+)ESI, m/z]: 255 [M-H]'
90

WO 2006/135687

PCT/US2006/022326

Step B. Methyl 4'-{[3-Q[(pyriciin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1 '-biphenyl-2-carboxylate
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with ZmethoxycarbonyO-l.l'-
biphenyl-4-carboxylic acid of Step A. Purification by flash chromatography using a
solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that
crystallized from ethyl acetate/hexane to afford the title compound (0.257 g, 77%) as
a white solid, m.p. 179.5-180.5 °C.
MS [(+)ESI, m/z]: 557 [M+Hf
HRMS [(+)ESI, m/z]: 557.21758 [M+H]+. Calcd for CszsN: 557.21758
EXAMPLE 64
TERT-BUTYL-4'-{[3-{[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYL}-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEP1N-10(11 H)-YL]CARBONYL}-1,1'-BIPHENYL-
2-CARBOXYLATE
Step A. 2-Bromobenzoic acid ferf-butyl ester
To a solution of 2-bromobenzoyl chloride 2.0 g, 9.11 mmol) in dry diethyl ether (40
mL) was added 2-methyl-2-propanol (0.96 mL, 10.02 mmol) followed by 4-
(dimethylamino)pyridine (111 mg, 0.911 mmol) and the reaction mixture stirred at
room temperature under nitrogen for 48 hours. The resulting white suspension was
then partitioned between ethyl acetate (100 mL) and 1 M hydrochloric acid (100 mL).
The organic phase was separated, washed with 1 M hydrochloric acid (100 mL), 2 M
sodium hydroxide (2 x 100 mL), water (100 mL) and brine (100 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow oil.
Purification by flash chromatography using ethyl acetate/hexane as eluant gave the
title compound (1.22 g, 52%) as a colorless oil.
StepB. 2Xtert-Butoxycarbonyl)-1,1'-biphenyl-4-carboxylicacid
The title compound was prepared in essentially the same manner as Example 51,
Step A, replacing 1-(2-bromo-phenyl)-ethanonewith 2-bromobenzoic acid fert-butyl
ester of Step A. The title compound (1.28 g, 91%) was obtained as a white solid,
m.p. 180-182 °C.
MS [(-)ESl, m/z]: 297 [M-HT
Anal. Calcd for C1aH1804: C, 72.47; H, 6.08. Found: C, 72.12; H, 5.69.
91

WO 2006/135687

PCT/US2006/022326

Step C. tert-Butyl 4'-{[3-(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1 '-biphenyl-2-carboxylate
The title compound was prepared in essentially the same manner as Example 51,
Step B, replacing 2'-acetyl-biphenyl-4-carboxylic acid with 2'-(tert-butoxycarbonyl)-
1,1'-biphenyl-4-carboxylic acid of Step B. Purification by flash chromatography using
a solvent gradient of 1 to 5% methanol in dichloromethane gave a cream foam that
was crystallized from ethyl acetate/hexane to afford the title compound (956 mg,
66%) as a white crystalline solid, m.p. 163-165 °C.
MS [(+)ESI, m/z]: 599 [M+H]+
MS [(-)ES!, m/z]: 597 [M-H]'
HRMS [(+)ESI, m/z]: 599.26473 [M+H]+. Calcd for CsyHssCv 599.26528
EXAMPLE 65
-{-{[(PYRIDIN-S-YLMETHYgAMINOlCARBONYLl-SH-PYRROLOp,!-
C][1,4]BENZODIAZEPIN-10(11H)-YL]CARBONYL}-1,1'-BIPHENYL-2-CARBOXYLIC
ACID
To a solution of tert-butyl 4'-([3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1'-biphenyl-2-carboxylate of Example 64
(0.710 g, 1.186 mmol) in dry dichloromethane (10 ml_) was added trifluoroacetic acid
(10 ml_) and the reaction mixture stirred at room temperature under nitrogen'for 1.75
hours. The reaction mixture was then concentrated in vacuo and the resulting solid
dissolved in ethyl acetate (50 ml_). The organic phase was extracted with 2 M
sodium hydroxide (2 x 50 mL) and the combined aqueous extracts acidified to pH 1
by the addition of concentrated hydrochloric acid. The resulting white suspension
was cooled to 4 °C for 1 hour, the solid product filtered, washed with water and then
dried in vacuo at 50 °C overnight to afford the title compound (0.345 g, 54%) as a
white solid, m.p. 189 -191 °C.
MS [(+)ESI, m/z]: 543 [M+H]+
MS [(-)ESI, m/z]: 541 [M-HT
HRMS [(+)ESI, m/z]: 543.20133 [M+H]+. Calcd for C33H27N4Cy. 543.20268
EXAMPLE 66
10-({2'-[2-(ETHYLAMINO)-2-OXOETHYL]-1,1 '-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
92

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 68,
replacing 4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1'-biphenyl-2-carboxylic acid with (4'-{[3-
{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
yl]carbonyl}-1,1'-biphenyl-2-yl)acetic acid of Example 35, and dimethylamine with
ethylamine. Purification by flash chromatography using a solvent gradient of 1 to 4%
methanol in dichloromethane gave the title compound (0.152 g, 61%) as a white
solid.
MS [(+)ESI, m/z]: 584 [M+H]+
MS [(-)ESI, m/z]: 582 [M-HT
HRMS [(+)ESI, m/z]: 584.26482 [M+H]+. Calcd for CaeHNsOs: 584.26562
EXAMPLE 67
10-({2'-t2-(DIETHYLAMINO)-2-OXOETHYL]-1,1'-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 68,
replacing 4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1'-biphenyl-2-carboxylic acid with (4'-{[3-
{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
yl]carbonyl}-1,1'-biphenyl-2-yl)acetic acid of Example 35, and dimethylamine with
diethylamine. Purification by flash chromatography using a solvent gradient of 1 to
4% methanol in dichloromethane gave the title compound (0.158 g, 60%) as an off-
white solid.
MS[(+)ESI,m/z]:612[M+H]+
MS [(-)ESI, m/z]: 610 [M-H]"
HRMS [(+)ESI, m/z]: 612.29644 [M+Hf. Calcd for C38H38N5O3: 612.29692
EXAMPLE 68
10-({2'-[(DIMETHYLAMINO)CARBONYL]-1,r-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a solution of 4'-{[3-{[(pyridin-3-yImethyl)amino]carbonyl}-5H-pyrrolo[2,1 -
cinbenzodiazepin-IOtUHJ-yllcarbonyQ-l.r-biphenyl-carboxylic acid of Example
65 (92 mg, 0.17 mmol) in 1-methy!-2-pyrrolidinone (4.5 mL)was added a 2.0 M
93

WO 2006/135687

PCT/US2006/022326

solution of dimethylamine in tetrahydrofuran (0.42 mL, 0.848 mmol) followed by 0-(7-
azabenzotriazol-1-yl)-N,N,N',N',tetramethyluronium hexafluorophosphate (71 mg,
0.187 mmol) and the reaction mixture stirred at room temperature under nitrogen for
2 hours. The reaction mixture was then partitioned between ethyl acetate (5.0 mL)
and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with
2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam.
Purification by flash chromatography using a solvent gradient of 1 to 7% methanol in
dichloromethane gave a colorless glass that was crystallized from ethyl
acetate/hexane to afford the title compound 0.082 g, 85%) as a white solid, m.p. 206
-207 °C.
MS [(+)ESI, m/z]: 570 [M+Hf
MS [(-)ESI, m/z]: 568 [M-HV
Anal. Calcd for CasHsnNsCfe: C, 73.80; H, 5.49; N, 12.29. Found: C, 73.44; H, 5.22; N,
12.10.
EXAMPLE 69
10-({2'-[(METHYLAMINO)CARBONYL]-1,r-BIPHENYL-4-YL}CARBONYL)-N-
(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZOD)AZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 68,
replacing dimethylamine with methylamine. Purification by flash chromatography
using a solvent gradient of 1 to 7% methanol in dichloromethane gave a colorless
glass that was crystallized from ethyl acetate to afford the title compound (0.078 g,
45%) as a white solid, m.p. 221-224 °C.
MS [(+)ESI, m/z]: 556 [M+H]+
MS [(-)ESI, m/z]: 554 [M-HT
HRMS [(+)ESI, m/z]: 556.23397 [M+H]+. Calcd for C34H30N5O3: 556.23432
EXAMPLE 70
10-[(3MV1ETHOXY-2-METHYL-[1,1'-BIPHENYL]-4-YL)CARBONYL]-N-(3-
PYRIDINYLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 47,
replacing 2-methoxyphenylboronic acid with 3-methoxyphenylboronic acid.
94

WO 2006/135687

PCT/US2006/022326

Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in
dichloromethane gave a white foam that was crystallized from
dichloromethane/hexane to afford the title compound (0.142 g, 74%) as white solid,
m.p. 176-177°C.
MS [(+)ESI, m/z]: 543 [M+H]+
MS [(-)ESI, m/z]: 541 [M-H]"
HRMS [(+)ESI, m/z]: 543.23862 [M+H]+. Calcd for C34H31N4O3: 543.23907
EXAMPLE 71
10-[(2'-METHOXY-1,1'-BlPHENYL-4-YL)SULFONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 10-[(4-Bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepine
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10 g, 0.0543
mol) and N, N-diisopropylethylamine (14.2 mL, 0.0814 mol) in dry dichloromethane
(200 mL) at 0 °C under nitrogen was added dropwise a solution of 4-
bromobenzenesulfonyl chloride (10.4 g, 0.0407 mol) in dry dichloromethane (80 mL)
over 10 minutes. The ice bath was removed and the reaction mixture stirred at room
temperature for 18 hours. The reaction mixture was then washed with 1 M
hydrochloric acid (2 x 250 mL), 0.5 M sodium hydroxide (250 mL) and water (250
mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a
purple syrup (17.91 g). Purification by flash chromatography using a solvent gradient
of 5 to 10% ethyl acetate in hexane afforded a tan solid (3.21 g) that was
recrystallized from ethyl acetate/hexane to afford the title compound (2.55 g, 16%) as
a tan crystalline solid, m.p. 128 -129 °C.
MS t(+)ESI, m/z]: 403 [M+H]+
Anal. Calcd for C18H15BrN202S: C, 53.61; H, 3.75; N, 6.95. Found: C, 53.74; H, 3.75;
N, 6.82.
Step B. 1-{10-[(4-Bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}-2,2,2-trichloroethanone
To a solution of 10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepine of Step A (2.32 g, 5.753 mmol) and N, N-dimethylaniline (1.17 mL,
9.204 mmol) in dry dichloromethane (20 mL) at 0 °C under nitrogen was added
dropwise trichloroacetyl chloride (0.96 mL, 8.629 mmol). The ice bath was removed
95

WO 2006/135687

PCT/US2006/022326

and the reaction mixture stirred at room temperature for 21 hours. The reaction
mixture was then washed with 2 M hydrochloric acid (2 x 100 mL) and water (100
mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give an
olive foam. Purification by flash chromatography using a solvent gradient of 5 -15%
ethyl acetate in hexane afforded a cream solid that was recrystallized from diethyl
ether/hexane to afford the title compound (1.986 g, 63%) as an off-white crystalline
solid, m.p. 182-183 °C.
StepC. 10-[(4-Bromophenyl)sulfonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
To a solution of 1-{10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepin-3-yl}-2,2,2-trichloroethanone of Step B (1.80 g, 3.297 mmol) and
dimethyl sulfoxide (1.17 mL, 16.487 mmol) in dry acetonitrile (30 mL) at room
temperature under nitrogen was added 3-(aminomethyl)pyridine (0.67 mL, 6.595
mmol) and the reaction mixture heated to reflux for 20 hours. The cooled reaction
mixture was concentrated in vacuo, the oily residue dissolved in ethyl acetate (100
mL), washed with 1M sodium hydroxide (2 x 100 mL), water (100 mL) and brine (100
mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to
give a yellow foam. Purification by flash chromatography using a solvent gradient of
0 to 3% methanol in dichloromethane gave the title compound (1.61 g, 91%) as a
yellow foam.
MS [(+)ESI, m/z]: 537 [M+H]+
Anal. Calcd for C25H2iBrN403S: C, 55.87; H, 3.94; N, 10.42. Found: C, 55.53; H,
3.80; N, 10.23.
Step D. 10-[(2'-IVIethoxy-1,1'-biphenyl-4-yl)sulfonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A mixture of 10-[(4-bromophenyl)sulfonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamideof Step C (0.500 g, 0.93 mmol), 2-
methoxyphenylboronic acid (0.212 g, 1.40 mmol) and potassium carbonate (0.386 g,
2.79 mmol) in dimethoxyethane : water (8 mL : 2 mL) was purged with nitrogen for 10
minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium [II] (38 mg, 0.0465
mmol) was then added and the reaction mixture heated to 90 °C for 21 hours. The
cooled reaction mixture was partitioned between ethyl acetate (100 mL) and 1 M
sodium hydroxide (100 mL). The separated organic phase was washed with water
96

WO 2006/135687

PCT/US2006/022326

(100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to give a brown syrup (0.60 g). Purification by flash
chromatography using a solvent gradient of 0 to 3% methanol in dichloromethane
gave the title compound (0.520 g, 99%) as a yellow foam.
MS [(-)ESI, m/z]: 563 [M-H]'.
EXAMPLE 72
10-K2'-CHLORO-1,1'-BIPHENYL-4-YL)SULFONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 71,
Step D, replacing 2-methoxyphenylboronic acid with 2-chlorophenylboronic acid, as a
white foam (0.100 g, 32%)
Anal. Calcd for C3iH25CIN403S: C, 65.43; H, 4.43; N, 9.85. Found: C, 65.47; H, 4.35;
N, 9.54.
EXAMPLE 73
10-(1,r-BIPHENYL-4-YLMETHYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODlAZEP)NE-3-CARBOXAMIDE
Step A. 10-(1,1'-Biphenyl-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepine
A mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.200 g, 1.09
mmol), 4-bromomethyl-biphenyl (0.322 g, 1.303 mmol) and potassium carbonate
(0.300 g, 2.17 mol) in dry N, N-dimethyl formamide (6 mL) was stirred at room
temperature under nitrogen for 24 hours. The reaction mixture was then partitioned
between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The separated
organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and
brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo
to afford a colorless syrup (0.42 g). Purification by flash chromatography using a
solvent gradient of 0 to 5% ethyl acetate in hexane afforded a white foam that was
crystallized from ethyl acetate/hexane to afford the title compound (0.261 g, 68%) as
a white crystalline solid, m.p. 135-137 °C.
MS [(-)ESI, m/z]: 349 [M-H]Anal. Calcd for C25H22N2: C, 85.68; H, 6.33; N, 7.99. Found: C, 85.89; H, 6.24; N,
7.83.
97

WO 2006/135687

PCT/US2006/022326

StepB. 10-(1,r-Biphenyl-4-ylmethyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of 10-(1,1'-biphenyl-4-ylmethy!)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepine of Step A (0.93 g, 2.65 mmol) and N, N-dimethylaniline (0.51 mL,
3.98 mmol) in dry dichloromethane (30 mL) at 0 °C under nitrogen was added
dropwise trichloroacetyl chloride (0.33 mL, 2.92 mmol). The ice bath was removed
and the reaction mixture stirred at room temperature for 19 hours. The reaction
mixture was then quenched by the addition of 2 M sodium hydroxide (30 mL) then
partitioned between additional dichloromethane (75 mL) and 2 M sodium hydroxide
(75 mL). The separated organic phase was washed with 2 M sodium hydroxide (75
mL) and water (75 mL), dried over anhydrous magnesium sulfate, and concentrated
in vacuo to give a yellow syrup (2.12 g). Purification by flash chromatography using
a solvent gradient of 1 - 5% ethyl acetate in hexane afforded 1-{10-[(1,1'-biphenyl)-4-
ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-
trichloroethanone (0.88 g, 67%) as a cream foam. To a solution of 1-{10-[(1,1'-
biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-
trichloroethanone (0.4 g, 0.807 mmol) and dimethyl sulfoxide (0.29 mL, 4.034 mmol)
in dry acetonitrile (5 mL) at room temperature under nitrogen was added 3-
(aminomethyl)pyridine (0.17 mL, 1.613 mmol) and the reaction mixture was heated to
reflux for 2 days. The cooled mixture was concentrated in vacuo, the semi-solid
residue dissolved in ethyl acetate (50 mL), filtered and concentrated in vacuo to
afford a dark brown syrup. Purification by flash chromatography using a solvent
gradient of 0.5 to 3% methanol in dichloromethane afforded an orange semi-solid
that was crystallized from dichloromethane/hexane to give the title compound (0.047
g, 12%) as a cream solid, m.p. 161-165 °C (dec).
MS [(+)ESI, m/z]: 485[M+H]+
EXAMPLE 74
10-(4-IODO-3-METHYLBENZOYL)-A/-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5W-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 10-(4-lodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4] .
benzodiazepine
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (9.38 g, 0.0509
mol) and N,N-diisopropylethylamine (13.31 mL, 0.0764 mol) in dry dichloromethane
98

WO 2006/135687

PCT/US2006/022326

(250 mL) at 0 °C under nitrogen was added dropwise a solution of 4-iodo-3-methyl-
benzoyl chloride (10.71 g, 0.0382 mol) in dry dichloromethane (30 mL) overca. 10
minutes. The reaction mixture was allowed to warm slowly to room temperature with
stirring over 3 hours then quenched by the addition of water (100 mL). The organic
phase was separated, washed with 1 M hydrochloric acid (2 x 200 mL) and 5% wt/v
aqueous sodium carbonate solution (200 mL), dried over anhydrous magnesium
sulfate, and concentrated in vacuo to afford a cream solid. Diethyl ether (150 mL)
was added and the resulting suspension stirred vigorously for 3 hours then filtered to
afford the title compound (14.73 g, 90%) as a white solid, m.p. 152 -153 °C.
MS [(+)ESI, m/z]: 429 [M+H]+
Anal. Calcd for C20H17IN2O: C, 56.09; H, 4.00; N, 6.54. Found: C, 55.90; H, 3.86; N,
6.38.
Step B. 2,2,2-Trichloro-1-f10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl]ethanone
To a solution of 10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine of Step A (5.0 g, 0.0117 mmol) and N,N-diisopropylethylamine
(3.25 mL, 0.0187 mol) in dry dichloromethane (50 mL) at room temperature under
nitrogen was added dropwise trichloroacetyl chloride (1.95 mL, 0.0175 mol) and the
reaction mixture was stirred at room temperature for 23 hours. Additional N,N-
diisopropylethylamine (1.02 mL, 0.00583 mol) and trichloroacetyl chloride (0.65 mL,
0.00583 mol) were added and stirring continued at room temperature for 4 hours.
The reaction mixture was then partitioned between dichloromethane (200 mL) and 2
M hydrochloric acid (200 mL). The organic phase was separated, washed with 2 M
hydrochloric acid (200 mL) and water (200 mL), dried over anhydrous magnesium
sulfate, and concentrated in vacuo to afford a black syrup. Purification by flash
chromatography using a solvent gradient of 10 to 15% ethyl acetate in hexane gave
an orange foam. Diethyl ether (100 mL) was added and the resulting suspension
stirred vigorously for 4 hours then filtered to afford the title compound (5.21 g, 78%)
as an off-white solid, m.p. 163 CC.
Anal. Calcd for C22H1sCl3lN202: C, 46.06; H, 2.81; N, 4.88. Found: C, 45.91; H, 2.72;
N.4.81.
StepC. 10-(4-iodo-3-methylbenzoyl)-/\/-(pyridin-3-ylmethyl)-10,11-dihydro-5l-l-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
99

WO 2006/135687

PCT/US2006/022326

To a solution of 2,2,2-trichloro-1-[10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]ethanone of Step B (1 g, 1.74 mmol) in dry
acetonitrile (30 ml_) at room temperature under nitrogen was added dimethyl
sulfoxide (0.62 mL, 8.72 mmol) followed by 3-(aminomethyl)pyridine (0.36 ml_, 3.49
mmol) and the reaction mixture heated to reflux for 36 hours. The cooled reaction
mixture was concentrated in vacuo to a small volume then partitioned between ethyl
acetate (50 mL) and 1 M sodium hydroxide (50 mL). The organic layer was
separated, washed with water (50 mL) and brine (50 mL), dried over anhydrous
magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification
by flash chromatography using ethyl acetate as solvent afforded a white foam (0.94
g). Recrystallization from ethyl acetate/hexane gave the title compound (0.77 g, 79%)
as white solid, m.p. 176-177 °C.
MS [(+)ESI, m/z]: 563 [M+H]+
MS [(-)ESI, m/z]: 561 [M-HT
Anal. Calcd for CzrlN: C, 57.66; H, 4.12; N, 9.96. Found: C, 57.83; H, 4.04; N,
9.75.
EXAMPLE 75
10-(4-BENZOYLBENZOYL)-N-(PYRlDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODlAZEPlNE-3-CARBOXAMIDE
Step A. Phenyl[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yicarbonyl)
phenyl]methanone
To solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1 benzodiazepine (0.807 g, 4.38
mmol) in dry dichloromethane (20 mL) cooled in an ice bath was added N,N-
diisopropylethyl amine (1.14 mL). The solution was treated dropwise with a
suspension of 4-benzoylbenzoyl chloride (prepared from 3 mmol of 4-benzoylbenzoic
acid and oxalyl chloride) in 8 mL of dichloromethane. The solution was stirred
overnight at room temperature, diluted with dichloromethane, washed with water, 1N
hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over
anhydrous magnesium sulfate and evaporated to dryness. The residue was flash
chromatographed over silica gel Merck-60 with a solvent gradient of 5 to 20% of ethyl
acetate in hexane to provide the title compound (1.2 g) as a crystalline solid.
MS [(+)ESI, m/z]: 393.12 [M+H]+
100

WO 2006/135687

PCT/US2006/022326

Step B. 2,2,2-Trichloro-1-{[10-(4-benzoyl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}ethanone
To a solution of phenyl[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)
phenyl]methanone of Step A (1 g, 2.55 mmol) and N,N-diisopropylethyl amine (0.9
mL) in dry dichloromethane (20 mL) kept under nitrogen and cooled in an ice bath
was added dropwise trichloroacetyl chloride (0.88 mL). The solution was stired
overnight at room temperature, and then quenched with water. The organic layer was
washed with water, dried over anhydrous magnesium sulfate and evaporated to
dryness. The residue was flash chromatographed over silica gel Merck-60 using a
solvent gradient of 0 to 2% of ethyl acetate in dichloromethane to provide the title
compound as an off white, amorphous solid (1.43 g).
MS [(+)ESI, m/z]: 539.04 [M+H]+
Step C. 10-(4-Benzoylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide
To a suspension of 2,2,2-trichloro-1-{[10-(4-benzoyl)-benzoyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step B (1.2 g, 2.23 mmol) in dry
acetonitrile (30 mL) kept under nitrogen was added triethylamine (0.680 mL), and
dimethylsulfoxide (0.8 mL) followed by 3-(aminomethyl)pyridine (0.478 mL). The
mixture was stirred overnight at room temperature, and then evaporated to dryness.
The residue was dissolved in dichloromethane and the solution washed with brine,
dried over anhydrous sodium sulfate and evaporated to dryness. The residue was
flash chromatographed over silica gel Merck-60 using a solvent gradient of 0 to 50%
of ethyl acetate in dichloromethane to provide the title compound as a white solid,
m.p. 211-213 °C dec.
MS [(-)ESI, m/z]: 525.25 [M-H]"
Anal. Calcd for CHNa 0.40 C4H802: C, 73.97; H, 5.24; N, 9.97. Found: C,
73.62; H, 5.08; N, 10.05.
EXAMPLE 76
10-BENZOYL-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid 9H-
fluoren-9-ylmethyl ester
101

WO 2006/135687

PCTVUS2006/022326

To a solution of 10,11-dihydro-5H- pyrrolo[2,1-c][1 benzodiazepine (19.23 g, 0.104
mol) and N,N-diisopropylethylamine (27.3 mL, 0.157 mol) in dichloromethane (500
mL) was added 9-fluorenylmethyl chloroformate (27 g, 0.104 mol). The reaction
mixture was stirred at room temperature under nitrogen for 4 hours, and then washed
with 1 M hydrochloric acid (3 x 300 mL), water (300 mL) and brine (300 mL), dried
over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale yellow
solid. The solid was slurried in dichloromethane (75 mL), the slurry was diluted with
diethyl ether (300 mL) and the resulting white suspension stirred overnight. Filtration
afforded the title compound (34.64 g, 82%) as a white solid, m.p. 141-142 °C.
MS [APCI, m/z]: 407 [M+H]+
Anal. Calcd for C27H22N2O2: C, 79.78; H, 5.46; N, 6.89. Found: C, 79.44; H, 5.72; N,
6.67.
Step B. 2,2,2-Trichloro-1-[10-(fluorenylmethoxycarbonyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodizepin-3-yl]ethanone
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic
acid9W-fluoren-9-ylmethyl ester of Step A (13.9 g, 34.2 mmol) and N,N-
dimethylaniline (6.9 mL, 54 mmol) in dichloromethane (100 mL) at 0 °C under
nitrogen was added dropwise trichloroacetyl chloride (5.7 mL, 51 mmol) over ca. 5
minutes. The cooling bath was then removed and the reaction mixture stirred at
room temperature for 16 hours then quenched by the addition of water. The organic
phase was washed with 2 M hydrochloric acid (3 x 100 mL), water (100 mL) and
brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo
to give the crude product as a gray foam (19.1 g). Purification by filtration through a
plug of silica gel (90 g) eluting with diethyl ether afforded the title compound (18.3 g,
97%) as a pink foam.
Anal. Calcd for CzgHziCIaNzOa: C, 63.12; H, 3.84; N, 5.08. Found: C, 62.98; H, 3.61;
N.5.01.
Step C. N-(Pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepine-
3-carboxamide
To a solution of 2,2,2-trichloro-1-[10-(fluorenylmethoxycarbonyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodizepin-3-yl]ethanone of Step B (19.04 g, 34.5 mmol) in dry
acetonitrile (11 mL) was added dry dimethylsulfoxide (12.25 mL, 172.5 mmol)
followed by 3-(aminomethyl)pyridine (10.54 mL, 103.5 mmol) and the reaction
102

WO 2006/135687

PCT/US2006/022326

mixture was heated to reflux under nitrogen for 19.5 hours. The reaction mixture was
slowly cooled to 4 °C and the resulting suspension filtered to afford the title
compound (8.45g, 77%) as an off-white solid, identical to the product of Example 12.
MS[(+)ESI,m/z]:319[M+H]+
Anal. Calcd for C19H18N40: C, 71.68; H, 5.70; N, 17.60. Found: C, 71.63; H, 5.53; N,
17.61.
StepD. lO-Benzoyl-Npyridin-S-ylmethyO-IO.H-dihydro-SH-pyrrolo.l-clII]
benzodiazepine-3-carboxamide
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrroIo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Step C (300 mg, 0.942 mmol) in dry
tetrahydrofuran (15 mL) at room temperature under nitrogen was added N,N-
diisopropylethylamine (0.26 mL, 1.508 mmol) followed by benzoyl chloride (0.165
mL, 1.41 mmol) and the reaction mixture stirred at room temperature for 21 hours.
The reaction was quenched by the addition of 2 M sodium hydroxide (5 mL) and then
the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50
mL). The organic phase was washed with 2 M sodium hydroxide (50 mL), water (50
mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in
vacuo to afford a yellow syrup. Purification by flash chromatography using a solvent
gradient of 0 to 4% methanol in dichloromethane gave a white foam that was
crystallized from diethyl ether/hexane to give the title compound (0.319 g, 80%) as a
white crystalline solid, m.p. 197 °C.
MS [(+)ESI, m/z]: 423 [M+H]+
MS [(-)ESI, m/z]: 421 [M-HT
Anal. Calcd for C26H22N402: C, 73.92; H, 5.25; N, 13.26. Found: C, 73.61; H, 5.41; N,
13.14.
EXAMPLE 77
10-(4-METHYLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with p-toluoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave the title compound (0.410 g, 99%) as a white foam.
MS [(+)ESI, m/z]: 437 [M+H]+
103

WO 2006/135687

PCT/US2006/022326

MS [(-)ESI, m/z]: 435 [M-H]"
HRMS [(+)ESI, m/z]: 437.19607 [M+H]+. Calcd for C27H25N402: 437.19775
EXAMPLE 78
10-(3-FLUOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 3-fluorobenzoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave the title compound (0.390 g, 94%) as a white solid, m.p. 101 °C.
MS[(+)ESI,m/z]:441[M+H]+
MS [(-)ESI, m/z]: 439 [M-H]"
HRMS [(+)ESI, m/z]: 441.17103 [M+H]+. Calcd for CasHzjFN: 441.17268
EXAMPLE 79
N-(PYRIDIN-3-YLMETHYL)-10-[4-(TRIFLUOROMETHYL)BENZOYL]-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-(trifluoromethyI)benzoyl chloride.
Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave the title compound (0.430 g, 93%) as a white foam.
MS [(-)ESI, m/z]: 489 [M-H]'
Anal. Calcd for CFaN: C, 66.12; H, 4.32; N, 11.42. Found: C, 65.81; H, 4.38;
N, 11.21.
EXAMPLE 80
10-(4-TERT-BUTYLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-ferf-butylbenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave the title compound (0.450 g, 99%) as a white foam.
MS [(+)ESI, m/z]: 479 [M+H]+
MS [(-)ESI, m/z]: 477 [M-HT
Anal. Calcd for C3oH3oN402: C, 75.29; H, 6.32; N, 11.71. Found: C, 74.93; H, 6.16; N,
11.32.
104

WO 2006/135687

PCT/US2006/022326

EXAMPLE 81
10-(3,4-DICHLOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 3,4-dichlorobenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a yellow solid that was recrystallized from
dichloromethane/diethyl ether to afford the title compound (0.376 g, 81%) as a white
crystalline solid, m.p. 192 °C.
MS [(+)ESI, m/z]: 491 [M+Hf
MS [(-)ESI, m/z]: 489 [M-H]"
HRMS [(+)ESI, m/z]: 491.10219 ][M+H]+. Calcd for C26H21CI2N402: 491.10415
EXAMPLE 82
N-(PYRIDIN-3-YLMETHYL)-10-[2-(TRIFLUOROMETHYL)BENZOYL]-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 2-(trifluoromethyl)benzoyl chloride.
Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a yellow solid that was recrystallized from diethyl ether/hexane
to afford the title compound (0.395 g, 85%) as a white solid, m.p. 157-158 °C.
MS [(+)ESI, m/z]: 491 [M+H]+
MS [(-)ESI, m/z]: 489 [M-H]"
Anal. Calcd for C27H21F3N402: C, 66.12; H, 4.32; N, 11.42. Found: C, 66.05; H, 4.48;
N,11.22.
EXAMPLE 83
10-(3-METHYLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with m-toluoyl chloride. Purification by
recrystallization from diethyl ether/ethanol gave the title compound (0.298 g, 45%) as
light orange needles.
MS [(+)ESl, m/z]: 437 [M+H]+
MS [(-)ESI, m/z]: 435 [M-H]"
105

WO 2006/135687

PCT/US2006/022326

HRMS [(+)ESI, m/z]: 437.19614 [M+H]+. Calcd for C27H25N402: 437.19775
EXAMPLE 84
10-[4-(DIMETHYLAMINO)BENZOYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIA2EPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-(dimethylamino)benzoyl chloride.
Purification by flash chromatography using ethyl acetate as solvent gave an orange
solid that was recrystallized from ethanol/ethyl acetate to afford the title compound
(0.280 g, 40%) as an orange crystalline solid.
MS [(+)ESI, m/z]: 466 [M+H]+
HRMS [(+)ESI, m/z]: 466.22317 [M+H]+. Calcd for C28H28N502: 466.22430
EXAMPLE 85
N-(PYRIDIN-3-YLMETHYL)-10-l4-(TRIFLUOROMETHOXY)BENZOYL]-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-(trifluoromethoxy)benzoyl chloride.
Purification by flash chromatography using ethyl acetate as solvent gave a white
foam that was recrystallized from diethyl ether to afford the title compound (0.499 g,
66%) as pale yellow needles.
MS t(+)ESI, m/z]: 507 [M+H]+
MS [(-)ESI, m/z]: 505 [M-Hr
Anal. Calcd for C27H21F3N4Cy. C, 64.03; H, 4.18; N, 11.06. Found: C, 63.85; H, 4.20;
N,11.01.
EXAMPLE 86
10-(2,6-DIFLUOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMlDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 2,6-difluorobenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave the title compound (0.210 g, 49%) as a white solid, m.p. 103-
109 °C.
MS [(+)ESI, m/z]: 459 [M+H]+
MS [(-)ESl, m/z]: 457 [M-HT
106

WO 2006/135687

PCT/US2006/022326

HRMS [(+)ESI, m/z]: 459.16143 [M+H]+. Calcd for C26H21F2N4O2: 459.16326
EXAMPLE 87
METHYL 4-{[3-{[(PYRID[N-3-YLMETHYL)AMINO]CARBONYL}-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPIN-10(11 H)-YL]CARBONYL}BENZOATE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-chlorocarbonyl-benzoic acid methyl ester.
Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a colorless syrup that was crystallized from diethyl
ether/dichloromethane to afford the title compound (3.06 g, 99%) as a white
crystalline solid, m.p. 170-172 °C.
MS [(+)ESI, m/z]: 481 [M+H]+
MS [(-)ESI, m/z]: 479 [M-HT
HRMS [(+)ESI, m/z]: 481.18613 [M+H]+. Calcd for CHNA,: 481.18758
EXAMPLE 88
4-{[3-{[(PYRIDIN-3-YLMETHYL)AMlNO]CARBONYL}-5H-PYRROLO[2l1-
C][1,4]BENZODIAZEPIN-10(11H)-YL]CARBONYL}BENZOICACID
To a solution of methyl 4-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}benzoate of Example 87 (0.315 g, 0.656
mmol) in methanol (4 mL) and water (2 mL) was added lithium hydroxide (31.4 mg,
1.31 mmol) and the reaction mixture heated to reflux for 1 hour. The cooled reaction
mixture was diluted with water (20 mL) and washed with ethyl acetate (2 x 20 mL).
The aqueous phase was then acidified to pH 4.5 by the addition of 2 M hydrochloric
acid and the resulting milky suspension allowed to stand at 4 °C for 16 hours. The
solid product was filtered, washed with water, and dried at 50 °C in vacuo overnight
to afford the title compound (0.271 g, 89%) as a white solid.
MS[(+)ESI, m/z]: 467 IM+H]+
MS [(-)ESI, m/z]: 465 [M-HV
EXAMPLE 89
10-(4-METHOXYBENZOYL)-N-(PYRIDIN-3-YLMETHYL)~10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with p-anisoyl chloride. Purification by flash
107

WO 2006/135687

PCT/US2006/022326

chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave the title compound (0.425 g, 99%) as a white solid, m.p. 110 -112 °C.
MS [(+)ESI, m/z]: 453 [M+H]+
Anal. Calcd for C27H24N4O3: C, 71.67; H, 5.35; N, 12.38. Found: C, 71.29; H, 5.51; N,
12.00.
EXAMPLE 90
10-(4-CYANOBENZOYL)-N-(PYRlDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-cyanobenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a pale yellow foam that was crystallized from ethanol to afford
the title compound (0.417 g, 62%) as a white crystalline solid.
MS [(+)ESI, m/z]: 448 [M+H]+
MS [(-)ESI, m/z]: 446 [M-HT
HRMS [(+)ESI, m/z]: 448.17627 [M+H]+. Calcd for C27H22N5O2: 448.17735
Anal. Calcd for C27H2iN502: C, 72.47; H, 4.73; N, 15.65. Found: C, 72.22; H, 4.60; N,
15.66.
EXAMPLE 91
10-(4-CHLOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-chlorobenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a light tan foam that was crystallized from ethyl acetate/diethyl
ether to afford the title compound (0.485 g, 71%) as light orange needles.
MS [(+)ESI, m/z]: 457 [M+H]+
MS [(-)ESI, m/z]: 455 [M-HT
HRMS [(+)ESI, m/z]: 457.14179 [M+H]\ Calcd for CMHHCIN: 457.14313
EXAMPLE 92
N-(PYRIDIN-3-YLMETHYL)-10-[3-(TRIFLUOROMETHYL)BENZOYL]-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
108

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 3-(trifluoromethyl)benzoyl chloride.
Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a tan foam that was crystallized from dichloromethane/diethyl
ether to afford the title compound (0.375 g, 51%) as a white solid.
MS [(+)ESI, m/z]: 491 [M+H]+
MS [(-)ESI, m/z]: 489 [M-HT
HRMS [(+)ESI, m/z]: 491.16856 [M+H]+. Calcd for CHaFsN: 491.16949
Anal. Calcd forC27H21F3N402: C, 66.12; H, 4.32; N, 11.42. Found: C, 66.23; H, 4.40;
N, 11.46.
EXAMPLE 93
10-(4-FLUOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-fluorobenzoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a yellow syrup that was crystallized from dichloromethane/diethyl ether/hexane
to afford the title compound (0.330 g, 80%) as a cream solid, m.p. 171-173 °C.
MS[(+)ESI,m/z]:441 [M+Hf
MS [(-)ESI, m/z]: 439 [M-HF
HRMS [(+)ESI, m/z]: 441.17104 [M+H]+. Calcd for C2SH22FN402: 441.17268
EXAMPLE 94
10-(2-METHYLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with o-toluoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a tan foam that was crystallized from diethyl ether to afford the title compound
(0.258 g, 39%) as a pale yellow solid.
MS [(+)ESI, m/z]: 437 [M+H]+
HRMS [(+)ESI, m/z]: 437.19625 [M+H]+. Calcd for C27H25N402: 437.19775
EXAMPLE 95
109

WO 2006/135687

PCT/US2006/022326

10-(3,5-DIFLUOROBENZOYL)-N-{PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 3,5-difluorobenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a colorless syrup that was crystallized from
dichloromethane/diethyl ether/hexane to afford the title compound (280 mg, 65%) as
a white solid, m.p. 138 -140 °C.
MS [(+)ESI, m/z]: 459 [M+H]+
MS [(-)ESI, m/z]: 457 [M-Hp
HRMS [(+)ESI, m/z]: 459.16185 [M+H]+. Calcd for C26H2iF2N402: 459.16326
EXAMPLE 96
10-(1,3-BENZODIOXOL-5-YLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with benzo[1,3]dioxo!e-5-carbonyl chloride.
Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a colorless syrup that was crystallized from diethyl ether to
afford the title compound (0.390 g, 89%) as a white crystalline solid, m.p. 169-171
°C.
MS [(+)ESI, m/z]: 467 [M+H]+
Anal. Calcd for C27H22N4O4: C, 69.52; H, 4.75; N, 12.01. Found: C, 69.25; H, 4.72; N,
11.76.
EXAMPLE 97
10-(2-FLUOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 2-fluorobenzoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a yellow syrup that was crystallized from diethyl ether/hexane to afford the title
compound (0.280 g, 67%) as a white solid, m.p. 142 -143 °C.
MS [(+)ESI, m/z]: 441 [M+H]+
110

WO 2006/135687

PCT/US2006/022326

Anal. Calcd for C26H2iFN402: C, 70.90; H, 4.81; N, 12.72. Found: C, 70.66; H, 4.76;
N, 12.57.
EXAMPLE 98
10-(4-PROPYLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-propylbenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a yellow syrup that was crystallized from diethyl ether to afford
the title compound (0.343 g, 78%) as a white solid.
MS[(+)ESI,m/z]:465[M+Hf -
HRMS [(+)ESI, m/z]: 465.22876 [M+Hf. Calcd for C29H29N402: 465.22905
EXAMPLE 99
10-(4-NITROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-nitrobenzoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a yellow syrup that was crystallized from diethyl ether to afford the title
compound (0.292 g, 66%) as a yellow solid.
MS [(+)ESI, m/z]: 468 [M+H]+
MS [(-)ESI, m/z]: 466 [M-H]"
HRMS [(+)ESl, m/z]: 468.16613 [M+H]+. Calcd for CaN-A,: 468.16718
EXAMPLE 100
10-(3,4-DIFLUOROBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 3,4-difluorobenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a yellow syrup that was crystallized from diethyl ether to afford
the title compound (0.190 g, 44%) as a pale yellow solid.
MS [(+)ESI, m/z]: 459 [M+H]+
HRMS [(+)ESI, m/z]: 459.16255 [M+H]+. Calcd for C26H21F2N40:459.16326
111

WO 2006/135687

PCT/US2006/022326

Anal. Calcd for C26H2oF2N402: C, 68.12; H, 4.40; N, 12.22. Found: C, 67.82; H, 4.57;
N, 11.95.
EXAMPLE 101
10-(4-PHENOXYBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPlNE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-phenoxybenzoyl chloride. Purification by
flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a white foam that was crystallized from diethyl ether to afford
the title compound (0.307 g, 63%) as a white solid.
MS[(+)ESI,m/z]:515[M+H]+
HRMS t(+)ESI, m/z]: 515.20868 [M+H]+. Calcd for C32H27N403: 515.20832
Anal. Calcd for C32H26N403: C, 74.69; H, 5.09; N, 10.89. Found: C, 74.38; H, 5.05; N,
10.70.
EXAMPLE 102
10-[4-(DIETHYLAMINO)BENZOYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 76,
Step D, replacing benzoyl chloride with 4-diethylaminobenzoyl chloride. Purification
by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a white foam that was crystallized from diethyl ether to afford
the title compound (0.254 g, 55%) as a white solid.
MS [(+)ESI, m/z]: 494 [M+Hf
HRMS [(+)ESI, m/z]: 494.25473 [M+H]+. Calcd for C3oH32N502: 494.25560
EXAMPLE 103
TERT-BUTYL(4-{[3-{[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYL}-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEP1N-10(11H)-
YL]CARBONYL}BENZYL)CARBAMATE
Step A. 4-{[(te/t-Butoxycarbonyl)amino]methyl}benzoic acid
To a solution of 4-(aminomethyl)benzoic acid (5.00 g, 0.0331 mol) in dioxane (60
mL), water (30 mL), and 1 M sodium hydroxide (34 mL, 0.034 mol) at 0 °C was
added di-tert-butylpyrocarbonate (7.94 g, 0.0364 mol) and the reaction mixture stirred
at 0 °C for 1 hour. The reaction mixture was concentrated in vacuo to 30 mL, ethyl
112

WO 2006/135687

PCT/US2006/022326

acetate (80 mL) added and the mixture acidified to pH 4 by the addition of 1 M
aqueous potassium hydrogen sulfate solution with vigorous stirring. The organic
phase was separated, washed with water (80. mL), dried over anhydrous sodium
sulfate, and concentrated in vacuo to afford a white solid. Recrystallization from ethyl
acetate (60 mL) gave the title compound (3.94 g, 47%) as a white crystalline solid,
m.p. 165 °C.
MS [(-)ESI, m/z]: 250 [M-HT
Anal. Calcd for C13H17N04: C, 62.14; H, 6.82; N, 5.57. Found: C, 61.74; H, 6.51; N,
5.42.
Step B. tert-Butyl (4-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolot2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}benzyl)carbamate
To a suspension of 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid of Step A
(3.55 g, 0.0141 mmol) in dry dichloromethane (40 mL) at room temperature under
nitrogen was added dry N,N-dimethylformamide (2 drops, cat.) followed by a 2.0 M
solution of oxalyl chloride in dichloromethane (14.1 mL, 0.0283 mol) and the reaction
mixture stirred at room temperature for 4.5 hours. The reaction mixture was then
concentrated in vacuo to afford (4-chlorocarbonyl-benzyl)carbamic acid tert-butyl
ester as a white solid. The crude acid chloride was dissolved in dry tetrahydrofuran
(20 mL), added to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-.
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (3 g, 9.42
mmol), and N,N-diisopropylethylamine (4.92 mL, 28.27 mmol) in dry tetrahydrofuran
(20 mL), and the reaction mixture stirred at room temperature for 19 hours. The
reaction was quenched by the addition of 2 M sodium hydroxide (20 mL) and then
partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL).
The separated organic phase was washed with 2 M sodium hydroxide (200 mL),
water (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated
in vacuo to afford an orange solid (3.95 g). Purification by flash chromatography
using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless
glass that was recrystallized from ethyl acetate/hexane to afford the title compound
(1.29 g, 25%) as a cream crystalline solid, m.p. 171 °C.
MS [(+)ESI, m/z]: 552 [M+H]+
HRMS [(+)ESI, m/z]: 552.26037 [M+H]+. Calcd for C32H34N5O4: 552.26108
EXAMPLE 104
113

WO 2006/135687

PCT/US2006/022326

10-(3-METHYL-4-THlEN-2-YLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
A mixture of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74 (0.300 g, 0.53
mmol), 2-thiopheneboronic acid (0.102 g, 0.80 mmol) and potassium carbonate
(0.221 g, 1.60 mmol) in dimethoxyethane : water (8 mL: 2 mL) was purged with
nitrogen for 10 minutes. [1,1'-bis(Diphenylphosphino)ferrocene] dichloropalladium [II]
(0.022 g, 0.0266 mmol) was then added and the reaction mixture heated to 90 °C for
4 hours. The cooled reaction mixture was partitioned between ethyl acetate (100
mL) and 1 M sodium hydroxide (100 mL). The organic phase was separated,
washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium
sulfate, and concentrated in vacuo to give a brown syrup (0.34 g). Purification by
flash chromatography using 280 : 8:1 dichloromethane: ethanol: aqueous
ammonia as solvent gave an orange foam that was crystallized from diethyl
ether/hexane to afford the title compound (0.168 g, 61%) as a tan solid.
MS[(+)ESI,m/z]:519[M+H]+
MS[(-)ESI,m/z]:517[M-HT
EXAMPLE 105
N-(PYRIDIN-3-YLMETHYL)-10-(4-PYRIMIDIN-2-YLBENZOYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPIIME-3-CARBOXAMIDE
Step A. 4-Pyrimidin-2-ylbenzoic acid
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 2-
bromopyrimidine (0.630 g, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M
aqueous sodium carbonate (20 mL) and the mixture was purged with nitrogen for 10
minutes. Tetrakis(triphenylphosphine) palladium(O) (240 mg) was then added and
the reaction mixture heated to 90 °C for 17 hours. The hot reaction mixture was
filtered through celite and concentrated in vacuo to remove the acetonitrile. The
resulting aqueous suspension was washed with dichloromethane (2 x 30 mL) and
then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting
white suspension was diluted with water (20 mL), filtered and the solid product dried
in vacuo at 50 °C overnight to give the title compound (0.709 g, 89%) as a white
solid, m.p. 237 °C.
MS [(+)ESI, m/z]: 201 [M+H]+
114

WO 2006/135687

PCT/US2006/022326

MS[(-)ESI,m/z]:199[M-H]-
Anal. Calcd for CHBN202: C, 66.00; H, 4.03; N, 13.99. Found: C, 65.72; H, 3.87; N,
14.01.
Step B. N-(Pyridin-3-ylmethyl)-10-(4-pyrimidin-2-ylbenzoyl)-10,11-dihydro-5W-
pyrro!oI2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of 4-pyrimidin-2-ylbenzoic acid of Step A (0.283 g, 1.41 mmol) in dry
tetrahydrofuran (20 ml_) at room temperature under nitrogen was added N,N-
dimethylformamide (1 drop, cat) followed by a 2.0 M solution of oxalyl chloride in
dichloromethane (1.41 mmol, 2.82 mmol) and the reaction mixture was stirred at
room temperature for 3 hours. The mixture was then concentrated in vacuo to afford
4-pyrimidin-2-yl-benzoyl chloride as a yellow syrup. The crude acid chloride was
dissolved in dry tetrahydrof-uran (5 ml_), added to a suspension of N-(pyridin-3-
ylmethyl)-10,11-dihydro-5Hpyrrolo[2,1-c][1,4] benzodiazepine-3-carboxamide of
Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.49 mL,
2.83 mmol) in dry tetrahydrofuran (5 mL), and the reaction mixture stirred at room
temperature under nitrogen for 20 hours. The reaction was then quenched by the
addition of 2 M sodium hydroxide (10 mL) and the mixture partitioned between ethyl
acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was
separated, washed with 2 M sodium hydroxide (2 x 50 mL), water (50 mL) and brine
(50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo
to afford a yellow foam. Purification by flash chromatography using a solvent
gradient of 1 to 5% methanol in dichloromethane gave an cream foam that was
crystallized from diethyl ether/hexane to afford the title compound (0.395 g, 84%) as
white solid, m.p. 234 - 236 °C.
MS [(+)ESI, m/z]: 501 [M+H]+
Anal. Calcd for C30H24N6O2: C, 71.99; H, 4.83; N, 16.79. Found: C, 71.65; H, 4.91; N,
16.56.
EXAMPLE 106
N-(PYRIDIN-3-YLMETHYL)-10-(4-PYRIMIDIN-5-YLBENZOYL)-10,11-DlHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 4-Pyrimidin-5-ylbenzoic acid
115

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 105,
Step A, replacing 2-bromopyrimidine with 5-bromopyrimidine to give the title
compound (0.687 g, 86%) as a white solid, m.p. > 275 °C.
MS[(-)ESI, m/z]:199[M-H]'
Step B. N-(Pyridin-3-ylmethyl)-10-(4-pyrimidin-5-ylbenzoyl)-10,11 -dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-pyrimidin-5-ylbenzoic acid of
Step A. Purification by flash chromatography using a solvent gradient of 0 to 4%
methanol in dichloromethane gave a white foam that was crystallized from
dichloromethane/diethyl ether to afford the title compound (0.318 g, 67%) as a white
solid, m.p. 172-175 °C.
MS [(+)ESI, m/z]: 501 [M+Hf
MS [(-)ESI, m/z]: 499 [M-H]"
Anal. Calcd for C3oH24N602: C, 71.99; H, 4.83; N, 16.79. Found: C, 71.68; H, 4.85; N,
16.72.
EXAMPLE 107
10-(4-PYRIDIN-2-YLBENZOYL)-A/-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 4-Pyridin-2-ylbenzoic acid
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 2-
bromopyridine (0.38 mL, 3.98 mmol) in dry acetonitrile (20 ml_) was added 0.4 M
aqueous sodium carbonate (20 mL) and mixture purged with nitrogen for 10 minutes.
Tetrakis(triphenylphosphine) palladium(O) (0.240 g) was then added and the reaction
mixture heated to 90 °C for 20 hours. The hot mixture was filtered through celite and
concentrated in vacuo to remove acetonitrile. The resulting aqueous suspension was
diluted with water (20 mL), washed with dichloromethane (2 x 40 mL), and then
acidified to pH 6 by the addition of concentrated hydrochloric acid. The resulting
white suspension was diluted with water (20 mL), filtered and the solid product dried
in vacuo at 50 °C overnight to give the title compound (0.662 g, 84%) as a white
solid, m.p. 232-234 °C.
MS [(+)ESI, m/z]: 200 [M+H]+
MS [(-)ESI, m/z]: 198 [M-KT
116

WO 2006/135687

PCT/US2006/022326

Anal. Calcd for C12H9N02: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.04; H, 4.38; N,
6.89.
Step B. 10-(4-Pyridin-2-ylbenzoyl)-/V-(pyridin-3-ylmethyl)-10,11-dihydro-5W-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-pyridin-2-ylbenzoic acid of Step
A. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol
in dichloromethane gave a colorless syrup that was crystallized from
dichloromethane/diethyl ether/hexane to afford the title compound (0.323 g, 69%) as
a white solid, m.p. 159 -161 °C.
MS [(+)ESI, m/z]: 500 [M+H]+
HRMS t(+)ESI, m/z]: 500.20754 [M+H]+. Calcd forCaNsOz: 500.20810
EXAMPLE 108
10-(4-PYRlDIN-3-YLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 4-Pyridin-3-ylbenzoic acid
The title compound was prepared in essentially the same manner as Example 107,
Step A, replacing 2-bromopyridine with 3-bromopyridine to give the title compound
(0.648 g, 82%) as a white solid, m.p. > 275 °C.
MS [(+)ESl, m/z]: 200 [M+H]+
MS[(-)ESI, m/z]:198[M-H]-
Step B. 10-(4-Pyridin-3-ylbenzoyl)-/V-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-pyridin-3-ylbenzoic acid of Step
A. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol
in dichloromethane gave a colorless syrup that was crystallized from
dichloromethane/diethyl ether/hexane to afford the title compound (0.282 g, 60%) as
a white solid, m.p. 120 -125 °C.
MS [(+)ESI, m/z]: 500 [M+H]+
MS [(-)ESI, m/z]: 498 [M-HT
HRMS [(+)ESI, m/z]: 500.20748 [M+H]+. Calcd for C31H26N502: 500.20810
117

WO 2006/135687

PCT/US2006/022326

EXAMPLE 109
10-[4-(3-METHYLPYRIDIN-2-YL)BENZOYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 4-(3-Methylpyridin-2-yl)benzoic acid
The title compound was prepared in essentially the same manner as Example 107,
Step A, replacing 2-bromopyridine with 2-bromo-3-methylpyridine to give the title
compound (0.556 g, 41%) as a white solid, m.p. 178 °C.
MS [(+)ESI, m/z]: 214[M+H]+
MS [(-)ESI, m/z]: 212 [M-H]"
StepB. 10-[4-{3-Methylpyridin-2-yl)benzoyl]-A/-(pyridin-3-ylmethyl)-10,11-dihydro-
5/-/-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-(3-methylpyridin-2-yl)benzoic
acid of Step A. Purification by flash chromatography using a solvent gradient of 1 to
5% methanol in dichloromethane gave a colorless syrup that was crystallized from
dichloromethane/hexane to afford the title compound (0.348 g, 72%) as a white solid,
m.p. 150-151 °C.
MS [(+)ESI, m/z]: 514 [M+Hf
HRMS [(+)ESI, m/z]: 514.22362 [M+Hf. Calcd for CazHzsNsOz: 514.22375
EXAMPLE 110
10-(4-PYRIDIN-4-YLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DlHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. Sodium 4-pyridin-4-yl-benzoate
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 4-
bromopyridine hydrochloride (0.770 g, 3.98 mmol) in dry acetonitrile (20 mL) was
added 0.4 M aqueous sodium carbonate (20 mL) and the mixture was purged with
nitrogen for 10 minutes. Tetrakis(triphenylphosphine) palladium(O) (0.240 g) was
then added and the reaction mixture heated to 90 °C for 22 hours. The precipitated
sodium salt was filtered, washed with acetonitrile and then dried in vacuo at 50 °C
overnight to give the title compound (0.162 g, 18%) as a grey solid.
MS [(+)ESI, m/z]: 200 [M+2H-Na]+
MS [(-)ESI, m/z]: 198 [M-NaT
118

WO 2006/135687

PCT/US2006/022326

Step B. 10-(4-Pyridin-4-ylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with sodium 4-pyridin-4-y!-benzoate of
Step A. Purification by flash chromatography using a solvent gradient of 1 to 5%
methanol in dichloromethane gave a colorless glass that was crystallized from
dichloromethane/hexane to afford the title compound (0.055 g, 27%) as a white solid,
m.p. 119-124 °C.
MS [(+)ESI, m/z]: 500 [M+H]+
MS [(-)ESl, m/z]: 498 [M-HT
HRMS [(+)ESI, m/z]: 500.20788 [M+H]+. Calcd forC31H26N502: 500.20810
EXAMPLE 111
N-(PYRIDIN-3-YLMETHYL)-10-[4-(1,3-THIAZOL-2-YL)BENZOYL]-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 4-(1,3-Thiazol-2-yl)benzoic acid
The title compound was prepared in essentially the same manner as Example 107,
Step A, replacing 2-bromopyridine with 2-bromothiazole to give the title compound
(0.674 g, 83%) as a white solid, m.p. 235 -237 °C.
MS [(+)ESI, m/z]: 206 [M+H]+
MS [(-)ESI, m/z]: 204 [M-H]'
StepB. NPyridin-S-ylmethyO-IO-I.S-thiazol-yObenzoylJ-IO.H-dihydro-SH-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-(1,3-thiazol-2-yl)benzoic acid of
Step A. Purification by flash chromatography using a solvent gradient of 1 to 5%
methanol in dichloromethane gave a yellow glass that was recrystallized from diethyl
ether/hexane to afford the title compound (0.449 g, 94%) as a cream solid, m.p. 178 -
179 °C.
MS [(+)ESl, m/z]: 506 [M+H]+
Anal. Calcd for C29H23N502S: C, 68.89; H, 4.59; N, 13.85. Found: C, 68.89; H, 4.51;
N, 13.75.
EXAMPLE 112
119

WO 2006/135687

PCT/US2006/022326

10-[4-(1H-PYRAZOL-1-YL)BENZOYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. Methyl 4-(1 H-pyrazol-1 -yl)benzoate
A mixture of methyl 4-fluorobenzoate (2 g, 0.0130 mol), pyrazole (1.33 g, 0.0195
mmol) and potassium carbonate (3.59 g, 0.0260 mol) in dry 1-methyl-1-pyrrolidinone
(20 mL) was heated to 130 °C for 44 hours. The cooled reaction mixture was then
partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL).
The organic phase was separated, washed with 2 M sodium hydroxide (200 mL), 2 M
hydrochloric acid (2 x 200 mL), water (200 mL), and brine (200 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to afford a white solid
(0.71 g). Recrystallization from hexane (40 mL) gave the title compound (0.533 g,
20%) as a white crystalline solid, m.p. 115 °C.
MS [(+)ESI, m/z]: 203 [M+H]+
Anal. Calcd for CnHnMCfe: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.28; H, 4.99; N,
13.61.
Step B. 4-Pyrazol-1-yl-benzoic acid
To a solution of methyl 4-(1H-pyrazol-1-yl)benzoate of Step A (0.529 g, 2.62. mmol) in
methanol (20 mL) and water (4 mL) was added lithium hydroxide monohydrate
(0.220 g, 5.23 mmol) and the reaction mixture heated to reflux for 2 hours. The
cooled reaction mixture was concentrated in vacuo to remove methanol and then
diluted with water (40 mL). The resulting aqueous solution was washed with diethyl
ether (40 mL), then acidified to pH 3 by the addition of concentrated hydrochloric
acid. The solid product was filtered and dried in vacuo at 50 °C overnight to afford
the title compound (0.479 g, 97%) as a white solid, m.p. 270-272 °C.
MS [(+)ESI, m/z]: 189[M+H]+
MS [(-)ESI, m/z]: 187[M-HT
Anal. Calcd for C10H8N2O2: C, 63.83; H, 4.28; N, 14.89. Found: C, 63.56; H, 4.23; N,
14.89.
Step C. 10-[4-(1 H-Pyrazol-1 -yl)benzoyl]-/V-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
pyrrolo[2„1 -c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-pyrazol-1-yl-benzoic acid of
Step B. Purification by flash chromatography using a solvent gradient of 1 to 5%
120

WO 2006/135687

PCT/US2006/022326

methanol in dichloromethane gave a yellow syrup that was crystallized from
dichloromethane/ hexane to afford the title compound (0.372 g, 81%) as a white
solid, m.p. 107 °C (shrinking).
MS [(+)ESI, m/z]: 489 [M+H]+
MS [(-)ESI, m/z]: 487 [M-H]"
HRMS [(+)ESI, m/z]: 489.20286 [M+H]+. Calcd for C29H25N602: 489.20335
EXAMPLE 113
10-(4-PIPERIDIN-1-YLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 4-Piperidin-1-ylbenzonitrile
A mixture of 4-fluorobenzonitrile (1 g, 8.26 mmol), piperidine (0.90 ml_, 9.08 mmol)
and potassium carbonate (2.28 g, 16.51 mmol) in dry 1-methyl-2-pyrrolidinone (10
ml_) was stirred at 120 CC under nitrogen for 20 hours. The cooled reaction mixture
was then diluted with water (100 ml_) and extracted with ethyl acetate (100 ml_). The
organic extract was washed with water (100 ml_) and brine (100 mL), dried over
anhydrous magnesium sulfate, and concentrated in vacuo to afford an orange oil.
Purification by flash chromatography using a solvent gradient of 1 to 7% ethyl acetate
in hexane gave an orange oil that was crystallized from hexane to afford the title
compound (1.41 g, 92%) as an orange crystalline solid, m.p. 54 °C.
MS [(+)ESI, m/z]: 187[M+H]+
Anal. Calcd for C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.30; H, 7.41; N,
15.06.
Step B. 4-Piperidin-1-yl-benzoic acid
A suspension of 4-piperidin-1-ylbenzonitrile of Step A (1.13 g, 6.07 mmol) in acetic
acid (30 mL) and concentrated hydrochloric acid (30 mL) was stirred at 100 °C for 18
hours. The cooled reaction mixture was then poured over crushed ice, the pH
adjusted to 3 by the addition of 2 M sodium hydroxide, and the resulting suspension
allowed to stand overnight. The solid product was filtered and dried at 50 °C in
vacuo overnight to afford the title compound (1.09 g, 88%) as a white solid, m.p. 225-
230 °C (dec).
MS [(+)ESI, m/z]: 206 [M+Hf
Anal. Calcd for C12H15N02: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.06; H, 7.34; N,
6.69.
121

WO 2006/135687

PCT/US2006/022326

Step C. 10-(4-Piperidin-1-ylbenzoyl)-/\/-(pyridin-3-ylmethyl)-10l11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared in essentially the same manner as Example 105,
Step B, replacing 4-pyrimidin-2-ylbenzoic acid with 4-piperidin-1-yl-benzoic acid of
Step B. Purification by flash chromatography using a solvent gradient of 1 to 5%
methanol in dichloromethane gave a cream solid that was recrystallized from
dichloromethane/ hexane to afford the title compound (0.322 g, 68%) as off-white
crystals, m.p. 196 -197 °C (dec).
HRMS [(+)ESI, m/z]: 506.25531 [M+H]+. Calcd for C3iH32N502: 506.25505
EXAMPLE 114
10-[3-(AMINOSULFONYL)-4-MORPHOLIN-4-YLBENZOYL]-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE HEMIHYDRATE
Step A. 2-Ch!oro-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
ylcarbony!)benzenesulfonamide
A solution containing1.02 g (0.004 mol) of 4-chloro-3-sulfamoy!benzoyl chloride,
0.74 g (0.004 mol) of 10,11-dihydro-5H-pyrolo[2,1-c][1 benzodiazepine and 0.48 g
(0.004 mol) of N,N-dimethylaniline in 50 ml of 1,4-dioxane was allowed to stand at
room temperature for 2 hours. The reaction mixture was then poured into 500 mL of
water with stirring. The precipitate was collected, washed and dried to provide the
title compound (0.7 g), m.p. 137 °C dec.
MS [(+)ESI, m/z]: 402 [M+H]+.
MS [(-)ESI, m/z]: 400 [M-HT
StepB. 2-Morpholin-4-yl-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
ylcarbonyl)benzenesulfonamide
A solution of 1 g of 2-chloro-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
ylcarbonyl)benzenesulfonamide of Step A in 20 mL of morpholine was heated for 20
hours under reflux. The reaction solution was allowed to cool to room temperature
and poured into 50 mL of water with stirring. The precipitate was collected and
washed with an additional 50 mL of water and dried to provide the title compound (
0.8 g), m.p. 242-245 °C dec
MS [(+)ESI, m/z]: 453 [M+H]+
MS [(-)ESI, m/z]: 451 [M-HT
122

WO 2006/135687

PCT/US2006/022326

Anal. Calcd for C23H24N4O4S • 0.30 H20: C 60.33, H 5.41, N 12.23. Found: C 59.92,
H 5.14, N, 12.05.
Step C. 2-Morpholin-4-yl-5-{[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4] benzodiazepin-
10(11 H)-yl]carbonyl}benzenesulfonamide
A solution containing 0.77 g (0.0017 mol) of 2-morpholin-4-yl-5-(5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-ylcarbonyl)benzenesulfonamide of Step B and 0.62 g
(0.0034 mol) of trichloroacetyl chloride in 50 ml_ of 1,4-dioxane was heated under
reflux for 3 hrours. The solution was allowed to cool to room temperature and then
poured into 750 mL of water with stirring. The solid was collected, washed and dries
to provide the title compound (0.88 g), m.p. 165-167 °C dec .
MS K+)ESI, m/z]: 597 [M+Hf
MS [(-)ESI, m/z]: 595 [M-HT
Anal. Calcd for CasHzaCOgS : C 50.22, H 3.88, N 9.37. Found: C 49.88, H
3.84, N 9.12.
Step D. 10-[3-(Aminosulfonyl)-4-morpholin-4-ylbenzoyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamidehemihydrate
A solution containing 0.83 g (0.0014 mol) of 2-morpholin-4-yl-5-{[3-(trichloroacetyl)-
5H-pyrrolo[2,1-c][1,4] benzodiazepin-10(11H)-yl]carbonyl}benzenesulfonamide of
Step C and 0.30 g (0.0028 mol) of 3- aminomethylpyridine in 25 mL of 1,4-dioxane
was stirred under reflux overnight. The reaction mixture was allowed to cool to room
temperature and poured into 200 mL of water. The beige solid that precipitated was
collected and washed with water to provide the title compound (0.35 g), m.p. 159-161
°C
MS [(+)ESI, m/z]: 587 [M+H]+.
MS [(-)ESI, m/z]: 585 [M-HT
Anal. Calcd for C3oH30N605S-0.5 H20:C 60.49, H 5.25, N 14.11. Found: C 60.21,
H 5.48, N 13.92.
EXAMPLE 115
N-(PYRIDIN-3-YLMETHYL)-10-(THIEN-2-YLCARBONYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.478 g, 1.5 mmol),
and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) in dry tetrahydrofuran (15 mL)
123

WO 2006/135687

PCT7US2006/022326

was added dropwise 2-(thiophene)carbonyl chloride (0.24 ml_, 2.2 mmol) and the
reaction mixture stirred at room temperature under nitrogen for 21 hours. The
reaction was then quenched by the addition of 2 M sodium hydroxide (10 mL) and
the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50
mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL),
water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford a tan solid. The crude product was recrystallized
from ethanol to give the title compound (0.250 g, 39%) as rust colored prisms.
MS [(+)ESI, m/z]: 429 [M+H]+
HRMS [(+)ESI, m/z]: 429.13738 [M+H]+. Calcd forC24H2iN402S: 429.13797
EXAMPLE 116
10-(PYRIDIN-2-YLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 115,
replacing 2-(thiophene)carbonyl chloride with picolinoylchloride hydrochloride.
Recrystallization from ethanol/ethyl acetate gave the title compound (0.409 g, 64%)
as brown needles.
MS [(+)ESI, m/z]: 424 [M+H]+
HRMS [(+)ESl, m/z]: 424.17653 [M+Hf. Calcd for C25H22N502: 424.17680
• EXAMPLE 117
10-[(6-CHLOROPYRIDIN-3-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 115,
replacing 2-(thiophene)carbonyl chloride with 6-chloronicotinoyl chloride.
Recrystallization from dichloromethane gave the title compound (0.871 g, 61%) as a
cream solid.
MS [(+)ESI, m/z]: 458 [M+H]+
HRMS [(+)ESI, m/z]: 458.13754 [M+H]+. Calcd for C25H21CIN502: 458.13783
EXAMPLE 118
10-[(2,5-DICHLOROTHIEN-3-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 115,
replacing 2-(thiophene)carbonyl chloride with 2,5-dichlorothiophene-3-carbonyl
124

WO 2006/135687

PCT/US2006/022326

chloride. Purification by flash chromatography using a solvent gradient of 0 to 4%
methanol in dichloromethane gave a tan foam that was triturated with diethyl ether to
afford the title compound (0.483 g, 77%) as a white solid.
MS [<+)ESI, m/z]: 497 [M+H]+
HRMS [(+)ESI, m/z]: 497.05937 [M+H]+. Calcd for CzgCfeNS: 497.06003
EXAMPLE 119
10-{[6-(BEN2YLAMINO)PYRIDIN-3-YL]CARBONYL}-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
A mixture of 10-[(6-chloropyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 117 (0.100 g,
0.219 mmol) and benzylamine (0.12 mL, 1.094 mmol) was heated to 100 °C in a
sealed tube for 17 hours. The cooled reaction mixture was then diluted with
dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate
solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated in
vacuo to afford a yellow semi-solid. Purification by flash chromatography using a
solvent gradient of 1 to 5% methanol in dichloromethane gave a white solid that was
triturated with diethyl ether to afford the title compound (0.054 g, 47%) as a white
solid.
MS [(+)ESI, m/z]: 529 [M+H]+
HRMS [(+)ESI, m/z]: 529.23385 [M+H]+. Calcd for C32H29N602: 529.23465
EXAMPLE 120
10-({6-[(2-METHOXYBENZYL)AMINO]PYRIDlN-3-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with 2-methoxybenzylamine. Purification by flash
chromatography using a solvent gradient of 1 to 7% methanol in dichloromethane
gave a white foam that was triturated with diethyl ether to afford the title compound
(0.071 g, 58%) as a white solid.
MS [(+)ESI, m/z]: 559[M+H]+
HRMS [(+)ESI, m/z]: 559.24504 [M+H]+. Calcd forCsaHaiNsOa: 559.24522
Anal. Calcd for C33H3oN603: C, 70.95; H, 5.41; N, 15.04. Found: C, 70.61; H, 5.36; N,
14.93.
125

WO 2006/135687

PCT/US2006/022326

EXAMPLE 121
10-lSONICOTINOYL-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPlNE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 115,
replacing 2-(thiophene)carbonyl chloride with isonicotinoyl chloride hydrochloride.
Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in
dichloromethane gave a yellow oil that was triturated with diethyl ether to afford the
title compound (0.193 g, 49%) as a cream solid.
MS [(+)ESI, m/z]: 424 [M+H]+
MS [(-)ESI, m/z]: 422 [M-HV
HRMS [(+)ESI, m/z]: 424.17682 [M+H]+. Calcd for C25H22N502:424.17680
EXAMPLE 122
10-({6-[(4-METHOXYBENZYL)AMlNO]PYRIDIN-3-YL}CARBONYL)-N-(PYRlDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with 4-methoxybenzylamine. Purification by flash
chromatography using a solvent gradient of 1 to 8% methanol in dichloromethane
gave a yellow oil that was triturated with diethyl ether to afford the title compound
(0.054 g, 44%) as a pale yellow solid.
MS [(+)ESI, m/z]: 559 [M+H]+
HRMS [(+)ESI, m/z]: 559.24438 [M+H]+. Calcd for C33H3iN603: 559.24522
EXAMPLE 123
10-(PYRAZIN-2-YLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 115,
replacing 2-(thiophene)carbonyl chloride with 2-pyrazinecarbonyl chloride.
Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in
dichloromethane gave a white foam that was triturated with diethyl ether to afford the
title compound (0.213 g, 53%) as a yellow solid.
MS [(+)ESI, m/z]: 425 [M+H]+
HRMS [(+)ESI,. m/z]: 425.17128 [M+Hf. Calcd for C24H2iN602:425.17205
126

WO 2006/135687

PCT/US2006/022326

Anal. Calcd for C24H2oN602: C, 67.91; H, 4.75; N, 19.80. Found: C, 67.62; H, 4.84; N,
19.48.
EXAMPLE 124
10-(PYRlDIN-3-YLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 115,
replacing 2-(thiophene)carbonyl chloride with nicotinoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a cream foam that was triturated with diethyl ether to afford the title compound
(0.211 g, 53%) as a yellow solid.
MS[(+)ESl,m/z]: 424 [M+H]+
MS [(-)ESI, m/z]: 422 [M-H]"
HRMS [(+)ESI, m/z]: 424.17615 [M+H]+. Calcd for C25H22N502: 424.17680
EXAMPLE 125
10-[(6-PIPERIDIN-1-YLPYRIDIN-3-YL)CARBONYL]-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with piperidine. Purification by flash chromatography using a
solvent gradient of 1 to 4% methanol in dichloromethane gave a yellow oil that was
triturated with diethyl ether to afford the title compound (0.076 g, 69%) as a white
solid.
MS [(+)ESI, m/z]: 507 [M+H]+
MS [(-)ESI, m/z]: 505 [M-HT
HRMS [(+)ESI, m/z]: 507.2506 [M+H]+. Calcd for C3oH3iN602: 507.25030
Anal. Calcd for C3oH3oN602: C, 71.13; H, 5.97; N, 16.59. Found: C, 70.79; H, 5.87; N,
16.30.
EXAMPLE 126
10-({6-[(2-PHENYLETHYL)AMINO]PYRIDIN-3-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPlNE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with phenethylamine. Purification by flash chromatography
using a solvent gradient of 0 to 4% methanol in dichloromethane gave a yellow oil
127

WO 2006/135687

PCT/US2006/022326

that was triturated with diethyl ether to afford the title compound (0.054 g, 46%) as a
white solid.
MS [(+)ESI, m/z]: 543 [M+Hf
HRMS [(+)ESI, m/z]: 543.25071 [M+H]+. Calcd for C33H31N602: 543.25030
EXAMPLE 127
10-({6-[(3-PHENYLPROPYL)AMINO]PYRIDIN-3-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with 3-phenyl-1 -propylamine. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a yellow foam that was triturated with diethyl ether to afford the title compound
(0.062 g, 51%) as a white solid.
MS [(+)ESI, m/z]: 557 [M+H]+
HRMS [(+)ESI, m/z]: 557.26568 [M+Hf. Calcd for C34H33N602 557.26595
Anal. Calcd for C34H32N6O2: C, 73.36; H, 5.79; N, 15.10. Found: C, 73.57; H, 5.76; N,
15.06.
EXAMPLE 128
10-{[6-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL]CARBONYL}-N-(PYRIDlN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119
replacing benzylamine with 1-methylpiperazine. Purification by flash chromatography
using a solvent gradient of 0 to 16% methanol in dichloromethane gave a clear oil
that was triturated with diethyl ether to afford the title compound (0.092 g, 81%) as a
white solid.
MS [(+)ESI, m/z]: 522 [M+H]+
HRMS [(+)ESI, m/z]: 522.26064 [M+H]+. Calcd for C3QH32N702: 522.26120
EXAMPLE 129
10-({6-t(3-METHOXYBENZYL)AMINO]PYRIDIN-3-YL}CARBONYL)-N-(PYRIDlN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
128

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with 3-methoxybenzylamine. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a clear oil that was triturated with diethyl ether to afford the title compound
(0.048 g, 39%) as a white solid.
MS [(+)ESI, m/z]: 559 [M+H]+
HRMS [(+)ESI, m/z]: 559.24487 [M+H]+. Calcd for C33H31N603: 559.24522
EXAMPLE 130
10-({6-[BENZYL(METHYL)AMINO]PYRlDIN-3-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with A/-benzylmethylamine. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a clear oil that was triturated with diethyl ether to afford the title compound
(0.090 g, 76%) as a white solid.
MS [(+)ESI, m/z]: 543 [M+H]+
HRMS [(+)ESI, m/z]: 543.24937 [M+H]+. Calcd for C33H31N602: 543.25030
EXAMPLE 131
N-(PYRIDIN-3-YLMETHYL)-10-({6-[(PYRIDIN-3-YLMETHYL)AMINO]PYRIDIN-3-
YL}CARBONYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODlAZEPINE-3-
CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with 3-(aminomethyl)pyridine. Purification by flash
chromatography using a solvent gradient of 0 to 16% methanol in dichloromethane
gave a clear oil that was triturated with diethyl ether to afford the title compound
(0.084 g, 73%) as a white solid.
MS [(+)ESI, m/z]: 530 [M+H]+
HRMS [(+)ESl, m/z]: 530.22996 [M+H]+. Calcd for C31H28N702: 530.22990
EXAMPLE 132
10-({6-t(2-HYDROXYETHYL)AMINO]PYRIDIN-3-YL}CARBONYL)-N-(PYRIDIN-3-
YLMETHYL)-10,11-DlHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-
CARBOXAMIDE
129

WO 2006/135687

PCT/US2006/022326

The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with ethanolamine. Recrystallization from diethyl ether gave
the title compound (0.067 g, 64%) as a white solid.
MS [(+)ESl, m/z]: 483 [M+Hf
HRMS: [(+)ESI, m/z]: 483.21328 [M+H]+. Calcd for C27H27N603 : 483.21391
EXAMPLE 133
10-{[6-(BUTYLAMINO)PYRlDIN-3-YL]CARBONYL}-N-(PYRIDIN-3-YLMETHYL)-
10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 119,
replacing benzylamine with butylamine. Purification by flash chromatography using a
solvent gradient of 0 to 4% methanol in dichloromethane gave a clear oil that was
triturated with diethyl ether to afford the title compound (0.032 g, 30%) as a white
solid.
MS [(+)ESI, m/z]: 495 [M+H]+
HRMS [(+)ESI, m/z]: 495.25015 [M+Hf. Calcd for C29H31N602: 495.25030
EXAMPLE 134
10-{[6-(BENZYLOXY)PYRIDIN-3-YL]CARBONYL}-N-(PYRIDIN-3-YLMETHYL)-
10,11-DlHYDRO-5H-PYRROLOt2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
To a solution of benzylalcohol (0.025 mL, 0.241 mmol) in dry tetrahydrofuran (5 mL)
at 0 °C under nitrogen was added a 1.0 M solution of sodium bis(trimethylsilyl)amide
in tetrahydrofuran (0.26 mL, 0.26 mmol) and the reaction mixture stirred at 0 °C for
20 minutes. A solution of 10-[(6-chloropyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)~
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 117
(0.100 g, 0.219 mmol) in dry tetrahydrofuran (5 mL) was added and the reaction
mixture was stirred at room temperature for 72 hours. The reaction was quenched by
the addition of saturated aqueous ammonium chloride solution (10 mL) and then
diluted with ethyl acetate (10 mL). The organic phase was separated, washed with
water (10 mL) and brine (10 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford a yellow oil. Purification by flash chromatography
using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam
that was triturated with diethyl ether to afford the title compound (0.034 g, 30%) as a
white solid.
130

WO 2006/135687

PCT7US2006/022326

MS [(+)ESI, m/z]: 530 [M+Hf
HRMS [(+)ESI, m/z]: 530.21883 {M+H]+. Calcd for C32H28N503: 530.21867
EXAMPLE 135
10-[(4-TERT-BUTYLPHENOXY)ACETYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIA2EPINE-3-CARBOXAMIDE
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol),
and N,N-diisopropylethylamine (0.26 ml_, 1.508 mmol) in dry tetrahydrofuran (10 ml_)
was added dropwise 4-tert-butylphenoxyacetyl chloride (0.32 g, 1.41 mmol) and the
reaction mixture was stirred at room temperature under nitrogen for 21 hours. The
reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the
mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50
mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL),
water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford a yellow foam. Purification by flash chromatography
using a solvent gradient of 0 to 4% methanol in dichloromethane gave a colorless
syrup that was triturated with diethyl ether to afford the title compound (0.280 g, 58%)
as a white solid, m.p. 85 °C.
MS I(+)ESI, m/z]: 509 [M+H]+
MS [(-)ESI, m/z]: 507 [M-HT
HRMS [(+)ESI, m/z]: 509.25353 [M+H]+. Calcd forC3iH33N403: 509.25472
EXAMPLE 136
10-(PHENOXYACETYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODlAZEPlNE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 135,
replacing 4-tert-butylphenoxyacetyl chloride with phenoxyacetyl chloride. Purification
by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a colorless syrup that was triturated with diethyl ether to afford
the title compound (0.280 g, 66%) as a white solid.
MS [(+)ESI, m/]: 453 [M+H]+
MS [(-)ESI, m/z]: 451 [M-H]"
HRMS [(+)ESI, m/z]: 453.19084 [M+H]+. Calcd for C27H2SN4O3: 453.19212
EXAMPLE 137
131

WO 2006/135687

PCT/US2006/022326

10-(2-PHENOXYPROPANOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 135,
replacing 4-ferf-butylphenoxyacetyl chloride with 2-phenoxypropionyl chloride.
Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in
dichloromethane gave a white foam that was triturated with diethyl ether to afford the
title compound (0.420 g, 96%) as a white solid, m.p. 83 °C.
MS [(+)ESI, m/z]: 465 [M-HT
HRMS [(+)ESI, m/z]: 467.20621 [M+H]+. Calcd for C28H27N403: 467,20777
EXAMPLE 138
10-[(4-CHLOROPHENOXY)ACETYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 10-[(4-Chlorophenoxy)acetyl]-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine
This compound was prepared from 10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine and 4-chlorophenoxyacetyl chloride in the same manner as
the preparation of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1 benzodiazepine of Example 139, Step B, m.p. 120-122 °C.
MS K+)ESI, m/z]: 353 [M+H]+
Anal. Calcd for C20H17CIN2O2: C, 68.09; H, 4.86; N, 7.94. Found: C, 67.82; H, 4.87;
N, 7.87
Step B. 2,2,2-Trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
The title compound was prepared from 10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A in the same manner as the
preparation of 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 139, Step C, m.p.
165-167 °C.
MS [(+)ESl, m/z]: 497 [M+Hf
Anal. Calcd for C22H16Cl4N203: C, 53.04; H, 3.24; N, 5.62. Found: C, 53.10; H, 3.39;
N, 5.36.
Step C. 10-[(4-Chlorophenoxy)acetyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
132

WO 2006/135687

PCT/US2006/022326

A solution of 2t2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step B (0.28 mmol), and 3-
aminomethylpyridine (0.59 mmol), in dimethylsulfoxide (1.5 mmol) and acetonitrile
(2.5 mL) was stirred at 80 GC for 18 hours. The solvent was evaporated and the
residue dissolved in dichloromethane, washed with water, dried over anhydrous
sodium sulfate, and evaporated. The material was purified by HPLC (Normal phase,
Luna CN bonded packing) and crystallized from ethyl acetate/hexane. (0.103g; 75%),
m.p. 169-171 °C.
MS [(+)ESI, m/z]: 487 [M+Hf
Anal. Calcd for C27H23CIN4O3: C, 66.60; H, 4.76; N, 11.51. Found: C, 66.66; H, 4.86;
N, 11.53.
EXAMPLE 139
10-[(4-CHLORO-2-METHYLPHENOXY)ACETYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-
DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
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 mmol) followed by one drop of
N,N-dimethylformamide. Bubbling began immediately. After 30 minutes the reaction
mixture was warmed in a 45 °C oil bath for 1.5 hours. The solution was cooled to
room temperature and all volatiles were removed by evaporation. Dry nitrogen gas
was introduced into the evaporator and more dry dichloromethane was added. 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-[(4-Chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine
To a solution of the acid chloride of Step B (17.4 mmol) in dichloromethane (25 mL)
was added a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1 benzodiazepine (17.4
mmol) and triethylamine (19.14 mmol) in dichloromethane (25 mL) in a rapid
dropwise fashion. The mixture was stirred for one hour at room temperature, then
washed with 0.1 N hydrochloric acid (2x) and water (1x), dried over anhydrous
sodium sulfate and evaporated. The product was isolated by crystallization from hot
ethyl acetate/t-butyl methyl ether (2/1), m.p. 166-167 X.
133

WO 2006/135687

PCT/US2006/022326

MS [(+)ESI, m/z]: 367 [M+H]+
Anal. Calcd forCziHCINzOz: C, 68.76; H, 5.22; N, 7.64. Found: C, 68.53; H, 5.18;
N.7.53.
Step C. 2,2,2-Trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepin-3-yl}ethanone
To a cold (0 °C) solution of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine (2.70 mmol) and triethylamine (0.76 mL) in
dichloromethane (15 mL) was added trichloroacetyl chloride (0.90 mL). This was
stirred and allowed to warm to room temperature overnight. The reaction mixture was
washed with water (2x), 0.1 N hydrochloric acid (2x), dilute aqueous sodium
bicarbonate (2x) and finally with water (1x). The organic phase was dried over
anhydrous sodium sulfate and evaporated. The product was purified by
crystallization from warm ethyl acetate/hexane (3/1), m.p. 156-158 °C.
MS [(+)ESI, m/z]: 511 [M+H]+
Anal. Calcd for C23H18CI4N203: C, 53.93; H, 3.54; N, 5.47. Found: C, 53.90; H, 3.45;
N, 5.40.
Step D. 10-[(4-Chloro-2-methylphenoxy)acetyl]-N-(pyridin-3-ylmethyl)-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-[(4-chloro-2-
methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-,
yl}ethanone of Step C (0.34 mmol), and 3-aminomethylpyridine (0.71 mmol), in a
manner similar to the synthesis of 10-[(4-chlorophenoxy)acetyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamideof
Example 179 (0.126 g; 74%),
m.p. 168 °C.
MS [(+)ESI, m/z]: 501 [M+H]+
Anal. Calcd for OsCIN: C, 67.13; H, 5.03; N, 11.18. Found: C, 66.79; H, 5.06;
N, 11.06.
EXAMPLE 140
10-([(4-BROMOPHENYL)THIO]ACETYL}-N-{[5-HYDROXY-4-(HYDROXYMETHYL)-
6-METHYLPYRlDlN-3-YL]METHYL}-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
134

WO 2006/135687

PCT/US2006/022326

Step A. 10-{[2-(4-Bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine
The title compound was synthesized from (4-bromo-phenylsu!fanyl)-acetic acid and
10,11-dihydro-5H-pyrrolo[2,1 -c][1 benzodiazepine in the manner of Example 1,
Step E.
Step B. 2,2,2-Trichloro-1-[10{[(4-bromophenyl) thio]acetyl}-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone
The title compound was synthesized from 10-{[2-(4-bromophenyl)thio]acetyl}-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A in the manner of Example 1,
Step F.
Step C. 10-{[(4-Bromophenyl)thio]acetyl}-N-{[5-hydroxy-4-(hydroxymethyl)-6-
methylpyridin-3-yl]methyl}-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{[(4-bromopheny!)
thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of
Step B and 3-aminotnethylpyridine in the manner of Example 1, m.p. 199-200 CC.
MS [(+)ESI, m/z]: 607 [M+H]+
EXAMPLE 141
10-{[(4-BROMOPHENYL)THIO]ACETYL}-N-(PYRIDIN-3-YLMETHYL)-10,11-
DlHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was synthesized from 2,2,2-trichloro-1-[10{[(4-bromophenyl)
thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of
Example 140, Step B, and pyridoxamine dihydrochloride hydrate in the manner of
Example 1,m.p. 136-7 °C.
MS [(+)ESI, m/z]: 547 [M+H]+
Anal. Calcd for C27H23BrN402S: C, 59.24; H, 4.23; N, 10.23. Found: C, 59.03; H,
4.28; N, 10.01.
EXAMPLE 142
10-[(4-CHLOROPHENYL)ACETYL]-N-(PYRIDIN-3-YLMETHYL)-10l11-DIHYDRO-
5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE .
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol),
135

WO 2006/135687

PCT/US2006/022326

and N.N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL)
was added 4-chlorophenylacetyl chloride (267 mg, 1.41 mmol) and the reaction
mixture stirred at room temperature under nitrogen for 21 hours. The reaction was
then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture
partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The
organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water
(50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo to afford a orange foam. Purification by flash chromatography
using a solvent gradient of 0 to 4% methanol in dichloromethane gave a yellow syrup
that was triturated with diethyl ether to afford the title compound 0.230 g, 52%) as a
yellow solid, m.p. 83 °C.
MS [(+)ESI, m/z]: 471 [M+Hf
MS [(-)ESI, m/]: 469 [M-H]"
HRMS [(+)ESI, m/z]: 471.15711 [M+Hf. Calcd for C27H24CIN4O2: 471.15823
EXAMPLE 143
10-(1,1'-BIPHENYL-4-YLACETYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 142,
replacing 4-chlorophenylacetyl chloride with biphenyl-4-ylacetyl chloride. Purification
by flash chromatography using a solvent gradient of 1 to 4% methanol in
dichloromethane gave a yellow syrup that was crystallized from diethyl ether to afford
the title compound (0.136 g, 28%) as a cream crystalline solid, m.p. 153 -155 °C.
MS [(+)ESl, m/z]: 513 [M+H]+
MS [(-)ESI, m/z]: 511 [M-HT
Anal. Calcd for Cgal-bCy. C, 77.32; H, 5.51; N, 10.93. Found: C, 77.07; H, 5.51; N,
10.69.
EXAMPLE 144
10-[(2E)-3-PHENYLPROP-2-ENOYL]-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1 -C][1,4]BENZODIAZEPlNE-3-CARBOXAMIDE
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol)
and N.N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL)
was added trans-cinnamoyl chloride (0.235 g, 1.41 mmol) and the reaction mixture
136

WO 2006/135687

PCT/US2006/022326

was stirred at room temperature under nitrogen for 21 hours. The reaction was then
quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned
between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic
phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL)
and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in
vacuo to afford a yellow foam. Purification by flash chromatography using a solvent
gradient of 1 to 4% methanol in dichloromethane gave a yellow syrup that was
crystallized from diethyl ether/ethyl acetate/hexane to afford the title compound
(0.360 g, 85%) as an off-white solid, m.p. 175 °C.
MS [(+)ESI, m/z]: 449 [M+Hf
Anal. Calcd for C28H24N402: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.76; H, 5.37; N,
12.33.
EXAMPLE 145
10-(1-NAPHTHOYL)-N-(PYRIDIN-3-YLMETHYL)-10;i1-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 144,
replacing trans-cinnamoyl chloride with 1-naphthoyl chloride. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave a yellow syrup that was crystallized from diethyl ether/hexane to afford the title
compound (0.410 g, 92%) as a white solid, m.p. 188 "C.
MS [(+)ESI, m/z]: 473 [M+H]+
HRMS [(+)ESI, m/z]: 473.19776 [M+H]+. Calcd for C3oH25N402:473.19720
EXAMPLE 146
10-(2-NAPHTHOYL)-N-(PYRlDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMlDE
The title compound was prepared in essentially the same manner as Example 144,
replacing trans-cinnamoyl chloride with 2-naphthoyl chloride. Purification by flash
chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane
gave a yellow syrup that was triturated with diethyl ether to afford the title compound
(0.223 g, 50%) as a white solid.
MS [(+)ESl, m/z]: 473 [M+H]+
HRMS [+}ESI, m/z]: 473.19659 [M+H]+. Calcd for C3oH25N402:473.19720
EXAMPLE 147
137

WO 2006/135687

PCT/US2006/022326

10-(9H-FLUOREN-2-YLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-
5H-PYRROLO[2,1-C]t1,4]BENZODIAZEPINE-3-CARBOXAMIDE
Step A. 10-(9H-Fluoren-2-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine
Asolution containing 1.84 g (0.01 mol) of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]
benzodiazepine, 2.28 g (0.01 mol) of 9H-fluorene-2-carbonyl chloride (generated via
the reaction of 9H-fluorene-2-carboxylic acid and thiony] chloride) and 1.21 g (0.01
mol) of N,N-dimethylaniline in 125 mL of 1,4-dioxane was allowed to stand at room
temperature for two hours. The reaction mixture was poured into 1 L of water, the
precipitate was collected, washed with water and dried to provide the title compound
(3.59 g). The material was recrystallized from acetone, m.p. 202-204 °C.
MS [(+)ESI, m/z]: 377 [M+H]+.
Anal. Calcd for CzeHzoNzO-0.25 H20: C 81.97, H 5.42, N 7.35. Found: C 82.00, H
5.24, N 7.35.
StepB. 2,2,2-Trichloro-1-[10-(9H-fluorene-2-carbonyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepin-3-yl]-ethanone
To 25 mL of 1,4-dioxane was added 0.59 g (0.0016 mol) of 10-(9H-fluoren-2-
ylcarbonyl)-10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine opf Step A followed
by the addition of 0.31 g (0.0017 mol) of trichloroacetyl chloride. The solution was
heated under reflux for 10 minutes, cooled to room temperature and poured into ice
water with stirring .The precipitate was collected, washed with water and dried
yielding 0.74 g of title compound which was used directly in the next step.
MS [(+)ESI, m/z]: 521 [M+H]+.
StepC. 10-(9H-Fluoren-2-ylcarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A solution of 0.7 g (0.0014 mol) of 2,2,2-trichloro-1-[10-(9H-fluorene-2-carbonyI)-
10,11-dihydro-5H- pyrrolo[2,1-c][1,4]benzodiazepin-3-yrj-ethanone of Step B and
0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was heated
under reflux for 1 hour. The reaction mixture was cooled to room temperature and
poured into 75 mL of water with stirring. The precipitate was collected, washed with
water, and recrystallized from ethanol to provide the title compound, m.p. 116-119
°C.
MS[(+)ESI,m/z]:511 [M+Hf.
138

WO 2006/135687

PCT/US2006/022326

MS [(-)ESI, m/z]: 509 [M-HT
CalcdforC33H26N4O20.67H2O: C 75.84, H 5.27, N 10.72. Found: C 75.53, H
5.15, N 11.01.
EXAMPLE 148
10-(3,3-DIMETHYLBUTANOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 144,
replacing trans-cinnamoyl chloride with tert-butylacetyl chloride. Purification,by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave a colorless syrup that was triturated with diethyl ether to afford the title
compound (0.390 g, 99%) as a white solid, m.p. 103 -107 °C.
MS [(+)ESI, m/z]: 417 [M+H]+
MS [(-)ESI, m/z]: 415 [M-HT
Anal. Calcd for CHO;,: C, 72.09; H, 6.78; N, 13.45. Found: C, 71.97; H, 6.72; N,
13.45.
EXAMPLE 149
10-(CYCLOHEXYLCARBONYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-
PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMlDE
The title compound was prepared in essentially the same manner as 144, replacing
trans-cinnamoyl chloride with cyclohexanecarbonyl chloride. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave a colorless syrup that was azeotroped with diethyl ether to afford the title
compound (0.370 g, 92%) as a white foam.
MS [(+)ESI, m/z]: 429 [M+H]+
HRMS [(+)ESI, m/z]: 429.22758 [M+H]\ Calcd for C26H29N402: 429.22850
EXAMPLE 150
10-ISOBUTYRYL-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-
C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE
The title compound was prepared in essentially the same manner as Example 144,
replacing trans-cinnamoyl chloride with isobutyryl chloride. Purification by flash
chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane
gave a colorless syrup that was triturated with diethyl ether to afford the title
compound (0.310 g, 85%) as a white solid.
139

WO 2006/135687

PCT/US2006/022326

MS [(+)ESI, m/z]: 389 [M+H]+
HRMS K+)ESI, m/z]: 389.19631 [M+H]+. Calcd for C23H25N4O2: 389.19720
Biological Activity Examples
The subject compounds of the present invention were tested for biological
activity according to the following procedures.
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.
EXAMPLE 151
FOLLICLE-STIMULATING HORMONE RECEPTOR-DEPENDENT CRE-
LUCIFERASE REPORTER GENE ASSAY FOR THE IDENTIFICATION OF
FOLLICLE-STIMULATING HORMONE (FSH) ANTAGONISTS
A Chinese hamster ovarian cell line that stably produces the human FSH
receptor and a luciferase reporter gene regulated by cAMP response elements was
used to identify and determine the relative potencies of human FSH receptor
antagonists. See for example, Kelton, C.A., et al. Mol. Cell. Endocrinol. 89:141-151
(1992), Tilly, J.L., et al. Endocrinology 131:799-806(1992), and George, S.E., et al. J.
Biomol. Screening 2:235-240 (1997).
Materials and Methods: Reagents
Compound Vehicle: Stock compounds were solubilized in an appropriate
vehicle, e.g., phosphate buffered saline (PBS) or dimethyl sulfoxide (DMSO), at 30
mM. The compounds subsequently were 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 (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 ug
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 3-[(2S*,5R*)-5-{[2-(1 H-lndol-3-yl)-
ethylcarbamoyl]-methyl}-4-oxo-2-(5-phenylethynyl-thiophen-2-yl)-thiazolidin-3-yl]-
140

WO 2006/135687

PCT/US2006/022326

benzamide (an FSH-R thiazolidinone antagonist) was prepared by processes
described by R.A. Scheuerman et al. in U.S. Pat. No. 6,426,357 (Affymax).
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 engineered
genetically 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 ul/wel! in growth medium. On the day of
treatment, the growth medium was removed from the wells by aspiration and 50 pi of
fresh growth medium was added to each well. The cells were incubated at 37 °C in a
humidified incubator with 5% C02/95% 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 pi 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%
C02/95% 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 pi 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), EC10o of phFSH
(1000 ng/ml), and IC50 of 3-t(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
141

WO 2006/135687

PCT/US2006/022326

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 also was
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
percent 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). IC5o values were calculated using statistical software from
SAS (SAS Institute, Inc., Cary, N.C.)
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 EC5o concentration of
purified human FSH in dose-response format.
EXAMPLE 152
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.
142

WO 2006/135687

PCT/US2006/022326

Methods: Reagents
Compound Vehicle: Stock compounds were solubilized in 100% DMSO
(Sigma-Aldrich Chemical Co., St. Louis, MO) at a concentration of 30 mM. The
compounds subsequently were diluted in sterile assay medium consisting of Opti-
MEM® I (Invitrogen/Life Technologies, Carlsbad, CA) with 0.1% (w/v) BSA (Sigma-
Aldrich) prior to use in the bio-assay. The final concentration of DMSO in the assay
was 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®, BD Biosciences, San Jose, CA) at a density of
30,000 cells/well in DMEM/F12 medium (Invitrogen/Life Technologies) supplemented
with 5% FETALCLONE® II (Hyclone), 2 mM L-glutamine (Invitrogen/Life
Technologies) and penicillin/streptomycin (100 U/ml, Invitrogen/Life Technologies).
Plated cells are then incubated at 37° C in a humidified 5% C02 /95% air
atmosphere.
Assay: On the day of the assay, cells were washed three times with 100
ul/well of assay medium consisting of Opti-MEM® I (Invitrogen/Life Technologies)
with 0.1% (w/v) BSA (Sigma-Aldrich). 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 pi 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 pi of 0.2N hydrochloric acid to each
well and cAMP-accumulation was measured by radioimmunoassay (RIA) using a
commercially available kit (Amersham Biosciences, Piscataway, NJ).
Experimental Groups
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 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 EC20dose. The
ability of the compounds to inhibit the cAMP-accumulation induced by hFSH was
evaluated by RIA.
143

WO 2006/135687

PCT/US2006/022326

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 - 30uM in the presence of the
hFSH at its EC2o concentration (1.85 ng/ml or 53 pM).
Along with the test compounds, FSH was run also as a postive 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
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 uM-1000 uM.
Non-Receptor Mediated Responses:
cAMP-accumulation assays using CHO-K1 cells (parental cell line) 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 uM. Controls and
test compounds were evaluated in quadruplicate. Cells were treated with vehicle, 5
[jM forskolin that induces the equivalent fmol/ml concentration of cAMP-accumulation
induced by the hFSH at its EC20 (5 uM forskolin, Sigma-Aldrich Chemical Co, St.
Louis, MO; 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.
144

WO 2006/135687

PCT7US2006/022326

Along with the test compounds, forskolin was also run as a positive control in
agonist mode using concentrations ranging from 0.01 uM to 1000 uM.
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 ECao=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 not to antagonize binding of FSH to
its receptor (Table 1). As such, the compounds of this invention can be useful as
female contraceptive agents.
Table 1

Example CRE
%
inhibition
(MM) CRE
IC50
(MM)' cAMP

IC50
(MM) Efficacy
3
1
8
28
20
5
21
22 0.92*
1
0.54
2.0**
3.7
13.8
2.9
15 0.08*
0.2
0.5
0.8
1.3
1.5
1 96
99
99
94
98
91
100
145

WO 2006/135687 PCT/US2006/022326

7 5.4 0.7 85
23 36(30)
24 10.7 1.6 96
25 11(30)
26 >30
6 8.9 5.4 58
27 22.7
13 2.8 0.7 99
9 17
47 0.65 0.2 97
70 5.6 2.4 91
10 25(30)
48 1.6 0.3 97
49 0.6 0.1 100
29 0.9 0.4 100
50 1 0.3
4 0.95 0.8
51 0.29 0.1 100
52 0.116 0.1 100
56 1.04 0.9 100
57 2.12** 0.7 100
58 0.4 0.2 100
59 0.1 0.06 100
60 29(30)
30 1.10** 0.27 100
31 0.94** 0.33 99
61 0.1 0.05 100
32 0.156** 0.02 100
33 1.45** 0.9 98
17 0.29** 0.13 100
14 1.61** 0.77 98
62 1.06** 0.55 100
34 1.547** 0.59 97
35 31
53 0.159** 0.12 100
54 0.317** 0.15 100
55 1.048 0.62 99
36 1.86** 0.43 98
12 16.4
15 1.1** 0.37 100
63 1.18** 0.38 100
64 >30
65 >30
37 1.64** 0.49 100
38 0.078** 0.09 100
39 0.414** 0.25 99
146

WO 2006/135687 PCT/US2006/022326

40 0.921** 0.32 100
66 3.67** 0.81 99
67 29.14
42 7.09 2 100
41 25.1
43 0.257* 0.14 100
44 2.94** 1.71 100
45 3.58** 0.78 100
46 2.19** 0.37 100
18 0.041* 0.07 100
16 0.994
69 14.55
19 2.4
71 17.3(30)
72 6.61(30)
73 2
74 10.54 3.1 100
75 >30 21 71
76 30
77 18.8
78 18.1
79 17.8
80 4.96** 1.1 98
81 18.4
82 2.4(30)
83 16.6
84 5.82 1.2 98
85 6.44 1.1
86 40(30)
8.7 38(30)
89 12.17
90 13(30)
91 37(30)
92 9.9
93 >30
94 17(30)
95 45(30)
96 30
97 18(30)
98 4.96** 0.4 100
99 35(30)
100 31.5**
101 12
102 5.82 0.8 99
103 >30
147

WO 2006/135687 PCT/US2006/022326

104 3.0** 0.4 98
105 2.48** 0.2 99
106 21(30)
107 3.12** 0.2 99
108 9.53** 1.8 99
113 8.84** 0.8 100
109 2.92** 0.3 99
110 7.65
111 5.48
112 7.99 1.3 99
114 >30
115 34(30)
116 >30
117 24(30)
118 27.7
119 10.45** 6.7 75
120 49.6
122 36.47 >30
123 41(30)
124 7(30)
125 31(30)
126 18.7**
127 9(30)
129 16(30)
130 26(30)
131 15.8
132 26(30)
133 14.46
134 4(30)
139 9.86
135 34(30)
136 41 (30)
137 16(30)
138 15.8
141 32(30)
142 18.5
143 48(30)
144 35(30)
145 40(30)
146 11.34**
148 35(30)
149 8(30)
150 20(30)
*n=3; **n=2; wherein n=number of samples tested from which the average
value is reported.
148

WO 2006/135687

PCT/US2006/022326

Those skilled in the art will recognize that various changes and/or
modifications may be made to aspects or embodiments of this invention and that
such changes and/or modifications may be made without departing from the spirit of
this invention. Therefore, it is intended that the appended claims cover all such
equivalent variations as will fall within the spirit and scope of this invention. Each
reference cited in the present application, including literature references, books,
patents and patent applications, is incorporated herein by reference in its entirety.
149

WO 2006/135687 PCT/US2006/022326
WHAT IS CLAIMED IS:
1. A compound having the Formula I:

wherein
R1 and R2 are selected independently from hydrogen, (C1-C6) alkyl, halogen,
trifluoromethyl, hydroxyl, (C1-C6) alkoxy, OCF3, carboxy, -CONH[(C1-C6)
alkyl], or -CON[(C1-C6) alkyl]2, amino, (C1-C6) alkylamino, -NHCO[(C1-C6)
alkyl];
R3 is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6)
alkoxy, hydroxyl, amino, (C1-C6) alkylamino, C(O)-(C1-C6) alkyl, and halogen;
A is selected from the group consisting of C=O, CH2, and SO2;
B is

wherein R5, R6, R7, R8, R9, R10, R100, R101, and R102 are selected independently
from the group consisting of hydrogen, alkyl, alkoxy, trihalomethyl, halogen, -
C(O) alkyl, hydroxy, hydroxyalkyl, alkyloxyalkyl, -CH(OH)alkyl, -
CH(alkoxy)alkyl, formyl, nitro, thioalkyl, - SO2alkyl, -SO2NHR11, -SO2N(R11)2,-
(CH2)PCN , -{CH2)pCOOR12, -(CH2)pNR13R14, -(CH2)pCONR13R14, -CH=NOH, -
150

WO 2006/135687 PCT/US2006/022326

Rn and R12are each independently hydrogen or alkyl;
R13 and R14 are each independently hydrogen or alkyl; or can be
taken together with the nitrogen to which they are attached to form a
4-6 membered saturated ring optionally containing one or more
additional 0, S or N atoms;
p is 0 or 1;

wherein
R15 is hydrogen or alkyl;
X is selected independently from the group consisting of

wherein
R,6 at each occurrence is independently selected from hydrogen or
alkyl;
R17 is one to three substituents independently selected from the group
consisting of hydrogen, alkyl, halogen, hydroxy, aryloxy, or
hydroxyalkyl;
R18 is 5 or 6-membered saturated heterocycle containing one nitrogen
atom;
m is an integer from 1 to 4;
q is an integer from 1 to 2; and
r is 0 or 1;
provided that:
if A is C=0, m is 1 or 2, r is 0, R7 is methyl or methoxy and R5, R6, RB,
R9, Rio, R17. R100, and R101 are hydrogen, then R102 is not
methyl or methoxy;
151

WO 2006/135687

PCT/US2006/022326

if A is C=0, m is 2, r is 0, R6 is methoxy and R5, R6l R7, R9, Ri0, R17,
R100, R101, and R102 are hydrogen, then R8 is not methoxy;
if A is C=0, m is 1 or 2, r is 0, R6 is methyl or methoxy, and R5, R6, R7,
Rs, R10, R17, Rioo, R101, and Ri02 are hydrogen, then R9 is not
methoxy;
if A is C=0, m is 2, r is 0, R8 is chlorine, R10o is methoxy, then R101 is
not methoxy wherein R5, R7, R8, R9, R10, R17, and R102 are
hydrogen, or R102 is not methyl wherein R5, R7, R8, Rg, Rio, Ri7>
and R10i are hydrogen;
if A is C=0, m is 1 or 2, r is 0 or 1, R7 is methyl, and R5, R6, R9, R10, R17,
Rioo, R101, and Ri02 are hydrogen, then R8 is not trifluoromethyl;
if A is C=0, m is 1, r is 0, R7is methoxy, R5l Re, R9, R10, R17, Rioo, and
R102 are hydrogen then R8 is not chlorine wherein R10i is
hydrogen or R10i is not methoxy wherein R8 is hydrogen;
if A is C=0, m is 1, r is 0, R5 is methoxy, R7 is chlorine, and R6l R10,
Ri7> R100, R1011 and R102 are hydrogen, then R8 is not
trifluoromethyl, chlorine, or methyl wherein R9 is hydrogen, or
R9is not methoxy wherein R8 is hydrogen;
if A is C=0, m is 2, r is 0, R7 is methyl, and R5, Re, R9, Rio, R17, R100,
R10i, and R102 are hydrogen, then R8 is not methoxy,
if A is C=0, m is 1 or 2, r is 0 or 1, R6 is chlorine, R10o is methoxy, and
Rs, R7, R9, R10, R17 are hydrogen, then R8 is not ethoxy wherein
R10i and R102 are hydrogen, or R101 is not methyl wherein R8
and R102are hydrogen, or R102 is not fluorine, trifluoromethyl, or
methyl wherein R8 and R10i are hydrogen;
if A is C=0, m is 1 or 2, r is 0, R7is methyl, and R5, R6, R8, R9, R10, Ri7,
R100 and R102 are hydrogen, then R10i is not methoxy;
if A is C=0, m is 1, r is 0 or 1, R6 is methoxy, R102 is trifluoromethyl,
and R5, R7, Rs, R9, R10, R17, and R101 are hydrogen, then R100is
not hydrogen or methoxy;
if A is C=0, m is 1 or 2, r is 0, R8 is methyl, and R5, R7, R9, R10, Ri7,
R100, R101 and R102 are hydrogen, then R6 is not hydrogen or
methyl; and
152

WO 2006/135687

PCT/US2006/022326

if A is C=0, m is 1 or 2, r is 0, and R5, R6, R7, R9, R10, Ri7, R100, R«i
and R102 are hydrogen, then RB is not methoxy; or
a pharmaceutical acceptable salt thereof.
2. A compound of claim 1 wherein Ri, R2 and R3are each hydrogen and R15
is hydrogen or methyl.
3. A compound of claim 1 or claim 2 wherein each Ri6is hydrogen, m is 1
and r is 0, and at least one Rt7 is not hydrogen.
4. A compound of 1 or claim 2 wherein R16 is hydrogen, m is 1, r is 0, and no
R17is hydrogen.
5. A compound of 1 or claim 2 wherein each R1sand Ri7 are hydrogen, q is 1
and r is 0, and R18is a 5-membered saturated cycloalkylamine.

6. A compound of any one of claims 1 to 10 wherein A is S02.
7. A compound of 1 or claim 2 wherein Ri6and R17 are hydrogen, m is 1,
r is 0 and R6 is methyl.
8. A compound of claim 1 or claim 2 wherein R16 and R17 are hydrogen,
m is 1, r is 0 and R7 is methyl or methoxy.
9. A compound of claim 1 or claim 2 wherein R16 and R17 are hydrogen,
m is 1, r is 0, and R8is selected from the group consisting of methyl, chlorine,
hydroxy, methoxy, ~COCH3, -CHO, -CH(OH)CH2CH3, -CH2OH, -CN, -
CH(CH3)2, -CO(phenyl), -CH2OCH3, -CH2COOCH3, -OCH2CH3, -CH2CN, -
SCH3l -CH2COOH, -CH(OH)CH3, -COCH(CH3)2, -S02CH3, -COOCH3, -
COOC(CH3)3, -COOH, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, - .
CH2CONH(CH2CH3), -CH2CON(CH2CH3)2, -CH(OH)CH(CH3)2, -CON(CH3)2, -
CH2N(CH3)2, -CH2NHCH3, -CH2C(NH2)=NOH, -CH2NH2, -S02NH2, -
CONHCH3, and 4-6 membered saturated ring optionally containing one or
more O, S or N atoms.
10. A compound of claim 8 wherein R8 is selected from the group
consisting of-CH2OH, -CH2OCH3, -CH2COOCH3, -CH(OH)CH3, -CH2CONH2,
and -CH2C(NH2)=NOH.

11. A compound of claim 1 or claim 2 wherein R16 and R17 are hydrogen,
m is 1, r is 1, R7 is methyl and R8 is methyl.
12. A compound having the Formula I-2:
153

WO 2006/135687 PCT/US2006/022326

wherein
R6' is H or (C1.3)alkyl;
R8' is selected from the group consisting of H, (Cw)alkoxy, halogen, (Ci.
3)alkyl, (Chydroxyalkyl, -C(0)R60o, CN, (Cslkoxyslkyl, CH2C(O)R60i, CH2CN,
HC=NOH, OH, S((C1.3)alkyl), S02((CM)alkyl)1 CH2N(R602)(R6o3), CH2C(NH2)=NOH,
and S02NH2;
R9' is H, halogen or (Ci)alkyl;
Rio' is H, halogen, (Calkyl, or C(0)(Ci.3)alkyl;
R102' is H or (Cialkyl;
R1S is hydrogen or alkyl;
R50o is H, OH, halogen, (Ci-3)alkyi, or O-phenyl;
R50i and R502 are each independently H or OH; and
k is 0 or 1;
wherein
R600 is H, OH, (C)alkyl, phenyl, (dalkoxy, or NReoaReos;
R60i is OH, (C)alkoxy, or NR602R603; and
R602and R603are each independently H or (dalkyl, or
R602 and R603 together form a 5-6 membered heterocycle with
up to 3 additional N or O atoms;
provided that:
154

WO 2006/135687 PCT7US2006/022326
when RQ is methyl, R8' is not methoxy;
when Re' is methyl, and one of R8' or R102' is methyl, then either:
(a) the other of R8' or R102' is not H; or
(b) k=1;and
if Re', Rs', R10', R102'. R500, R501, and R502 are all H, then R8 is not methyl or
methoxy.
13. A compound having the structure of Formula II:

wherein
R1 and R2 are selected independently from hydrogen, (Ci-C6) alky
halogen, trifluoromethyl, hydroxy!, (CrCs) alkoxy, OCF3, carboxy,
CONH[(CrC6) alky!], or-CON[(CrC6) alkyl]2, amino, (CrC6)
alkylamino, -NHCOt(CrC6) alkyl];
R3 is a substituent selected from the group consisting of hydroger
(CrC6) alkyl, (CrC6) alkoxy, hydroxyl, amino, (CrC6) alkylamino,
C(0)-(CrC6) alkyl, and halogen;
A is selected from the group consisting of C=0, CH2, and S02;
C is selected from the group consisting of

wherein
R19 and R20 are selected independently from the group
consisting of hydrogen, alkyl, alkoxy, halogen, trifluoromethyl,
trifluoromethoxy, -COOR21, dialkylamino, nitro, cyano, aryloxy,
155

WO 2006/135687 PCT/US2006/022326
aroyl, naphthyl and -CH2NHC(0)0-alkyl; or R19 and R20 can be
taken together with the phenyl moiety to which they are
attached to form a structure of the formula -0(-CH2)n-0-
wherein n is 1 or 2;
R21 is hydrogen or alkyl;
Y is selected from the group consisting of alkyl, cycloalkyl,
naphthyl,

wherein
R22 is selected from the group consisting of hydrogen,
alkyl, halogen, aralkyloxy-, alkylamino,
hydroxyalkyiamino, cycloalkylamino, N-alkyl piperazino,
(pyridinoalkyl) amino, (N-alkyl) aralkyl amino and
aralkyl amino wherein the aryl is optionally substituted
with alkoxy;
R23 and R24 are each independently hydrogen or
halogen;
R25 and R30 are each independently hydrogen or alkyl;
R26, R27, R28, and R29 are selected independently from
the group consisting of hydrogen, alkyl and halogen;
R31 is hydrogen, alkyl, halogen or aryl; and
156

WO 2006/135687 PCT/US2006/022326
R32 is each independently H, OH or taken together with
the carbon to which they are attached form -C=0;
Z consists of the moiety D-E, wherein
D is an aryl optionally substituted by one or more
substituents selected from the group consisting of
hydrogen, alkyl, alkoxy, halogen, nitro, -S02NH2, and
trifluoromethyl; and
E is selected from the group consisting of

wherein R33 is hydrogen or alkyl; and

wherein
Ri5o is hydrogen or alkyl;
X is selected independently from the group consisting of

wherein
R160 is hydrogen or alkyl;
R17o is one to three substituents selected from the group
consisting of hydrogen, alkyl, halogen, hydroxy, aryloxy, and
hydroxyalkyl;
157

WO 2006/135687 PCT/US2006/022326
R180 is 5 or 6-membered saturated cycloalkylamine;
m' is an integer from 1 to 4;
q' is an integer from 1 to 2;
r' is 0 or 1;
or a pharmaceutical acceptable salt thereof.
158
14. A compound of claim 13 wherein Ri9and R20are each selected
independently from the group consisting of hydrogen, alkyl and halogen.
15. A compound of claim 13 wherein R-|9 and R20 are each selected
independently from the group consisting of hydrogen, methyl, methoxy,
fluorine, chlorine, trifluoromethyl, aroyl, -OCF3, -C(CH3)3, -(CH2)2CH3, -
COOCH3, -COOH, -CN, -N(CH3)2, -N(0)=0, -N(CH2CH3)2, -
CH2NHCOOC(CH3)3, and -Ophenyl.
16. A compound of claim 13 wherein D is an unsubstituted aryl and E is
selected from the group consisting of


WO 2006/135687 PCT/US2006/022326

chlorine or phenyl and R32 is each independently H.
24. A compound of claim 13 where Y is selected from the group consisting
of 3,3-dimethylbutane, cyclohexyl, isobutane, 1-naphthyl, or 2-naphthyl.
25. A compound of claim 1 that is:
a. 10-{[2'-(1-Hydroxyethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
b. 10-{[2-(Hydroxymethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
c. 10-{[2'-(Methoxymethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
d. Methyl (4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4] benzodiazepin-10(11 H)-yl]carbonyl}-1,1 '-biphenyl-2-yI)acetate;
e. (-)-10-({2'-[1-Hydroxyethyl]-1,1'-biphenyl-4-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
f. 10-{[2'-(2-Amino-2-oxoethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11 -dihyd ro-5 H-py rrolo[2,1 -c][1,4]benzodiazepine-3-
carboxamide; or
159

WO 2006/135687

PCT/US2006/022326

g. 10-({242-Amino-2-(hydroxyimino)ethyl]-1,r-biphenyl-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide; or
a pharmaceutical acceptable salt thereof.
26. A compound of claim 1 that is:
a) N-{[3-Hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]methy!}-
10-[(2-methoxy-2'-rriethyM .I'-biphenyM-yOcarbonyll-IO.I1-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
b) 10-[(2,2'-Dimethyl-1,1'-biphenyl-4-yl)carbonyl]-N-[(1-
oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
c) N-[(5-Bromopyridin-3-yl)rnethyll]-10-[(2'-methoxy-1,1 '-biphenyl-
4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
d) 10-[(2'-Methoxy-1,1 '-biphenyl-4-yl)carbonyl]-N-[(2-
phenoxypyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
e) 10-[(2'-Methoxy-1,1 '-biphenyl-4-yl)carbonyl]-N-(2-pyridin-3-yl-2-
pyrrolidin-1 -ylethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
f) N-(Pyridin-3-ylmethyl)-10-[(2,2\6'-trimethyl-1 ,1 '-biphenyl-4-
yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
g) N-(Pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 c][1,4]benzodiazepine-3-carboxamide;
h) lO-KZ.e'-Dimethyl-l.l'-biphenyM-yOcarbonyll-N-Cpyridin-S-
y!methyl)-10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-
3-carboxamide;
i) 10-(1.1'-BiphenyM-ylcarbonyO-N-lpyridin-S-ylmethyO-IO.11-
dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
j) 10-{[2'-(Methylthio)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide 0.67 hydrate;
160

WO 2006/135687 PCT/US2006/022326
k) 10-{[2'-(Methy1sulfonyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-
3-ylmethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
I) 10-{[2'-(Aminosulfonyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,41benzodiazepine-
3-carboxamide;
m) 10-{[2'-(Cyanomethyl)-1,1 '-bipheny l-4-yl]carbony l}-N-(py ridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
n) 10-({2'-[2-Amino-2-(hydroxyimino)ethyl]-1,1'-biphenyl-4-
yl}carbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
o) N-(Pyridin-3-ylmethyl)-10-{[2'-(1 H-tetrazol-5-ylmethyl)-1,1 '-
biphenyl-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
p) 10-t(2'-Fluoro-2-methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolot2,1-
c][1,4]benzodiazepine-3-carboxamide;
q) 10-[(2'-Chloro-2-methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
r) 10-[(2,4'-Dimethyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
s) 10-[(3'-Ch!oro-2-methyM ,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
t) 10-[(4'-ChIoro-2-methyM, 1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
u) 10-[(3',4'-Dichloro-2-methyl-1,1 '-biphenyl-4-yl)carbony!]-N-
(pyridin-3-yImethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
161

WO 2006/135687

PCT/US2006/022326

v) 10-[(4'-Acetyl-2-methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
w) 10-[(2'-Acetyl-2-methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-
3-carboxamide;
x) 10-[(2'-Cyano-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
y) 10-[(2'-lsopropyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
z) Methyl (4'-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-
pyrrolo[2,1-c][1,4]
benzodiazepin-10(11H)-yl]carbonyl}-1,1'-biphenyl-2-yl)acetate;
aa) 10-[(2'-Ethoxy-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
bb) 10-[(2'-Hydroxy-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
cc) (4'-{[3-{[(Pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1 ,T-biphenyl-2-
yl)acetic acid;
dd) 10-[(2'-lsobutyryl-1,1'-biphenyl-4-y!)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
ee) 10-{[2'-(1 -Hydroxy-2-methylpropyl)-1,1 '-biphenyl-4-yl]carbonyl}-
N-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
ff) 10-{[2'-(2-Amino-2-oxoethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
162

WO 2006/135687

PCT/US2006/022326

gg) 10-({2'-[2-(Methylamino)-2-oxoethyl]-1,1 '-biphenyl-4-
yl}carbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
hh) 10-({2'-[2-(Dimethylamino)-2-oxoethyl]-1,1 '-biphenyl-4-
yl}carbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
ii) N-(Pyridin-3-ylmethyl)-10-{[2'-(pyrrolidin-1-ylmethyl)-1,1'-
biphenyl-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
jj) 10-({2'-[(Methylamino)methyl]-1,1 '-bipheny l-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
kk) 10-{[2'-(Morpho!in-4-ylmethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
II) 10-{[2'-(Piperidin-1-ylmethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c]t1,4]benzodiazepine-3-carboxamide;
mm) 10-({2'-[(Dimethylamino)methyl]-1,1'-biphenyl-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
nn) 10-{[2'-(Aminomethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
oo) 10-[(2'-Ethoxy-2-methyl-1,1 '-biphenyl-4-yl)carbonyll-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolot2,1-
c][1,4]benzodiazepine-3-carboxamide;
pp) 10-{[2'-(Methoxymethyl)-2-methyl-1,1'-biphenyl-4-yl]carbonyl}-
N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
qq) 10-{[2'-(1 -Hydroxyethyl)-2-methyl-1,1 '-biphenyl-4-yl]carbonyl}-
N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
163

WO 2006/135687

PCT/US2006/022326

rr) 10-[(2'-Acetyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-
3-carboxamide;
ss) 10-{[2'-(1 -Hydroxyethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-'(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
tt) (-)-10-({2'-[1 -Hydroxyethy!]-1,1 '-biphenyl-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
uu) (+)-10-({2'-[1-Hydroxyethyl]-1,1'-bipheny!-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
vv) 10-{[2'-(1-Hydroxyethyl)-1,1'-biphenyl-4-yl]carbonyl}-N-t(1-
oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
ww) 10-[(2'-Formyl-1,1'-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
xx) 10-[(2-Methyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
yy) 10-{[2'-(1-Hydroxypropyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
zz) 10-{[2'-(Hydroxymethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
aaa) 10-[(2'-Benzoyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
bbb) 10-{[2'-(Methoxymethyl)-1,1 '-biphenyl-4-yl]carbonyl}-N-(pyridin-
3-ylmethyl)-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
164

WO 2006/135687

PCT/US2006/022326

ccc) 10-({2'-[(E)-(Hydroxyimino)methyl]-1,1 '-biphenyl-4-yl}carbonyl)-
N-Cpyridin-S-ylmethyO-IO.II-dihydro-SH-pyrrolop.l-
c][1,4]benzodiazepine-3-carboxamide;
ddd) Methyl-4'-{[3-{[(Pyridin-3-ylmethy!)amino]carbonyl}-5H-
pyrrolo[2,1 -c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1 '-
biphenyl-2-carboxylate;
eee) tert-Butyl-4'-{[3-{[(Pyridin-3-ylmethyl)amino]carbonyl}-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1'-
biphenyl-2-carboxylate;
fff) 4'-{[3-{[(Pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1 -
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}-1,1 '-biphenyl-2-
carboxylic acid;
999) 10-({2'-[2-(Ethylamino)-2-oxoethyl]-1,1 '-biphenyl-4-yl}carbonyl)-
N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
hhh) 10-({2'-[2-(Diethylamino)-2-oxoethyl]-1,1 '-biphenyl-4-
yl}carbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
iii) 10-({2,-[(Dimethylamino)carbonyl]-1,1'-biphenyl-4-yl}carbonyl)-
N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
jjj) 10-({2'-[(I\/lethylamino)carbonyl]-1,1 '-biphenyl-4-yl}carbonyl)-N-
(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
kkk) 10-[(2'-Methoxy-1,1'-biphenyl-4-yl)sulfonyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-
3-carboxamide;
III) 10-[(2'-Chloro-1,1 '-biphenyl-4-yl)sulfonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
mmm) 10-(1,1'-Biphenyl-4-ylmethyl)-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
165

WO 2006/135687

PCT/US2006/022326

27. A compound of claim 13 that is:
a) lOlodo-a-methylbenzoyO-A/pyridin-S-ylmethylVIO.H-dihydro-
5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
b) 10-(4-Benzoylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
c) 10-Benzoyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide;
d) 10-(4-Methylbenzoy!)-N-(pyridin-3-yimethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
e) 10-(3-Fluorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxarnide;
f) N-(Pyridin-3-ylmethyl)-10-[4-(trifluoromethyl)benzoyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
g) 10-(4-fert-Butylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
h) 10-(3,4-Dichlorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
i) N-(Pyridin-3-ylmethyl)-10-[2-(trifluoromethyl)benzoyl]-10,11-
dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
j) 10-(3-Methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
k) 10-[4-(Dimethylamino)benzoyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrro!o[2,1-c][1,4]benzodiazepine-3-carboxamide;
I) N-(Pyridin~3-ylmethyl)-10-[4-(trifluoromethoxy)benzoyl]-10,11-
dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
m) 10-(2,6-Difluorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
n) Methyl 4-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1 -
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}benzoate;
o) 4-{I3-{[(Pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolot2,1-
c][1,4]benzodiazepin-10(11 H)-yl]carbonyl}benzoic acid;
p) 10-(4-Methoxybenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
166

WO 2006/135687

PCT/US2006/022326

q) 10-(4-Cyanobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
r) 10-(4-Chlorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
s) N-(Pyridin-3-ylmethyl)-10-[3-(trifluoromethyl)benzoyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
t) 10-(4-Fluorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
u) 10-(2-Methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
v) 10-(3,5-Difluorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
w) 10-(1,3-Benzodioxol-5-y]carbonyl)-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
x) 10-(2-Fluorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
y) 10-(4-Propylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
z) 10-(4-Nitrobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
aa) 10-(3,4-Difluorobenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
bb) 10-(4-Phenoxybenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
cc) 10-[4-(Diethylamino)benzoyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
dd) tert-Butyl (4-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-
yl]carbonyl}benzyl)carbamate;
ee) 10-(3-Methyl-4-thien-2-ylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
ff) N-(Pyridin-3-ylmethyl)-10-(4-pyrimidin-2-ylbenzoyl)-10,11-dihydro-
5/-/-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
167

WO 2006/135687

PCT/US2006/022326

gg) N-(Pyridin-3-ylmethyl)-10-(4-pyrimidin-5-ylbenzoyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
hh) 10-(4-Pyridin-2-ylbenzoyl)-A/-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrroIo[2,1-c][1,4]benzodiazepine-3-carboxamide;
ii) 10-(4-Pyridin-3-ylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
jj) 10-[4-(3-Methylpyridin-2-yl)benzoyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
kk) 10-(4-Pyridin-4-ylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
II) N-(Pyridin-3-ylmethyl)-10-[4-(1,3-thiazol-2-yl)benzoyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
mm) 10-[4-(1H-Pyrazol-1-yl)benzoyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
nn) 10-(4-Piperidin-1-ylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-py rrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
oo) 10-[3-(Aminosulfonyl)-4-morpholin-4-ylbenzoyl]-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide hemihydrate;
pp) N-(Pyridin-3-ylmethyl)-10-(thien-2-ylcarbonyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
qq) 10-(Pyridin-2-ylcarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
rr) 10-[(6-Chloropyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
ss) 10-[(2,5-Dichlorothien-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
tt) 10-{[6-(Benzylamino)pyridin-3-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
uu) 10-({6-[(2-Methoxybenzyl)amino]pyridin-3-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
168

WO 2006/135687

PCT/US2006/022326

vv) 10-Isonicotinoyl-N-{pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
ww) 10-({6-[(4-MethoxybenzyI)amino]pyridin-3-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
xx) 10-(Pyrazin-2-ylcarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
yy) 10-(Pyridin-3-ylcarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
zz) 10-[(6-Piperidin-1-ylpyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
aaa) 10-({6-[(2-Phenylethyl)amino]pyridin-3-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
bbb) 10-({6-[(3-Phenylpropyl)amino]pyridin-3-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
ccc) 10-{[6-(4-Methylpiperazin-1 -yl)pyridin-3-yl]carbonyl}-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
ddd) 10-({6-[(3-Methoxybenzyl)amino]pyridin-3-yl}carbonyl)-N-(pyridin-
3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
eee) 10-({6-[Benzyl(methyl)amino]pyridin-3-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
fff) N-(Pyridin-3-ylmethyl)-10-({6-[(pyridin-3-ylmethyl)amino]pyridin-3-
yl}carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
ggg) 10-({6-[(2-Hydroxyethyl)amino]pyridin-3-yl}carbonyl)-N-(pyridin-3-
ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
169

WO 2006/135687

PCT/US2006/022326

hhh) 10-{[6-(Butylamino)pyridin-3-yi]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
iii) 10-{[6-(Benzyloxy)pyridin-3-yl]carbonyl}-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
jjj) 10-[(4-tert-Butylphenoxy)acetyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
kkk) 10-{Phenoxyacetyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
III) 10-(2-Phenoxypropanoyl)-N-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
mmm) 10-[(4-Chlorophenoxy)acetyl]-N-(pyridin-3-ylmethyl)-10,11 -dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
nnn) 10-[(4-Chloro-2-methyIphenoxy)acetyl]-N-(pyridin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide;
ooo) 10-{[(4-Bromophenyl)thio]acetyl}-N-{[5-hydroxy-4-(hydroxymethyl)-
6-methylpyridin-3-yl]methyl}-10,11 -dihydro-5H-pyrrolo[2,1 -
c][1,4]benzodiazepine-3-carboxamide;
ppp) 10-{[(4-Bromophenyl)thio]acetyl}-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
qqq) 10-[(4-Chlorophenyl)acetyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
rrr) 10-(1,1'-Biphenyl-4-ylacetyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
sss) 10-[(2E)-3-Phenylprop-2-enoyl]-N-(pyridin-3-ylmethyl)-10,11-
dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
ttt) 10-(1-Naphthoyl)-N-(pyridin-3-ylmethyI)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
uuu) 10-(2-Naphthoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-
pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide;
170

WO 2006/135687

PCTYUS2006/022326

w) 10-(9H-Fluoren-2-ylcarbonyl)-N-(pyridin-3-y)methyl)-10,11-dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
www) 10-(3,3-Dimethylbutanoyl)-N-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;
xxx) 10-(Cyclohexylcarbonyl)-N-(pyridin-3-ylmethyl)-10,11 -dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide; or
yyy) 10-lsobutyryl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-3-carboxamide; or
a pharmaceutical acceptable salt thereof.
28. A composition comprising at least one compound of any one of claims
1 to 27 or a pharmaceutically acceptable salt thereof.
29. A method of inhibiting fertility in a mammal, said method comprising
administering an effective amount of at least one compound of any one of
claims 1 to 27 to said mammal.
30. A method of inhibiting fertility in a mammal, said method comprising
administering an effective amount of at least one compound of Formula III:
171

WO 2006/135687 PCT/US2006/022326

wherein
Ri, R21 R3, A, and R' are as defined hereinbefore;
B' is selected independently from the group consisting of

wherein
R5, Re, R7, Rs, R9 and R10 are as defined hereinbefore.
31. A method of preventing conception in a mammal, said method
comprising administering an effective amount of at least one compound of
any one of claims 1 to 27 to said mammal.
32. A method of preventing conception in a mammal, said method
comprising administering an effective amount of at least one compound of
Formula III:
172

WO 2006/135687

PCT/US2006/022326


wherein
Ri. R2, R3. A, and R' are as defined hereinbefore;
B' is selected independently from the group consisting of

R5, R6, R7, R8, Rs and R10 are as defined hereinbefore.
33. A method of blocking FSH-mediated follicular development in a
mammal, said method comprising administering an effective amount of at
least one compound of any one of claims 1 to 27 to said mammal.
34. A method of blocking FSH-mediated follicular development in a
mammal, said method comprising administering an effective amount of at
least one compound of Formula III:
173

WO 2006/135687

PCT/US2006/022326


III
wherein
R-i. R2. R3, A, and R' are as defined hereinbefore;
B' is selected independently from the group consisting of

(a) Rio (b)
wherein
R5, R6, R7, Ra, R9 and R10 are as defined hereinbefore.
174

This invention provides pyrrolobenzodiazepine pyridine carboxamides selected from those of
Formula (1), which act as follicle stimulating hormone receptor antagonists. The invention also provides pharmaceutical compositions and methods of treatment utilizing the compounds of Formulae (1) and (2).