(o)R4 andR°" each independently represent cyclopropyhnethoxy;
(p) R4 and R*> each independently represent a group of the formula

(C4) R4 and R^ each independently represent SCH3; and
(r) R4 andR6 each independently represent phenyl;
(s) R4 and R^ each independently represent hydrogen;
Still additional particular aspects of the novel compounds of the present invention
are those wherein the compound is a compound of Formula I, wherein R^ and R7 are as
follows:
(a) R.5 and R^ each independently represent hydrogen, hydroxxy, halo, (Cr
CeJaUcyl, or (C1-C6)alkoxy,
(b) R5 and R? each independently represent hydroxy,
(c) R^ and R? each independently represent chloro, bromo, or fluoro;
(d) R5 and R^ each independently represent methyl, or methoxy,
(e) R5 and R? each independently represent hydrogen;
Yet additional particular aspects of the novel compounds of the present invention
are those wherein the compound of Formula I is one wherein R8 is as follows:
(a) R8 represents hydrogen, halo, (C1-C4)alkyl, hydroxy(C1-C6)alkyl, (Q-
C4)alkyl -(C1-Cs)alkoxy, COR12, (C3-C7)cycIoalkyl, aryl or substituted aryl;
(b) R8 represents bromo, chloro, or fluoro;
(c) R8 represents methyl, ethyl, propyl, isopropyl, or 2-methylpropyl;
(d) R8 represents hydroxymethyl;
(e) R8 represents (C1-C4)aIkyHCrC4)aIkoxy;
(f) R8 represents methoxymethyl;
(g) R8 represents COR12 wherein R*2 represents methoxy, ethoxy,
hydroxyamethyl, or methoxymethyl;
(h) R8 represents (C3-C7)cycloalkyI;
(i) R8 represents phenyl, methoxyphenyl, methylphenyl, or phenyl-phenyl;
(j) R8 represents hydrogen.
In addition, it will be understood that a most particular aspect of the novel
compounds of the present invention are those wherein the compound is any novel
compound of Formula I exemplified herein.
Compounds of the present invention, including novel compounds, can be further
divided into sections as represented by Formulas 1(a) through 1(g) below. As such,
methods and uses employing compounds of Formula 1(a) - 1(g), as well as novel
compounds of Formula 1(a) - 1(g), represent more particular aspects of the present
invention. Section 1, as given by Formula 1(a), contains derivatives of Formula I having
substitution on the "C" ring but not on the "A" or "B" rings. Section 2, as given by
Formula 1(b), contains derivatives of Formula I having substitution on the "C" ring and
further on the "A" and/or "B" rings. Section 3, as given by Formula 1(c), contains
derivatives of Formula I wherein the "C" ring further represents a heterocyclic or
benzofused heterocyclic. Section 4, as given by Formula 1(d), contains derivatives of
Formula I wherein the "A" and / or "B" ring further represents a heterocyclic ring.
Section 5, as given by Formula 1(e), contains derivatives of Formula I wherein the bridge
depicted by-X—Y- represents a fused cyclopropyl structure. Section 6, as given by
Formula 1(f), contains derivatives of Formula I wherein the bridge depicted by-X—Y-
contains a heteroatom or heteroatom containing group at either the X or Y position.
Finally, Section 7, as given by Formula 1(g), contains derivatives of Formula I wherein
R.8 is other than hydrogen and the bridge depicted by -X—Y- contains either a
heteroatom or heteroatom containing group at either the X or Y position or both X and Y
are CH2.

R* represents hydrogen, halo, hydroxy, cyano, nitro, amino, (C;-C6)alkyl, (Cr
Cs)alkoxy, halo(C1-C6)alkyl, bydroxy(CrC5)alkyl, haIo(C1-C6)alkoxyT S02NR9R10,
S02Rn, NHSO2R11, CH2NHSQzR11, N(CH3)S02R^, NR9r10, NHCOR12, COR12,
CH2NH2, SR*4, heterocycle, or substituted heterocycle;
R2 represents hydrogen, halo, hydroxy, (Cl-C6)alkyl, (Cl-C6)alkoxy, or halo(Cl-
C6)alkyl;
R3 represents hydrogen or halo;
R9 represents independently at each occurrence cyano, (C1-C6)alkyl, (C1-C4)alkyl-
(CrC6)alkoxy, halo(CrC6>alkyl, (C3-C7)cycloalkyl, aryl, or (CrC6)aIkyl-aryl;
R*0 represents independently at each occurrence hydrogen or (C1-C6)alkyl, or R^
and Rl 0 together with the nitrogen to which they are attached form a substituted or
unsubstituted heterocycle
Rl 1 represents independently at each occurrence amino, (C1-C<;)alkyi, halo(C1-
C6)alkyl, MH-(C1-C6)aIkylamine, N,N-(C1-C6)dialkylamine, aryl, substituted aryl,
heterocycle, or substituted heterocycle;
R1^ represents independently at each occurrence H, amino, (Cj-C6)alkyl, or
heterocycle; and
R14 represents (C1-C6)alkyL

R4 and R^ each independently represent hydrogen, halo, hydroxy, cyano, amino,
(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NHSCbR^, NR^rIO, NHCOR12,
COR1?, OR14, S02R11 , SR14, aryl, or heterocycle;
R5 and R? each independently represent hydrogen, halo, hydroxy, or (Q-
C6>alkoxy;
R^ represents independently at each occurrence cyano or (C1-Gs)alkyl;
RlO represents independently at each occurrence hydrogen or (G-C6)alkyl;
R\l represents independently at each occurrence amino, (C1-C6)alkyl, halo(C1-
C^alkyl, NH-(Ct-C6)aIkylamine, N,N-(C1-C6)&alkylamine, aryl, substituted aryl,
heterocycle, or substituted heterocycle;
Rl2 represents independently at each occurrence H, amino, (C1-C6)alkyl, (Cp
Qsjalkoxy, hydroxy(C1-C6)alkyl, (CrQalkyHQ-C^alkoxy, baloCC^alkyl, NH-
methylamine, >ffl^imetbylamine, NH-ethylamine, or heterocycle; and
R*4 represents independently at each occurrence (C1-C6)alkyl, (C1-C4)alkyl-aryl,
(C1-alkyl-substituted aryl, (C1-C)alkyl-heterocycIe, or (C1-C4)alkyl-(C3-C7)cycloalkyL

R5 and R7 each independently represent hydrogen, halo, hydroxy, (CrCgJalkyl, or
(C1-C6)alkoxy; and
Rll represents(C1-C6)alkyl.
wherein
"A" and "B", each independently represent phenyl or a heterocycle, provided at
least one of "A" and "B" is a heterocycle;
"C" is as previously defined;
"--------" represents a double bond
R* represents hydrogen, halo, hydroxy, amino, oxo, (C1-C6)aUcyL (Cj-C^alkoxy,
halo(C!-C6)alkyl, NHSQzRl 1, NHCORl2, COR*2, (Cj-C7)cycloalkyl, heterocycle, or
(Cj-C^alkyl-hcterocycle, provided that when "C" represents aryl then Rl is other than
oxo;
R2 represents hydrogen, halo, hydroxy, (C1-C6)alkyl, or (C3-C7)cycloalkyl;
R^ represents hydrogen;
R4 and R^ each independently represent hydrogen, halo, hydroxy, cyano, amino,
(d-C^alkyl, (CrGs)alkoxy, ha3o(C1-C<;)alkyI, or NHCOR12;
R^ and R' each independently represent hydrogen or halo;
R1 * represents (C1-C6)alkyl or aryl; and
R*2 represents independently at each occurrence (C1-C6)alkyl or (C1-C6)alkoxy.
Formula 1(e)

Wherein
W and Z each independently represent hydrogen, fluoro, or chloro
"....." represents a double bond
"C" represents phenyl or benzofused heterocycle;
R1 represents hydrogen, hydroxy, amino, oxo, or NHSO2R1 *, provided that when
"C" represents aryl then Rl is other than oxo;
R2 and R3 each represent hydrogen; and
R13 represents (C1-C4)alkyl.
wherein
"--------" represents a double bond;
"A" and "B" represent phenyl or heterocycle and "C" is as previously defined;
X and Y together represent -CH2— 0-, -O—CHr, -CHr— S- -S— CH2-
-CH2—SO-, -SO—CHr-, -CHr-SO.-, - SOr—CH2- -CHr—NR10-, - NR10—
CH2- -NRlO_ co_3 or - CO — NR1 °- , wherein R1 ° is as previously defined;
Rl represents hydrogen, halo, hydroxy, amino, oxo, (O-Cejalkyl, (C1-C6>aIkoxy,
b.alo(C,-C<;)alkyl, hydroxy(C1-C6)a]kyl, NHSO2R11, CHzNHCSOzR1*), NHCOR*2,
COR12, OR14, (C3-C7)cycloalkyl, or (C1-G,)alkyl-heterocycIe, provided that when "C"
represents aryl then Rl is other than oxo;
R2 represents hydrogen, halo, (O-Cyalkyl, (C3-C7)cycloaIkyl, heterocycle, or (Cr
C^alkyl-heterocycle;
r3 represents hydrogen, or (C1-C6)alkyl;
R4 andR^ each independently represent hydrogen, halo, (Cj-C6)alkyl, (Cj-
QOalkoxy, haloCd-QOalkyl, or COR12; and
R^ and R? each independently represent hydrogen, halo, (C1-C^alkyl, or (Cj-
C6)alkoxy.
R*0 represents independently at each occurrence hydrogen (C:-C4)alkyl;
R*1 represents independently at each occurrence (C1-C6)alkyl, halofCi-C^alkyl,
aryl, substituted aryl, or (C3-C7)cycloalkyI;
R*2 represents independently at each occurrence (C1-C^alkyl, (Cj-C^alkoxy,
NH-methylamine, ITO-dimethylamine, or NH-ethylarnine; and
R14 represents acetyl.

wherein
"-------" represents a double bond;
"A" and "B" represent phenyl or heterocycle and "C" is as defined previously;
X and Y together represent -CHr— O-, -O—CH2-, -CH7— S-, -S— CH2-,
-CHz— SO-, -SO— CH2-, -CHz—S02-, - SOr— CH2-, -CHr-NR™-, - NR™—
CH2-, -NRlft— CO-, or - CO—NR™-;
Rl represents hydrogen, halo, hydroxy, amino, oxo, and NHSO2R1 *, provided
that when "C" represents aryl then Rl is other than oxo;
R2 and R3 each individually represent hydrogen or halo;
R4 and R6 each independently represent hydrogen, halo, 3 and the reaction is partitioned between water and organic solvent. The solvent is
dried (Na2S04) and concentrated under reduced pressure to yield the crude product of
structure (13). The crude compound of structure (13) is purified by short path column
chromatography (silica gel, bexane containing EtOAc).
In Step D, derivatives of structure (14) are prepared by adding t-BuLi portionwise
(exotherm) to a solution of the vinyl bromide (13) in dry THF at -78°C under N2. The
reaction is stirred at -78°C for 45min and trimethyl borate is then added. The reaction is
warmed to room temperature and stirred for about an additional 30min. The mixture is
then concentrate using standard procedures, ethylene glycol and toluene are added, and
the reaction refluxed overnight. The reaction is then cooled to room temperature, the
layers separated and the ethylene glycol layer extracted with toluene, the toluene layers
are then combined and concentrated to provide the compound of structure (14). The
crude product (14) can then be purified by silica gel chromatography eluting with ethyl
acetate:hexanes:triemylamine.
In Step C, the vinyl bromide of structure (13) and aryl boronic acid are mixed in
dioxane. 2.0M aqueous Na2C03 is then added and the reaction sparged with N2 for 5min.
Pd(PPh3)4 is added and the reaction vial immediately sealed. The reaction is heated to
about 170-100CC for about 8-24 h. The reaction is then quenched with H20 and the
product of Formula I extracted into CH2C12. After drying (Na2SO,j) and concentration, the
crude product is purified using chromatography on silica gel, eluting with ethyl
acetate/hexanes to obtain the purified product of Formula I.
In Step E, a mixture of the vinyl borate of structure (14), a substituted or
unsubstituted chloroheterocycle, cesium fluoride and [l,r-bis(diphenylphosphino)-
ferrocenejdichloropalladium (H) (1:1 complex with CH2C12) in dioxane is heated at about
50-100°C for about 12-72 h. The solvent is removed using a stream of nitrogen and the
resulting residue is shaken with H20 and CH2CI2 and loaded onto a Varian ChemElut
CE1005 solid-phase extraction cartridge. Elute with CH2C12, and concentrate using
standard procedure to obtain the crude product of Formula I, wherein a heterocycle or
substituted heterocycle is attached to the tricyclic core. The crude product can then be
purified by mass-guided reverse-phase HPLC to obtain the purified product of Formula I.
Alternatively, in Step E, a mixture of vinyl borate (14), a substituted or unsubstituted
chioroheterocycle, K2CO3 and ethanol is sparged with N2 for lOmin. Pd(PPh3)4 is then
added and the reaction sealed immediately. The reaction is heated at about 70-100°C for
about 12-72 h. The mixture is then concentrated under N2, then H2O (ImL) and ethyl
acetate (ImL) are added. The residue is load onto a Varian ChemElut CE1005 solid-
phase extraction cartridge. Elute with ethyl acetate, collect, and concentrate the crude
reaction. The crude product can then be purified on silica gel, eluting with ethyl
acetate/hexanes to obtain the pure product of Formula I wherein a substituted or
unsubstituted heterocycle is attached to the tricyclic core.
Scheme VTJI provides yet additional procedures for the synthesis of compounds of
Formula I, particularly those wherein rings A and/or B are heterocyclic rings.

In Scheme VUL a solution of the appropriate substituted or unsubstituted benzyl
magnesium bromide in THF is added to a solution of (10) in THF under Ar. The resulting
solution is stirred for about 1-24 h at about 25 °C before quenching with saturated,
aqueous ammonium chloride. The mixture is filtered and the magnesium salts washed
with diethyl ether. The filtrate is then with water and brine, dried (Na2SC>4), and
concentrated under reduced pressure. The resulting tertiary alcohol can then be purified
by column chromatography (hexanes/ethyl acetate).
The crude carbinol is dissolved in CHCI3 and concentrated hydrochloric acid is
then added. The resulting dark solution is stirred for 2 h at about 25 °C. Water and
CHCI3 are added, the layers separated, and the organic layer washed successively with
saturated, aqueous sodium bicarbonate and brine. The crude product of Formula I is then
dried (MgSC>4) and concentrated via rotary evaporation. The crude material may then be
purified by flash chromatograpy(hexanes/ethyl acetate) to provide the purified final
product of Formula I (wherein A and / or B are, for example, heterocyclic rings).
Additional Schemes for the synthesis of compounds of the invention:
Scheme DC provides procedures useful for the synthesis of compounds of Formula
I wherein the "C" ring represents an N-substituted benzimidazole derivative.
In Scheme DC, Step A, 5-bromo-2-fluoro-nifrobenzene is mixed wiui about 2
equivalents of a substituted amine, for example 4-(2-aminocthyl)morpholinc, in THF. The
reaction is stirred at room temperature for about 18h. The THF is removed under reduced
pressure and the residue partitioned between water and ethyl acetate. The organic layer is
dried (MgS04) and concentrated to provide compound of structure (15).
In Scheme IX, Step B, the compound of structure (15)is dissolved in ethyl acetate
or THF and 5% Pt/C (sulfided)is added. The slurry is placed under 60psi hydrogen gas at
room temperature for about 8h. The reaction is then filtered and concentrated to provide,
for example, the compound of structure (16) as a dark red oil. Compound (16) may then
be purified, for example by using a short plug of silica gel and 10% 2N NH3 in
MeOH/dichloromethane.
In Scheme IX, Step C, the compound of structure (16) is mixed with NaHC03,
water, and methanol. Slowly, phenyl chloroformate (about 1.5 equivalents)is added and
the reaction is stirred for about lh at room temperature. 5N NaOH (about 1.5 equivalents)
is then added and the reaction is stirred overnight at room temperature. The solid of
structure (17) is collected by vacuum filtration and washed with methanol.
In Scheme IX, Step D, under a blanket of nitrogen, a solution of compound (17)in
THF is cooled to about 5°C and 3N ethylmagnesium bromide is added. After about l/2h,
the reaction is cooled to about -72°C and slowly 1.7M t-BuLi is added. The reaction is
allowed to warm to about -55°C, then trimethyl borate is added and the reaction is
allowed to stir at room temperature overnight. 5N HC1 is then added and the reaction
stirred for about 4h. The pH is adjusted to about 6-7 and the crude boronic acid is
extracted into ethyl acetate, dried and concentrated to give the crude acid which is then
slurried with toluene and pinacol is added. The reaction is heated briefly and stirred
overnight. Ethyl acetate and aqueous NaHC03 are added, the organics extracted with
water and the dried (MgS04) organic layer is evaporated to give the purified product of
compound (18).
Schemes X-XTfl provide procedures useful for the synthesis of compounds of
Formula I wherein the "A" and/or "B" ring represents a heterocyclic ring, which may be
substituted or unsubstituted. Also, Scheme X demonstrates an alternative procedure to
that described in SchemeVTi, Step A for converting the ketone moiety to a methylene by
use of the Tebbe reagent.
Scheme X
In Scheme X, Step A, to a solution of, for example, 9,10-dihydro-l-thia-
benzo[/]azulene-4-one (see P. Bollinger, P. Cooper.; H. U. Gubler, A. Leutwiler, T. Payne
Helv. Chim . Acta 1990, 73,1197) at about -40°C is added about 3 equiv of a 0.5 M
solution of Tebbe reagent in toluene and about 3 equiv of pyridine in THF (0.1 M) under
Ar. The resulting mixture is stirred for about 2 h then allowed to warm to 0 °C over ca.
30 min period before diluting with diethyl ether. 5 N sodium hydroxide is then added
carefully until bubbling ceases, then solid Na2S04, and the reaction stirred for about 1 h.
The mixture is then filered through Celite®, then the filtrate by rotary evaporation. The
crude residue of compound (19) may then be purified by standard techniques such as
column chromatography (hexanes) to give the purified product of structure (19).
In Scheme X, Steps B and C, the compound of structure (19) may be treated
according to the procedures as described in Scheme VII, Steps B and C to provide the
compound of Formula I.
In Scheme XI, procedures for the synthesis of compounds of Formula I wherein
"A" or "B" represents a chlorothiophenc are provided. In Scheme XI, Step A, about 2
equiv of n-BuLi-hexanes is added dropwise to a solution of a compound of Formula I(i),
for example 3^9,10-Dihyo^o-l-tlua-benzo[f]azulen-4-ylidenememyl)-phenylamine, in
THF at about 0 °C under Ar. The resultant dark solution is stirred for about 1 h before
adding about 2.5 equiv of hexachloroethane in THF. The reaction is stirred for about 2 h,
quenched with excess water, and acidified to neutral pH. The aqueous layer is extracted
with diethyl ether (3 X) and then dried QAgSOi), and the combined organic layers are
concentrated under reduced pressure. The crude product (Formula I(ii)) may then be
purifed using standard techniques, such as by column chromatography to give the 2-
chlorotbiophene derivative compound.
In Scheme XI, Step B, the amino group of Ring "C" may be treated according to
procedures as described in Scheme V(a), Step B to provide further methanesulfonamide
derivatives of Formula I(iii).

Scheme XTJ provides procedures for the synthesis of derivatives of Formula I
wherein Ring "A" and or "B" represents a methylated heterocyele, particularly a
methylated thiazole. In Scheme XH, Step A, add about ] .2 equiv of H-BuLi-hexanes
dropwise to a solution of compound (20)(4-methylcne-9,10-dihydro-4H-3-thia-2-aza-
benzo[f]azulene) in THF at about -78 °C under Ar. The resultant dark green solution is
stirred for about 5 min before adding about 1.2 equiv of iodometbane in THF. The
reaction is allowed to warm and stirred at room temperature for about 18 h before
quenching with excess water. The layers are separated and the aqueous layer extracted
with,for example, diethyl ether (3 X) and then dried (MgS04- The combined organic
layers may then be concentrated under reduced pressure and the product (Structure
(21))used in the next step without further purification.
In Scheme XT^Steps B and C, the compound of structure (21) is treated according
to procedures as described Scheme VII, Steps B and C to provide the compound of
Formula I wherein Ring "A" and or "B" represents a methylated heterocycle.

Scheme XUT provides additional procedures for the synthesis of compounds of
Formula I wherein Ring "A" and or "B" represents a thiazole. In Scheme XHI, Step A, a
flask is charged with equimolar metiryl dichloroacetate and 3-phenyl-prionaldehyde in
diethyl ether. The solution is cooled to about 0 °C and about 1 equiv of sodium
methoxide in methanol is added over a 1 h period. The mixture is vigourously stirred for
about 2 fa at about 0 C and then allow to warm to room temperature before adding brine.
The layers are separated, dried (MgSOji) and the organic concentrated to give the crude
residue of compound (22).
In Scheme XIII, Step B, reflux the compound of structure (22) and thiourea in
MeOH for about 4 h, then basify with ammonia-MeOH and add brine. The reaction is
then extract with, for example ethyl acetate, then the combined organic layers are washed
with brine, dried(MgS04), and concentrated under reduced pressure to give the compound
of structure (23).
In Scheme XHI,Step C, about one equiv of the compound of structure (23) and
about 3 equiv of isoamyl nitrite in THF are refluxed for about 3 h. Evaporate The volatile
components are evaporated to provide the compound of structure (24).
In Scheme XDI, Step D, a thick slurry of the compound of structure (24) and
polyphosphoric acid (PPA) is rapidly stirred and heated to about 140 °C for about 24 h
and then about 150 °C for about 5 h. Carefully the hot mixture is added to ice-cold
aqueous sodium hydroxide. The reaction is then extracted, for example with EtOAc, and
the combined organic layers washed with brine, dried (MgSC>4), and concentrated under
reduced pressure. The crude residue of structure(25) may then be purified by standard
techniques, such as by column chromatography (10% to 50% EtOAc:hexanes) to provide
the purified compound of structure (25).
In Scheme XDI, Step E, the compound of structure(25) is treated according to
procedures as described in Scheme VTJ, Step A to provide compound of structure (26).
In Scheme XEH, Steps F and G, the compound of structure (26) is treated
according to procedures as described Scheme VII, Steps B and C to provide the
compound of Formula I wherein Ring "A" and or "B" represents a thiazole ring.
Alternatively, the desired starting thiazole ketone can be prepared as as shown in
Scheme XEQTb), below. In step A, 2-chloro-3-oxo-butyric acid ethyl ester in THF is
treated with first NaH (1 equivalent) then n-BuLi (1 equivalent) while the temperature is
held at about -60 to -10°C and then the appropriately substituted benzyl bromide added.
In Step B, the intermediate 2-chloro-3-oxo-5-phenyl-pentanoic acid ethyl ester derivative
is reacted with thiourea in refluxing ethanol for 1-24 hours. This ester can be cyclized
using PPA and heating at from 160-250°C for 1-15 hours. As described in Scheme
XDI(a)5 Step C, the amino moiety can be converted to -H. This intermediate ketone can
be converted to final products as in Scheme XIII(a), Steps E, F and G.

Scheme XTV provides additional procedures for the synthesis of compounds of
Formula I wherein ring "A" and or "B" is substituted.

In Scheme XTV, Step A, a mixture of 2-3 cquiv of
bromomethyltriphenylphosphonium bromide (see G. Vassilikogjannakis, M.
Hatzimarinaki, M. Orfanapoulos J. Org. Chem., 65, 8180) in THF (0.5 M) is cooled to
about -78 °C and about 2-3 equiv of LiHMDS-THF is added dxopwise to give a bright
yellow mixture. The reaction is stirred for about 1 h at about -78 CC and then for about
10 min at 0 °C. The mixture is re-cooled to about—78 °C and the compound of structure
(27) is added. The dark mixture to is allowed to warm to room temperature and stirred for
about 3.5 h before adding saturated, aqueous saturated ammonium chloride and diluting
with pentane. The mixture is filtered through celite, the filtrate concentrated under
reduced pressure, and purifed by standard techniques such as column chromatography
(1% to 2% to 3% to 5% EtOAchexanes) to give the compound of structure (28) as a 1:1
mixture of geometric isomers.
In Scheme XIV, Step B, the compound of structure (28) is treated according to
procedures as described in Scheme VU, Step C to provide the compound of Formula I.
Scheme XV provides additional procedures for the synthesis of compounds of
Formula I wherein ring "A" and or "B" represents a heterocyclic ring and additionally
shows methodology to prepare useful intermediate vinyl borate ester derivatives.
In Scheme XV, Step A, about one equiv of, for example, 5,6-dihydro-
benzo[d]pyaolo[l,2-a]azepin-ll-one (structure(29))(see Y. Girard, J. G. Atkinson, P. C.
Belanger, J. J. Fuentes, J. Rokach, C. S. Rooney, D. C. Remy, C. A. Hunt J. Org. Chem.
1983, 48,3220) in THF is added to a solution of about 2.5 equiv of pinicol
lithio(trimethylsiIyl)methaneboronate (see D. S. Matteson, D. Majumder
OrganometaIlicsl9$3,2,230), about 1 equiv TMEDA, about 2.5 equiv,of
tetramethylpiperidine (TMP), and THF at about -78 °C. The solution is allowed to warm
to room temperature and stirred for about 3.5 h before quenching with excess water. The
reaction is extracted with EtzO (4 X), dried (MgSO*) and concentrated under reduced
pressure. The crude residue may then be purified by standard techniques such as column
chromatography (5% to 10% EtOAc Jiexanes) to give the pure E-isomer and Z-isomer of
structure (30).
In Scheme XV, Step B, the compound of structure (30) is treated according to
procedures as described in Scheme VH, Step C to provide the E and Z isomer of the
compound of Formula I.
Scheme XVI provides yet additional procedures for synthesizing compounds of
Formula I wherein ring "A" and or "B" represents a heterocyclic ring.
Scheme XVI
In Scheme XVI, Step A, diisopropylamine is dissolved in dry tetrahydrofuran and
the resulting mixture cooled to about -78 °C. Butyllithium is then added and the reaction
mixture is warmed to about 0 °C then a fine slurry of 2-methyl-nicotinic acid in THF (25
mL) is added portionwise during about 10 min. The resulting slurry is stirred for about lh,
then 3-fluorobenzyl bromide is added and the mixture is stirred for about 5 min. The
reaction is quenched with water and extracted with diethyl ether. The pH of the aqueous
layer is adjusted to about 3.1 with concentrated aqueous hydrochloric acid solution. The
resulting slurry is treated with ethyl acetate and stirred to dissolve all solids. The layers
are separated and the aqueous layer extracted with ethyl acetate. Concentrate the
combined extracts are then concentrated to dryness to provide the compound of structure
(31).
In Scheme XVI, Step B, the compound of Structure (31) is combined with
polyphosphoric acid (about 100 g) and heated to about 160 °C for about 6 h. The reaction
mixture is allowed to slowly cool over 12h, then reheated to about 160 °C and poured into
ice. The transfer is completed using water and the pH of the aqueous mixture adjusted to
about 8.0 with 50% aqueous sodium hydroxide solution. The product of structure (32) is
extracted with methylene chloride. The combined organic extracts are dried with
magnesium sulfate, filtered and concentrated. The compound of structure (32) may then
be purified using standard techniques such as flash chromatography (25% ethyl
acetate/hexanes to 50% ethyl acetate/hexanes) to provide the purified product of the
compound of structure (32). (See Journal of Heterocyclic Chemistry 1971,73).
In Scheme XVI, Step C, a mixture of compound (32) and dry THF is chilled to
about 0 °C This mixture is treated with methyl magnesium bromide, the cooling
removed, and the mixture is stirred at room temperature for about 15 min. The reaction is
quenched, while cooling with an ice-water bath, by adding saturated aqueous ammonium
chloride solution (50 mL). The layers are separated and the aqueous layer extracted with
methylene chloride (2x50 mL). The combined organic layers are dried with magnesium
sulfate, filtered, and concentrated to provide the intermediate product of structure (33) as
a thick crude oil. Without further purification, this residue is dissolved in a solution of
sulfuric acid in acetic acid (3% by volume, 50 mL) and the mixture stirred at room
temperature for about 12-18 h. The reaction mixture is concentrated to remove excess
solvent and the resulting orange residue dissolved in IN aqueous sodium hydroxide
solution (25 mL) and ethyl acetate (50 mL). the pH of the resulting mixture is adjusted to
about 8 with 5N aqueous sodium hydroxide solution. The layers are separted, and the
aqueous extracted with ethyl acetate (2x50 mL). The combined organic layers arc dried
with magnesium sulfate, filtered, and concentrated to provide the compound of structure
(33).
In Scheme XVL Step D, the compound of structure (33) is treated according to
procedures as described in Scheme VH, Step B, to provide E and Z isomer of compound
(34).
In Scheme XVI, Step E, the compound of structure (34) is treated according to
procedures as described in Scheme VH, Step C to provide the E and Z isomer of the
compound of Formula I.
Scheme XVH provides yet additional procedures for synthesizing compounds of
Formula I wherein ring "A" and or "B" represents a heterocyclic ring and wherein the
bridge depicted by —X—Y- contains a heteroatom or heteroatom containing group at
either the X or Y position.

In Scheme XVH, Step A, the compound of structure (35), for example, (8-fluoro-
llH-lO-oxa-l-aza-dibcnzo[a,d]cyclohepten-5-one) (see Journal of Medicinal Chemistry
1990,33,3095)and anhydrous tetrahydrofuran (25 xnL) are combined and the solution
cooled to about 0 °C . Tebbe reagent (0.5M/L solution in toluene) is then added, cooling
is removed, and the mixture stirred for about 10 min. The reaction is quenched by adding
saturated aqueous Rochelle's salt solution and the biphasic mixture stirred rapidly for
about 10 min. The layers are then separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers are dried with magnesium sulfate, filtered and
concentrated. The crude product of compound (36) may then be purified using standard
techniques such as flash chromatography (25% ethyl acetate/hexanes) to provide the
purified product of structure (36).
In Scheme XVII, Step B, the compound of structure (36) is treated according to
procedures as described in Scheme VII, Step B, to provide E and Z isomer of compound
(37).
In Scheme XVII, Step C, the compound of structure (37) is treated according to
procedures as described in Scheme VII, Step C to provide the E and Z isomer of the
compound of Formula L
Scheme XVHI provides general procedures for the synthesis of compounds of
Formula I wherein ring "A" and or "B" is contains an ether mocity
Scheme XVDI
In Scheme XVm, Step A, the compound of structure (i) (5-methylene-10,l 1-
dihydro-5H-dibeozo[a,d]cyclohepten-2-ol), prepared from commercially available 2-
hydroxy-10,1 l-dihydro-dibenzo[a,d]cyclohepten-5-one using procedures as described
Scheme VH, Step A, is treated under conditions as described in Scheme VD, Step B to
provide the compound of structure (ii) (5-bromomethylene-10,H-dihydro-5H-
dibenzo[a,d]cyclohcpten-2-ol)
In Scheme XVHI, Step B, 2.5 equivalents of PS-TBD Resin (commercially
available: Argonaut Technologies) is added to a fritted vessel. The bottom of the vessel is
capped and about 1.0 equivalent of 5-bromomethylene-10,l l-dihydro-5H-
dibenzo[a,d]cyclohepten-2-ol in acetonitrile is added. About 0.8 equivalents of the
appropriate alkyl halide in acetonitrile is then added and the top of the vessel is capped
and the vessel rotated for about 48-96 hours. The vessel is then uncapped and the filtrate
collected into a screw-cap vial. The resin is washed with acetonitrile followed by
dichloromethane. The filtrate is combined with the washings and concentrate under
vacuum.
In Scheme XVTTi, Step C, into the screw capped vial containing the
bromomethylene ether, about 1.2 equivalents of potassium carbonate and about 1.1
equivalents of, for example, N-[3-(4,4,5 ?5-tetramethyl-[ 1,3 ,2] -dioxaboronan-2-yl)-
phenylj-methanesulfonamide, is added. The solution is purged with nitrogen for about 5
min. then about 0.1 equivalents of palladium tetrakis(tripbenylphospbine) is added into
the vial. The vial is capped and heated to about 90-100 °C for about 16 hours with
continuous stirring. The reaction is then loaded onto Chem-Elute column (Varian Sample
Prep) primed with water and the column is eluted with ethyl acetate. The filtrate is then
concentrated under vacuum and may be purified by standard techniques such as silica gel
chromatography.
Determination of Biological Activity
To demonstrate that compounds of the present invention have affinity for steroid
hormone nuclear receptors, and thus have the capacity to modulate steroid hormone
nuclear receptors, soluble MR and GR binding assays are performed. All ligands,
radioligands, solvents, and reagents employed in the binding assays are readily available
from commercial sources, or can be readily synthesized by the ordinarily skilled artisan.
Mineralocorticoid Receptor Binding Assay:
The full length human MR gene is cloned from a human kidney or human brain
cDNA library. Briefly, using synthetic oligonucleotide primers (Eli Lilly and Company,
Indianapolis) directed to nucleotides 20-54 and 3700-3666 of the human MR, polymerase
chain reaction (PCR) is performed under standard conditions using a human cDNA
library. The PCR reaction is performed in a final volume of 50ul containing about lul of
a 5 OX stock solution of polymerase; about 1 pi of a 50X stock solution of dNTP; about
5ul of an appropriate PCR buffer; about lp.1 of each primer, about 5ul of a H. kidney or
H. brain cDNA library; and about 36p.l of water. The reaction is allowed to denature for
about 30 seconds at 95 degrees Celsius, anneal for about 30 seconds at 55 degrees
Celsius, and extend for about 5 minutes at 72 degrees Celsius, the sequence being
repeated for a total of about 35 cycles. The desired PCR product (3.6S Kb) is confirmed
by gel electrophoresis and subsequently cut from the gel and stored at about -20 degrees
Celsius until extraction. To extract the cDNA product from the agarose gel, the QIAEXII
Gel Extraction protocol (QIAGEN, Inc.) is employed according to the manufacturer's
instructions. Following extraction, the MR cDNA is cloned into an appropriate cloning
vector (Zero Blunt TOPO PCR Cloning Kit (Invitrogen, Inc.) and a pAcHLT-baculovirus
transfer vector (B.D./Pharminogen), then expressed in SF9 insect cells, essentially
according to manufacturer's instructions. Sf9 cells are grown at a scale where gram
quantity cell pellets are obtained for subsequent use in the MR binding assay. Harvested
cell pellets are lysed by repeated freeze-thaw cycles (about 4) in a suitable lysis buffer
then centrifuged at about 1X I03G (with the supernatant being saved for future assays).
MR binding assays are performed in a final total volume of about 250|il
containing about 20-25 ug of protein and 0.5nM of [^-aldosterone plus varying
concentrations of test compound or vehicle. The assay binding buffer consists of 30mM
sodium molybdate, 30mM of TRIS-HC1,5mM sodium phosphate, 5mM sodium
pyrophosphate, and about 10% glycerol, pH=7.5.
Briefly, assays are prepared at RT in 96-well Falcon 3072 plates, each well
containing 210ul of binding buffer, lOul of [3H]-aldosterone, lOul of test
compound/vehicle, and 20ul of the resuspended receptor protein extract. Incubations are
carried out at 4 degrees Celsius with shaking for about 16 hours. 200ul aliquots of each
incubation are filtered onto Millipore HA 0.45micron 96-well filter plates, pre-moistened
with cold 30mM TRIS-HCL The filter plates are suctioned dry with vacuum and
immediately washed 3X with cold 30mM TRIS-HC1. The plates are then punched out
and the amount of receptor-ugand complex is determined by liquid scintillation counting
using 4ml of Ready Protein Plus™ liquid scintillation cocktail.
IC50 values (defined as the concentration of test compound required to decrease
[3H]-aldosterone binding by 50%) are then determined. Ki values for each respective test
compound can then be calculated by application of the Cheng-Prusoff equation as
described in Cheng et al, Relationship Between The Inhibition Constant (Ki) and The
Concentration of Inhibitor Which Causes 50% Inhibition (IC50) of an Enzymatic
Reaction, Biochem. Pharmacol., 22: 3099-310S8; (1973).
Glucocorticoid Receptor Binding Assay:
To demonstrate the GR modulating potency of compounds of the present
invention the following source of glucocorticoid receptor is employed. A549 human lung
epithelial cells (ATCC) are grown at a scale where gram quantity cell pellets are obtained.
Harvested cell pellets are washed twice in cold phosphate buffered saline, centrifuged,
and resuspended in cold assay binding buffer. The assay binding buffer consists of 10%
glycerol, 50mM Tris-HCl (pH7.2), 75mM sodium chloride, 1.5mM magnesium chloride,
1.5mM EDTA, and lOmM sodium molybdate. Cell suspensions were lysed via
sonication, centrifuged, and the "extract" supernatant is snap frozen and stored at -80C
until needed.
GR binding assays are performed in a final volume of 140ul containing 50-200ug
of A549 cell extract and 1.86nM [^-dexamethasorie (Amersham) plus varying
concentrations of test compound or vehicle. Briefly, assays are prepared at RT in 96-welI
Fisher 3356 plates, each well containing lOOul of A549 cell extract, 20ul of
[^-dexamethasone, and 20ul of test compound/vehicle. Incubations are carried out at 4
degrees Celsius for 16 hours. After incubation, 70ul of 3X dextran-coated charcoal
solution is added to each reaction, mixed, and incubated for 8 minutes at RT.
3X-dextran-coated charcoal solution consists of 250ml assay binding buffer, 3.75g Norit
A charcoal (Sigma), and 1.25g dextran T-70 (Amersham). Charcoal/unbound radioligand
complexes are removed by centrifugation of the plate and 140ul of supernatant from each
well is transferred to another 96 well Optipiate (Packard Instruments). 200ul of
Microscint-20 scinillant (Packard Instruments) is added to each well and amount of
receptor bound radioligand is determined using Packard Instruments TopCount
instrument
IC50 values, defined as the concentration of test compound required to decrease
[3H]-dexamethasone binding by 50%, are then determined. Ki values for each respective
test compound can then be calculated by application of the Cheng-Prusoff equation as
described in Cheng et al., Relationship Between The Inhibition Constant (Ki) and The
Concentration of Inhibitor Which Causes 50% Inhibition (IC50) °f ^ Enzymatic
Reaction, Biochem. Pharmacol., 22: 3099-31088; (1973).
Binding assay protocols for PR, AR, and ER, similar to those described above for
MR and GR, can be readily designed by the ordinarily skilled artisan. United States
Patent No. 6,166,013 provides examples of such protocols. Representative compounds of
the present invention have a Ki in the MR or GR binding assay of < 50pM. Table I
(see infra.) provides MR and GR binding data for a representative sample of the
exemplified compounds of the present invention.
To demonstrate the ability of compounds of the present invention to modulate the
activity of a steroid hormone receptor (i.e. either agonize, antagonize, partially agonize, or
partially antagonize), bioassays are performed which detect modulation of target gene
expression in cells transiently transfected with a nuclear receptor protein and a hormone
response element-reporter gene construct. The solvents, reagents, and ligands employed
in the functional assay are readily available from commercial sources, or can be
synthesized by one of ordinary skill in the art.
Functional Assay of Mineralocorticoid Receptor Modulation:
For the MR transient transfection assay, COS-7 cells are transfected with full
length human MR and a 2XGRE-luciferase gene construct Following transfection, the
ability of test compounds to modulate expression of the luciferase reporter gene product is
monitored. Briefly, on day one, COS cells are harvested from cell culture plates using
standard procedures such as treatment with Trypsin-EDTA (GTBCO BRL). Culture
medium is then added to the cells and the cell-medium mixture is plated in 96 - well
plates coated with poly-(d)-lysine (approximately 3 X10* cells/well). Cells are grown
for about 4 hours then transfected with Fugene-6 reagent with plasmids containing human
MR, previously cloned into pcDNA 3.1 expression vector, and 2XGRE-reporter gene
construct (GRE-luciferase), previously cloned into pTAL-luc vector. Transfection is
carried out in DMEM with 5% fetal calf serum, charcoal treated. 24 hours later cells are
exposed to various concentrations of aldosterone in the presence and absence of test
compound and incubated for an additional 24 hours. The reaction is terminated by the
addition of lysis buffer followed by luciferin (luciferase substrate). Luciferase expression,
as an indicator of ligand induced MR transactivation, is monitored by chemilurninescence
measured using a microtiter plate luminometer (MLX). The kinetic inhibition constant
(Kb or Kp) can then be determined by analysis of dose-response curves for aldosterone, in
the presence and absence of test compound, using standard techniques.
The following preparations and examples further illustrate the invention and
represent typical synthesis of the compounds of Formula I, including any novel
compounds, as described generally above. The reagents and starting materials arc readily
available to, or may be readily synthesized by, one of ordinary skill in the art. As used
herein, the following terms have the meanings indicated: "i.v." refers to intravenously;
"p.o." refers to orally; "i.p." refers to intraperitoneally; "eq" or "equiv." refers to
equivalents; "g" refers to grams; "rng" refers to milligrams; "L" refers to liters; "mL"
refers to milliliters; "uL" refers to microliters; "mo3" refers to moles; "mmol" refers to
millimoles; "psi" refers to pounds per square inch; "mm Hg" refers to millimeters of
mercury; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers to degrees
Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance
liquid chromatography; "Rf" refers to retention factor; "RT refers to retention time; "5"
refers to part per million down-field from tetramethylsilane; "THF1 refers to
tetrahydrofuran; "DMF' refers to N,N-dimemyiformamide; "DMSO" refers to dimethyl
sulfoxide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to
isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether,
"PPI13" refers to triphenylphosphine; "DEAD" refers to diethyl azodicarboxyiatc; "RT"
refers to room temperature; "Pd-C" refers to palladium over carbon; NaBH(0Ac)3 refers
to sodium triacetoxyborohydride; "Bn" refers to benzyl; "B11NH2" refers to benzyl amine;
H2 refers to hydrogen; "Kj" refers to the dissociation constant of an enzyme-antagonist
complex and serves as an index of ligand binding; and "ID50" and "IDioq" refer to doses
of an administered therapeutic agent which produce, respectively, a 50 % and 100%
reduction in a physiological response.
Instrumental Analysis
Unless otherwise indicated, !H NMR spectra are recorded on a either a 300 MHz
or 400 MHz Varian spectrometer at ambient temperature. Data are reported as follows:
chemical shift in ppm from internal standard tetramethylsilane on the 5 scale, multiplicity
(b = broad, s = singlet, d=doublet, t = triplet, q = quartet, qn = quintet and m =
multiplet), integration, coupling constant (Hz) and assignment. Positive and negative
electrospray mass spectral data are obtained on a Micromass Platform LCZ equipped with
an autosampler. Analytical thin layer chromatography is performed on EM Reagent 0.25-
mm silica gel 60-F plates. Visualization is accomplished with UV light. HPLC analysis is
performed on an Agilent 1100 Series HPLC using an acetonitrile/0.03M phosphate buffer
(80/20) as the mobile phase using an Agilent Eclipse XDB-C8 analytical 4.6x150mm 5-
micron column. Melting points are determined on a Mettler Toledo FP62 melting point
apparatus. GC-MS data are obtained on an Agilent HP6S90 GC using a HP-5MS (30m,
0.25mm i.d., 0.25uxn film) column.
Section 1 (derivatives of Formula I having substitution on the "C" ring but not on the "A"
or "B" rings.)

1. Treat a mixture of o-toluenesulfonyl chloride (22g, 115mmol) in dioxane (200mL)
with triethylamine (28mL, 200mmol) and cool to 10°C. Add ethanol (50mL) and allow
the reaction to warm to room temperature. After IS h, acidify the reaction and remove
most of the solvent under reduced pressure. Partition the residue between water/EtOAc.
Dry the organic layer with MgS04 and concentrate to give 22.6g colorless oil. Purify
using flash chromatography (10% EtOAc/hexane) to give 7.4g of pure ester. lH NMR
(CDC13) 51.50 (t, 3H), 2.64 i]-
morpholine

Prepared in 29% yield as a white solid, nip 139.3°C. lH NMR (CDC13) 5 2.76-3.89 (m,
12H), 6.57-7.93 (m, 13H). MS (ES) 432 (M+H).
Example 9
4-Chloro-2-(l 0, ] 1 -dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-5-meihyl-
benzenesulfonamide
MS (ES) 408 (M-H). HPLC shows 81% purity.
Example 10
4-Chloro-2-(10,n-dihydrcKiibenzo[a3d]cycIohepten-5-ylidenemethyl)-5,N,N-trimethyI-
benzenesulfonarnide
White solid, rap 199.9°C. >H NMR (CDCI3) 5 2.36 (s, 3H), 2.95 (s, 6H), 2.98-3.66 (br m,
4H), 6.79-7.80 (m, 11H); MS (ES) 438 (M+H), 436 (M-H.; HPLC shows 98% purity.
Example 11
4-ChIoro-2-(l 0,11 -dihydro-dibenzoC^dlcyclohepten-S-ylidenemethy^-S-methyl-N-
propyl-benzenesulfonamide

White solid. MS (ES) 452 (M+H), 450 (M-H). HPLC shows 97% purity.
Example 12
4-[4-Chloro-2-( 10,11 -dihydro-dibenzo[a,d]cyclohepten-5-yhdenemethyl)-5 -methyl-
benzenesulfonylj-morpholiae
White solid, mp 194.7°C. 'H NMR (CDC13) 6 2.20 (s, 3H), 2.65-3.67 (m, 12H), 6.63-
7.60 (m, 11H); MS (ES) 480 (M+H). HPLC shows 98% purity.
Example 13
2-[2-(2-Ethyl-phenyl)-peQta-l?4-dienyI]-5-methyl-N-phenyl-bcri2:enesulfonamide;
compound with propcne

White solid, mp 220.4°C. lH NMR (CDC13) 5 2.31 (s, 3H), 2.85-3.60 (br m, 4H), 4.54
(br t, 1H), 6.10-7.84 (m, 17H); MS (ES) 452 (M+H), 450 (M-H). HPLC shows 93%
purity.
Example 14
N-Cyclopropyl-2-(10JlHiihydro-4) and concentrate to give 54g crude product Recrystallize from hexane to afford
26.6g (57%)light tan crystals, mp 104.7°C, 5H NMR (CDC13) 5 2.97 (br d, 2H), 3.43 (br
d, 2H), 6.50 (s, 1H), 6.86-7.47 (m, 12H); MS (FAB+) 360. HPLC shows 98.3% purity.
Anal: Calcd. for C22Hi7Br: C, 73.14; H, 4.74. Found: C, 73.22; H, 4.84.
Following the procedures essentially as described in Example 28 above, reaction
of the appropriate crude alcohol intermediate from Preparations 6-14 above, gives the
following compounds:
Example 29
5-(2-Bromo-benzy3idene)-10,ll-dihydro-5H-dibenzo-[a,d]cycloheptene

Following the procedure essentially as described for Example 219, below, and using 5-
bromomethylene-10Jl-^ihydro-5H-dibenzo[a,d]cycloheptene (300mg, 1.05mmol) and
(3-amino-4-methylpbeny])boronic acid hydrochloride (217mg, 1.16mmol), yields 245mg
(75%) 5-(10,l l-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methyI-
phenyiamine as a brown oil. Then, following procedures essentially as described in
Example 90, below, and using 5-(10,l l-^hydro-dibenzo[a,d]cycIohepten-5-
yUdenemethyl)-2-methyl-phenylatnine (lOOmg, 0.321mmol), affords 35mg (28%) of the
title compound as a colorless oil. MS (ES) 407 (M+NH4), 388 (M-H); HPLC shows 98%
purity.
Example 46
N-(3-Bromc*^methyl-phenyl)-methanesulfonarriide

Following the procedures essentially as described for Example 90, below, and using 3-
bromo-4-methylaniIine (5.00g, 26.9mmol), recrystallization from boiling toluene/hexanes
affords 6.08g (86%) of the title compound as a tan crystalline solid. MS (ES) 263 (M-H),
HPLC shows 100% purity.
Preparation IS
N-f4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yI)-phcnyI]-
methancsulfonamide

Mix N-{3-bromo-4-methyl-phenyl)-metfaanesulfonamide(500mg, 1.89mmol),
bis(pioacolato)diboron (576mgi 2.27nunol), and potassium acetate (557mg, 5.67mmol)
in DMSO (6mL). Sparge solution with N2 for lOrnin, then add Pd(dppf)Cl2 (1:1 complex
with CH2CI2, 154mg, 0.189mmol) and heat to 85°C overnight. Cool reaction mixture to
room temperature, dilute with ethyl acetate (1 OOmL), and wash organics four times with
H20. Dry (MgSO<) and concentrate organics to a brown oil. Chromatograph on silica gel
(40g), eluting with 20% to 40% ethyl acetate/hexanes affords 415mg (71%) of the title
compound as a colorless oil. MS (ES) 329 (M+NKU), 310 (M-H); HPLC shows 96%
purity.
Example 47
N-[3-(10,l 1 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-4-methyl-phenyl]-
methanesulfonamide

Following the procedures essentially as described in Example 219, below, and using N-
[4-methylO-(4,4,5,5-tetramethyl-[l,3,21dioxaborolan-2-y])-phenyl]-rnethanesuIfonamide
(120mg, 0.3S6mmoI) and 5-bromomethykne-10,l I-dihydro-5H-
dibenzo[a,d]cycloheptene (lOOmg, 0.351mmol) affords 83mg (61%) of the title
compound as a yellow solid. MS (ES) 407 (M+NH4), 3S8 (M-H), HPLC shows 91 %
purity.
Preparation 16
N-(3-Bromo-2-methyl-phenyl)-methanesu]fonamide

Following procedures essentially as described in Example 90, below, and using 2-methyl-
3-bromoaniline (5.00&, 26.87mmol), recrystallization from boiling toiuene/hexanes
affords 6.77g (95%) of the title compound as a light green solid. MS (ES) 263 (M-H);
HPLC shows 100% purity.
Preparation 17
N-[2-Meuiyl-3^4,4,5^-tetramethyl-[l,3J2]dioxaborolan-2-yl>pheny3]-
methanesulfonamide

Mix N^3-bromo-2-methyl-phenyl)-methanesulfonamide (500mg, 1.89mmol),
bis(pinacolato)diboron (576mg, 2J27mmol), and potassium acetate (557mg, 5.67mmoI)
in DMSO (6mL). Sparge solution with N2 for 5min, then add Pd(dppf)Cl2 (1:1 complex
with CH2CI2,154mg, 0.189mmol) and heat to 85°C overnight. Cool reaction mixture to
room temperature, dilute with ethyl acetate (1 OOmL), and wash organics three times with
H2O. Dry (MgSO/t) and concentrate organics to a brown oil. Chromatograph on silica gel
(40g), eluting with 20% to 40% ethyl acetate/hexanes affords 4S8mg (78%) of the title
compound as a colorless oil MS (ES) 310 (M-H); HPLC shows 76% purity.
Example 4S
N-[3-(l 0,11 -Dihydro-diben2ofa,djcyclohepten-5-yhdenemethyJ)-2-methyl-phenyI]-
methanesulfonamide

Following the procedures essentially as described in Example 219, below, and using N-
[2-methyI-3^4,4,5,5-tetramethyl-[ 1,3;2]dioxa^
(120mg, 0.386mmol) and 5-bromomethylene-10,l l-dihydro-5H-
dibenzo[a,d]cyclobeptene (lOOmg, 0.351mmol), purification by UV-guided semi-
preparatory reverse-phase HPLC affords 18mg (13%) of the title compound as a yellow
oil. MS (ES) 407 (M+NH4), 388 (M-H); HPLC shows 96% purity.
Preparation 18
5-Brcmo-2-fluoro-phenyiamine
Dissolve 4-bromo-l-fluoro-2-nitrobenzene (5.00g, 22.73mmol) and SnCk (dihydrate,
25.46g, 113.6rnmol) in ethanol (lOOmL) and heat to reflux overnight. Cool to room
temperature and concentrate in-vacuo. Dissolve residue in ethyl acetate and basify with
saturated aqueous NaHCC>3. Filter through a pad of Celite and extract filtrate with ethyl
acetate. Dry (MgSCv) and concentrate organics to a brown oil. Chromatograph on 90g
silica gel, eluting with 5% to 10% ethyl acetate/hexanes affords 2.85g (66%) of the title
compound as a tan oil. MS (ES) 191 (M+H); HPLC shows 99% purity.
Preparation 19
N-(5-Bromo-2-fiuoro-phenyI)-mcthancsulfonamide

Dissolve 5-bromo-2-fluoro-phenylamine (1.40g, 7.37mmoI), N,N-dimethylamino-4-
pyridine (90mg, 0.737mmol), and methanesulfonyl chloride (1.69g, 14.74mmol) in
CH2C12 (lQmL) and pyridine (lOmL). Stir under N2 for 4h and concentrate in-vacuo.
Dilute residue with l.OON aqueous HCl (20mL) and extract into ethyl acetate. Dry
(MgS04) and concentrate organics to a yellow solid. Dissolve in THF (20mL) and add
l.OM tctrabutylammonium fluoride/THF (4.83mL, 4.83mmol). Heat to reflux for 3h, then
add H26 and brine. Extract into ethyl acetate, then dry (MgS04) and concentrate organics
to a white solid. Recrystallization from boiling toluene/hexanes affords 768mg (39%) of
the title compound as a white solid. MS (ES) 267 (M-H); HPLC shows 100% purity.
Example 49
N-[5-(10,ll-DihydrcKuT)enzo[a,d]cyclohepten-5-ylidenemethyl)-2-fluoro-phenyI]-
methanesulfonamide
Following the procedures essentially as described in Example 219 (below) and using
(10,1 l-dihydro-dibenzo[a,d]cyc]ohepten-5-ylidene)-boronic acid (0.197M in dioxane,
3.35mL, 0.660mmol) and N-(5-brorno-2-fluoro-phenyl)-methanesulfonamide (147mg,
0.550mmol) affords 141mg (65%) of the title compound as a purple foam. MS (ES) 411
(M+NH4), 392 (M-H); HPLC shows 91% purity.
Preparation 20
N-(3-FIuoro-5-iodo-phenyl)-methanesulfonamide

Dissolve 3-fluoro-5-iodoaniIine (600mg, 2.53mmol) (prepared as described in published
PCT International Application W096/237S3 Al, published August 8,1996),
methanesulfonyl chloride (896mg, 7.83mmol), triethylamine (l.9Ig, 18.9mmoJ), and
N,N-dimethylamino-4-pyridine (31mg, 0.253mmol) in CH2CI2 (lOmL) and stir at room
temperature overnight. Dilute with l.OON aqueous HCI (20mL) and extract into ethyl
acetate. Dry (MgS04) and concentrate organics to a yellow solid. Dissolve solid in THF
(50mL) and add 1.0M tetrabutylammonium fluoride (2.8mL). Heat to reflux for 3.5h.
Cool to room temperature, dilute with H2O, and extract into ethyl acetate. Dry (MgSQj)
and concentrate organics. Chromatograph on silica gel (40g), eluting with 20% to 35%
ethyl acetate/hexanes affords 618mg (78%) of the title compound as a white solid. MS
(ES) 314 (M-H); HPLC shows 100% purity.
Example SO
N-[3-(l 0,11 -Dihydro^berizo[a,d]cyclohepten-5-ylidenemethyl)-5-fJuon>-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 219, below, and using 10,11-
dihydro-dibenzo[a,d]cycIohepten-5-ylidene)-boronic acid (0.19SM in dioxane, 5.1mL,
1.02mmol) and N-(3-fluoro-5-iodo-phenyl)-incthanesulfonamide (26Smg, O.S50mmol),
purification by UV-guided reverse-phase semi-preparatory HPLC affords 108mg (32%) of
the title compound as a colorless oil. MS (ES) 394 (M+H), 392 (M-H); HPLC shows
99% purity.
Example 51
5-(3,5-Dimethoxy-benzylidene)-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Preparation 5 and Example 28, above,
and using dibenzosuberone (2.0Og, 10.29mmol) and 3,5-dimethoxybenzaIdehyde (1,71g,
10.29mmol), affords 1.43g (41 %) of the title compound as a yellow foam. 'H-NMR
(CDCls) 5 2.79-3.64 (br m, 4H>, 3.55 (s, 6H), 6.20 (4 2H), 6.25 (t, 1H), 6.72 (s, 1H),
7.06-7.30 (m, 7H), 7.48 (ra, 1H); HPLC shows 99% purity.
Example 52
5-(2,5-Dimethoxy-benzylidene)-l 0,1 l-dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Preparation 5 and Example 28, above,
and using dibenzosuberone (2.00g, 10.29mmol) and 2,5-dimethoxybenzaldehyde (l-71g,
I0.29mmol) affords 1.27g (36%) of the title compound as a yellow solid. 'H-NMR
(CDCI3) S 2.74-3.67 (br m, 4H), 3.34 (s, 3H), 3.83 (s, 3H), 6.27 (d, 1H), 6.65 (dd, 1H),
6.77 (d, IH), 6.98-7.28 (m, 8H), 7.56 (dd, 1H); HPLC shows 99% purity.
Example 53
5-(2,4-Dimethoxy-benzylidene)-10,11 -dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Preparation 5 and Example 28, above,
and using dibenzosuberone (2.00g, 10.29mmol) and 2,4-dimethoxybenzaldehyde (1.71g,
1 0.29mmol) affords 231mg (7%) of the title compound as a white foam. 'H-MVER
(CDC13) 5 2.70-3.67 (br m, 4H), 3.73 (s, 3H), 3.84 (s, 3H), 6.15 (dd, 1H), 6.41 (d, 1H),
6.61 (d, 1H), 6.9-7.27 (m, 8H), 7.56 (dd, 1H); HPLC shows 98% purity.
Example 54
5-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-ben2ene-1,3-diol

Following procedures essentially as described in Example 57, below, and using 5-{3,5-
dirnethoxy-benzyUdene)-10,n-dihydro-5H-dibenzo[a,d]cyclohq3tene (664mg,
1.94mmol), affords 60Smg (99%) of the title compound as a colorless oil. 'H-NMR
(CDCI3) 6 2.73-3.62 (br m, 4H), 4.89 (br s, 2H), 6.07 (d, 2H), 6.14 (t, 1H), 6.64 (s, 1H),
7.04-7.2S (7H), 7.44 (m, 1H); HPLC shows 98% purity.
Example 57
3-( 10,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pheno3

1 n <1_
Stir a molten mixture of 5-(3-methoxy-benzylidene)-l 0,11 -dihydro-5H-
dibenzo[a,d]cycloheptene (1.1 lg, 3.55mmol) and pyridine hydrochloride (lOg, S7mmol)
at 215°C for 40 min. Cool the reaction mixture to 100°C, dilute with IN HC1, and extract
with ethyl acetate. Dry organics (MgSC>4), filter, and concentrate to a brown oil
containing the title compound. Purification via silica gel chromatography (1:6 ethyl
acetate :hexanes) affords 940mg (89%) of a tan oil. 'H NMR (CDC13) 5 2.76-3.63 (br m,
4H), 4.59 (s, 1H), 6.45 (s, 1H), 6.64 (m, 2H), 6.75 (s, 1H), 6.99-7.52 (m, 9H); MS (ES)
299 (M+H), 297 (M-H). HPLC shows 97% purity.
Example 60
4-( 10,11 -Dihydro-diben2o[a,d]cyclohepten-5-ylideneniethyl)-phenol

Following procedures essentially as described in Example 57, above, and using 5-(4-
memoxy-beiizylidene)-10,llKimydro-5H-diberiZo[a,d]cycloheptene gives the title
compound in 60% yield as a white crystalline solid, mp 56.9CC. 'H NMR (CDCI3) 5
2.77-3.60 (br m, 4H), 4.71 (s, 1H), 6.62 (d, 2H), 6.73 (s, 1H), 6.92 (d, 2H), 7.02-7.50 (m,
8H); MS (ES) 297 (M-H). HPLC shows 97% purity.
Example 62
4-( 10,11 -Dihydro-dibenzo[a,d]cycJohepten-5-ylidenemethyl)-benzene-1 ,2-diol

Following procedures essentially as described in Example 57, above, and using 5-(3,4-
dimethoxy-benzylidene)-] 0,1 l-dihydro-5H-dibenzo[a,d]cycloheptene gives the title
compound in 79% yield as a brown foam, mp I3S.0°C. *H NMR (CDC13) 5 2.76-3.62 (br
m, 4H), 4.84 (s, 1H), 5.07 (s, 1H), 6.47 (s, 1H), 6.55 (m, 11H); MS (ES) 313 (M-H).
HPLC shows 95% purity.
Example 63
2-Amino-4-(10,11 -dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol

Following procedures essentially as described in Example 57, above, and using 5-(10,l 1-
dihydxo-dibeii2»[a,d3cyclohepten-5-yHdenemethyl>2-methoxy-phenylamkie gives the title
compound in 75% yield as a brown foam, mp 158.8°C. 5H NMR (CDC13) 8 2.72-4.45 (to-
rn, 6H), 631-7.54 (br m, 13H). MS (ES) 314 (M+H), 312 (M-H). HPLC shows 98%
purity.
Example 64
N-[5-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-yIidenemethyl)-2-hydroxy-phenyl]-
methanesulfonamide
Cool a solution of N-[5-(10,l l-dihydro-dibenzo[a.d]cycIohepten-5-ylidenemethyl)-2-
methoxy-phenyl]-methancsulfonamide (lOOmg, 0.247mmol) in CHiCb (5mL) to 0°C.
Add 23.30L (62mg, 0.247mmol) BBr5 and warm up to room temperature. Stir for
20min, then add 30.0DL (79.5mg, 0.317mmol) more BBr3. Stir at room temperature for 1
h, then dilute reaction with 90mL saturated aqueous NaHC03. Stir overnight. Separate
the layers, and extract the aqueous layer with CH2Q2. Combine and dry organics
(MgS04), filter, and concentrate to afford 94mg (97%) of a white foam, mp 122.6°C. ]H
NMR (CDCI3) 8 2.70 (s, 3H), 2.79-3.59 (br m3 4H), 5.94 (s, 1H), 6.39 (s, 1H), 6.70-7.98
(m, 12H); MS (ES) 414 (M+Na), 390 (M-H). HPLC shows 99% purity.
Example 65
5-(3-Difluoromethoxy-benzylidene)-10,l 1 -dihydro-5H-dibenzo[a,d]cycloheptene

Add pellets of KOH (376mg, 6.7mmoI) to a solution of 3-(10,l 1-dihydro-
dibenzo[a,d]cyclohepten-5-ylidenemetbyl>phenol (200mg, 0.67mmol) in isopropanol
(1 OmL). Bubble chlorodifluoromeihane (Freon 22) slowly into the reaction mixture for 2
h. Concentrate the reaction mixture, and take the residue up in IN HCI. Extract into
ethyl acetate, dry organics (MgSCu), filter, and concentrate to a milky tan oil containing
the title compound. Purify via silica gel chromatography (1:20 ethyl acetate:hexanes) to
afford 108mg (20%) of a white solid, mp 91.3 °C lH NMR (CDCI3) 6 2.66-3.56 (br m,
4H), 6.12 (t, 1H, J=80Hz), 6.55-7.43 (m, 13H); MS (EI) 348. HPLC shows 97% purity.
Example 66
5-(2-Difluoromcthoxy-bcnzylidene)-10,1 l-dihydro-5H-dibenzo[a,d]cycloheptene

Following the procedures essentially as described in Example 65 above, 5-(2-
difluoromethoxy-benzylidene)-10,ll-dihydro-5H-diben2o[a,d]cycloheptene gives the title
compound in 20% yield as a white solid, mp 81.1°C. JH NMR (CDCI3) 5 2.76-3.72 (br m,
AS), 6.57 (t, 1H, J=72Hz), 6.75-7.57 (m, 13H); MS (EI) 348. HPLC shows 95% purity.
Example 67
5-(4-Difluoromethoxy-benzylidene)-l 0,1 l-dihydro-5H-dibenzo[a,d]cycloheptene

Following the procedures essentially as described in Example 65 above, 5-(4-
difluoromethoxy-benzylidene)-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene gives the title
compound in 46% yield as a white solid, mp 65.8°C. 'H NMR (CDCI3) 5 2.76-3.64 (br m,
4H), 6.44 (t, 1H, J=76Hz), 6.76 (s, 1H), 6.84-7.50 (m, 12H); MS (EI) 348. HPLC shows
100% purity.
Preparation 21
3-(10,l l-Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzenesulfonyl chloride

Under a blanket of nitrogen, cool 5-(3-bromo-bertzylidene)-10,l l-dihydro-5H-dibenzo-
[a,d]cycloheptene (2.Sg, 7.75mmol) in THF (40mL) to -7S°C and add n-BuLi (I.6M,
5.SmL, 9.3mmol) via syringe. After 20 min, add sulfuryi chloride (800u.l, lOmmol). The
color lightened immediately. Quench the reaction with saturated NEUC1 and mix the
reaction with water/EtOAc. Dry (MgSOj) and concentrate to give 2.7g pale yellow oil.
Purify on silica gel using a gradient of 100% hexane to 30% EtOAc/hexane to give
3S0mg (13%) sulfonyl chloride. Stir a small aliquot with dimethylamiEe for several
hours. MS (ES) gives the correct mass for the dimethylsulfonanude derivative.
Preparation 22
4-(lO,II-Dihydro-dibenzo[a,d]cyclohq5ten-5-ylidenemethyI)-benzenesulfonyl chloride

Prepared using Procedure E to give 142mg (8%) sulfonyl chloride as a pale yellow oil.
Example 68
4-(10Jl-I3ihydTo^ibenzo[a4]<^lolv^ten-5-ylidetieTnethyi)-benzaldehyde

Under nitrogen, cool 5-(4-bromo-ben2yMene)-10,n-dihydro-5H-dibenzo-
[a,d]cycloheptene (2.2g, 6.1mmol) in THF (40mL) to -65°C and add n-BuIi (1.6M, 5mL,
Srnmol) via syringe. After 15 minutes, add DMF (hnL, I4mmoI). After I h, the quench
the reaction with saturated MLsCl and partition between water/EfOAc. Dry (MgSO.0 and
concentrate to yield l.Sg crude aldehyde. Purify on silica gel using hexane/EtOAc to give
940mg colorless oil that slowly crystallized to give a white solid, mp 106.4°C; !H NMR
(CDC13) 5 2.80-3.60 (br dd, 4H), 6.84 (s, 1H), 6.92-7.63 (m, 12H), 9.90 (s, 1H); MS (EI)
310. HPLC shows 96% purity.
Example 69
2-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemcthyl)'benzaldehyde

Following procedures essentially as described in Example 68, the title compound was
prepared from the corresponding bromide derivative to give white crystals
(hexane/EtOAc, 42%), mp I98.9°C. lH NMR (CDC13) 5 2.80-3.60 (br s, 4H), 6.67-7.86
(m, 13H), 10.42 (s,lH); MS (EI) 310. HPLC shows 97% purity.
Example 70
3-{ 10,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzaldehyde

Following procedures essentially as described in Example 68 the title compound was
isolated as a white solid (38%), mp 86.7°C. lH NMR (CDC13) 82.80-3.60 (br dd, 4H),
6.84 (s, 1H), 6.93-7.65 (m, 12H), 9.81 (s, 1H); MS (EI) 310. HPLC shows 97% purity.
Example 71
5-(2-Difluoromethyl-bcnzylidene)-10,11 -dihydro-5H-dibenzo[a,d]cycloheptene

Dissolve 2-(10,ll-dihydro-dibenzo[aJd]cyclohepten-5-ylidenemethyl)-ben2aldehyde
(lOOmg, 0.32mmol) in CH2C12 (3mL) and add (diemylamino)sulfur trifluoride (DAST)
(210D1,1.6mmol). Stir the reaction overnight at ambient temperature. Shake the crude
reaction with saturated NaHCCV&kCfe- Dry (MgSCU) and concentrate to give 1 lOrng
crude product. Purify on silica gel using bexanc/CHfeCh to give 50mg (47%) title
compound as a-white solid, mp. 13.3°C. !H NMR (ODC13) 5 2.80-3.60 (br s, 4H), 6.72-
7.5S (m, 14H); MS (EI) 332. HPLC shows 98% purity.
Example 72
5-(3-Difluoromethyl-beiizyudene)-1041- 10,11 -dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Example 71, the title compound was
prepared as a colorless oil (39%); 'H NMR (CDCI3) 5 2.80-3.60 (br dd, 4H), 6.47 (t, IH,
J=55Hz), 6.72 (s, IH), 6.87-7.24 (m, 1 IH), 7.42 (m, IH); MS (EI) 332. HPLC shows
100%puricy.
Example 74
[2-(10,ll-Dihydro-dibcnzo[a,d]cycIohepten-5-ylidencmethyl)-phenyl]-mcthanoI

Treat a solution of 2-{10,l l-dihydro-dibcnzo[a,d]cyclohepten-5-ylidenemethyl)-
benzaldehyde (125mg, O.4mmol) in EtOH (4mL) with NaBR, (30mg, 0.8mrnol). After 4
h at room temperature, quench the reaction with IN HC1 and concentrate. Shake the
residue en with water/EtOAc. Dry the organic layer (MgS04) and concentrate to give
130mg crude product Purify on silica gel (EtOAc/hexane) to give 90mg (72%) colorless
oil which slowly crystallized, mp 121.8°C. 'H NMR (CDC13) 6 3.28 (or s, 4H), 4.85 (s,
2H), 6.77-7.60 (m, 13H; MS (EI) 312. HPLC shows 98% purity.
Example 75
[3-(10,ll-Dmydro-dil>erizo[a)d]cyclohc^ten-5-yu^enemethyI)-pheny]]-methanol

Following procedures essentially as described in Example 74, the title compound was
obtained as a colorless oil which slowly crystallized. 'H NMR (CDC13) 5 3.03 (br d, 2H),
3.47 (br d, 2H), 4.55 (s, 2H), 6.84 (s, 1H), 6.93-7.31 (m, 11H), 7.52 (in, 1H); MS (EI)
312. HPLC shows 93% purity.
Example 76
[4-(l 0,11-Dihydro-dibenzo[a.d]cyclohepten-5-ylidenemethyl)-pheny]]-methanol

Following procedures essentially as described in Example 74, the title compound was
obtained as a colorless oil (65%); ]H NMR (CDC13) 53.03 (br d, 2H), 3.47 (br d, 2H),
4.62 (s, 2H), 6.78 (s, 1H), 7.02-7.34 (m, 11H), 7.520 (m, 1H); MS (EI) 312.
Example 77
2-(10,l l-Dihydro-diben2o[a,d]cyclohepten-5-ylidenemethyl)-benzaldehyde oxime

Dissolve 2-(10,l l-dihydro-djben2o[a,d]cyclob.epten-5-ylidenemethyi)-benzaldehyde
(110mg,0.35mmol) in EtOH (4mL). In a separate flask, dissolve hydroxylamine
hydrochloride (35mg> 0.5mmol) in water (ImL). Add this solution the aldehyde solution
and stir at room temperature for 1 Sh. Pour the reaction into water (300mL) and extract
the product into EtOAc. Dry (MgSQj) and concentrate to give 140mg crude product
Purity on silica gel using EtOAc/hexane to give 82mg (72%) title compound as a white
solid lE NMR (CDC13) 8 3.31 (br s, 4H), 6.73-7.33 (m, 11H), 7.55 (m, 1H), 7.70 (dd,
1H), 8.58 (s, 1H); MS (ES) 326 (M^l), 324 (M-I). HPLC shows 98% purity.
Example 78
3-(10,l 1 -Dihydro-dibenzo[a,d]cycloheprcn-5-ylidenemethyl)-ben2aldchyde oxime

Following procedures essentially as described in Example 77, the title compound was
prepared in 55% yield from 3^10,llKlihyd«>-dibenzo[a,d]cyclohepten-5-ylideneme±yl)-
benzaldehyde (50mg, 0.161mmol). ]H NMR (CDC13) o 2.92 (br d, 2H), 336 (br d, 2H),
6.72 (s, 1H), 6.87-7.43 (m, 12H), 7.87 (s, 1H); MS (ES) 326 (M+l).
Example 79
4~{10,1 l-Dihydro-dibenzo[a,d]cycloheptcn-5-ylidenemethyl)-benzaldchyde oxime

Following procedures essentially as described in Example 77, the title compound was
prepared in 55% yield from 4-(10,l l-dihydro-dibenzo[a,d3cyclohepten-5-ylidenemethyl)-
benzaldehyde (117mg, 0.3Smmol). 'H NMR (CDC13) 8 2.77 (br d, 2H), 3.21 (br d, 2H),
6.57 (s, 1H), 6.61-7.64 (ro,12H), 7.82 (s, 3H); MS (ES) 326 (M+l). HPLC shows 97%
purity.
Example 80
2-(10,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-ben2onitnie

Sparge a mixture of 5-methyIcne-lO, 11 -dihydro-5H-dibenzo[a,d]cycloheptenc (2.0g,
9.7mmol) (prepared as described in Journal of Organic Chemistry, 53 (8) 1768-1774
(1988)), 2-bromobenzonitrile ((1.77g, 9.7mmol), NaOAc (lg, 12 mmol) and
dimethylacetamide (lOOmL) with nitrogen for 15 minutes. Add Hermann catalyst
(32Qmg, 0.46mmol)(Chero. Eur. J. 1357-1364 (1997)) and heat at 150°C for 6 days. Cool
the reaction and partition between water (1L) and EtOAc (500mL). Wash the organic
layer with water (3 x 1L). Dry (MgS04) and concentrate under reduced pressure to give
3.3g brown oil. Purify on silica gel using EtOAc/hexane 500mg nitrile that is 81 % pure
byglc. Recrystallize (EtOH) to give 213mg (7%) pale yellow plates, mp 185.4°C. lH
NMR (CDC13) 5 3.04 (br d, 2H), 3.47 (or s, 2H), 6.82-7.34 (m, 11H), 7.62 (m, 2H); MS
(ES) 308 (M+l). HPLC shows 98% purity.
Example 81
3-( 10,11 -Dihydro-dibenzo[a,d] cyclohepten-5-ylidenemethyl)-benzonitrile

Purge a solution of 5-(3-bromo-benzyiidene)-10,l l-dihydro-5H-dibenzo-
[a,d]cycloheptene (4.2g, 11.6mmol) in N-methylpyrrolidinonc (80mL) with nitrogen for
10 minutes. Add Cul (6.7g, 35mmoI) and CuCN (3. lg, 35mmoi) and heat to 130°C.
After 1 hour, cool the reaction to ambient temperature and shake with aqueous FeC^
(200mL) and EtOAc (200mL). Wash the organic layer with water, dry with MgSO* and
concentrate to obtain 6.4g crude product. Purify on silica gel using EtOAc/hexane to
obtain 2.55g (71%) title compound as a white solid, mp 115.7°C. 'H NMR (CDCI3) 6
3.02 (br d, 2H), 3.40 (brd, 2H), 6.77 (s, 1H), 6.93 (dd, 1H), 7.02-7.49 (m,HH); MS (EI)
307. HPLC shows 98% purity.
Example 82
4-( 10,11 -Dihydro-diben2o[a,d]cycloheptcn-5-yUdenemethyl)-benzonirri]e

Following procedures essentially as described in Example 8land using 5-(4-bromo-
benzylidene)-10,ll-diliydro-5H-dibenzo-[aJd]cycloheptene (4.2g, 11.6mmol) gives 2.02g
(57%) as tan viscous oil. lH NMR (CDC13) 5 3.06 (br d, 2H), 3.48 (br d, 2H), 6.85 (s,
1H), 6.98 (dd, 1H), 7.06-7.57 (m, 11H; MS (EI) 307. HPLC shows 97% purity.
Example 83
2-( 10,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzainide

Dissolve 2-(10,l l-dihydro-diben2o[a,d]cyclobepten-5-ybdenemethyl)-benzonitrile
(lOOmg, 0.32mmol) in DMSO (3mL) and add solid K2CO3 (50mg) followed by 30%
H2O2 (10001). Stir the reaction for 3 h. and quench by pouring into water. Collect the
white solid and dry in a vacuum oven to yield 84mg (Sl%). 'H NMR (DMSO-d^) 52.95
(br s, 2H), 3.38 (brs, 2H), 6.67-7.56 (m, 12H), 7.90 (s, 1H); MS (ES) 326 (M-f 1), 324
(M-l). HPLC shows 95% purity.
Example 84
3-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-yiideneraeth>i)-benzaniide

Following procedures essentially as described in Example 83 and starting with 3-(l 0,11 -
dmydrcKdfl>enzo[M]cyclobepten-5-yu"denemethyI)-beazonitrile (480mg, 1.56mmol) gives
445mg (88%)as an off-white solid. 'H NMR (DMSO-d*) 5 2.95 (br s, 2H), 3.40 (br s,
2H), 6.85-7.54 (m, 10H), 7.61 (d, 1H), 7.72 (s, 1H), 7.84 (s, IH); MS (ES) 326 (M+I),
324 (M-l). HPLC shows 94% purity.
Example 85
4^10;n-DmydrcKiibenzo[a,d]cyclohepten-5-yh'denemethyl)-benzamide

Following procedures essentially as described in Example 83 and starting with 4-(10,11-
dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzonimle (230mg, 0.75mmol) gives
226mg (93%) white powder. !H NMR pMSO-d*) 5 2.95 (br s, 2H), 3.38 (br s, 2H),
6.82-7.54 (m, 1 IH), 7.67 (d, IH), 7.87 (s, IH); MS (ES) 326 (M+l). HPLC shows 96%
purit)'.
Example 86
3-(1041-Dmydro^benzofa,d]cycloheptcn-5-ylidenemethyl)-phenylaniine

Dissolve 5-(3-bromo-benzylidene)-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene (3.00g,
8.30mmol) in toluene (75mL) and add the following reagents: tris{dibenzylidine
acetone)dipalladiuni(O) (3S0mg, 0.415mmol), racemic BINAP (517mg, 0.830mmol),
sodium t-butoxide (1.12g, 11.6mmol),'and benzophenone imine (3.4SmL, 3.76g,
20.76mmol). Heat the mixture to reflux overnight Cool to room temperature and dilute
with H2O. Extract into ethyl acetate and dry organics (MgSC^). Concentrate organics
and take the residue up in a 1:1 mixture of THF and IN HC1. After 2 h, extract into ethyl
acetate and dry organics (MgSQi). Concentrate to a brown solid containing the title
compound. Boil the solid in a 5:1:0.1 mixture of toluene:ethyl acetate:THF. Cool the
suspension to -26°C and filter, collect 1.98g (80%) of a white solid, mp 204.3°C. *H
NMR (DMSO-dg) 8 2.90 (br s, 2H), 3.36 (br d, 2H), 6.77-7.51 (m, 15H); MS (ES) 298
(M+H). HPLC shows 99% purity.
Example 87
2-(10,ll-Dihydro-dibenzo[a,d]cyclohepten-5-yiidenemethyl)-phenylainine

Following procedures essentially as described in Example S6, 5-{2-bromo-bcnzylidcnc}-
10,1 l-dihydro-5H-dibenzo[a,d]cycloheptene gives the title compound in 85% yield as a
yellow foam, mp 145.2°C after purification using silica gel chromatography (75:24:1
hexanes:CH2CI2:2M NH3/MeOH). 'H NMR (CDC13) 6 3.25 (br s, 4H), 3.80 (s, 2H),
6.45-7.51 (m, 13H); MS (ES) 298 (M+H). HPLC shows 95% purity.
Example 88
4-( 10,11 -Dihydro-dibenzo[a,d] cyclohepten-5-yhdenememyl)-phenylaniine

Following procedures essentially as described in Example 86,5-(4-bromo-benzylidene)-
10,1 l-dihydro-5H-dibenzo[a,d]cycloheptcne gives the title compound in 54% yield as an
orange solid, mp >250°C after purification by triturating with hot CH2C12. lH NMR
(DMSO-dg) 8 2.86 (br s, 2H), 3.32 (br d, 2H), 6.74 (s, 1H), 6.89-7.48 (m, 14H), MS (ES)
298 (M+H). HPLC shows 98% purity.
Example 89
5-(10,ll-Dihydro-diT)enzo[a,d](^lohepten-5-yUdenemethyl)-2-methoxy-phenylamine

Following procedures essentially as described in Example 86, 5-(3-brotno-4-methoxy-
benzylidene)-10,l l-dihydro-5H-dibenzo[a,d]cycloheptcne gives the title compound in
36% yield as a yellow foam, mp 62.7CC after purification via silica gel chromatography
(1:9 ethyl acetate:hexanes). 'H NMR (CDC13) 5 2.69-3.73 (br m, 6H), 3.80 (s, 3H), 6.36
(s, 1H), 6.48 (dd, 1H), 6.60 (d, 1H), 6.66 (s, 1H), 7.00-7.50 (m, 8H); MS (ES) 328
(M+H). HPLC shows 98% purity.
Example 90
N-[3-(10,ll-Dihydro-dibenzo[a,d]cycIoheptcn-5-ylidenemethyl)-phenyl]-
methanesulfonamide

Dissolve 3-<10,l 2nJihydro^ben2xi[a,d]cyclohepten-5-yiJdeiieniethyl)-phenyIamine
(400mg, 1.34mmol) in anhydrous pyridine (lOmL) and add methanesulfonyl chloride
(616mg, 4160L, 5.38mmol). Stir overnight at room temperature, then concentrate. Take
residue up in ethyl acetate and IN HC1 and separate the layers. Extract aqueous layer
with ethyl acetate, combine organics, and dry (MgSC^). Concentrate to a brown oil.
Purify via silica gel chromatography (2:3 ethyl acetate:hexanes) to yield 350mg (70%) of
yellow foam, mp 66.3°C. !H NMR (CDCb) 5 2.71 (s, 3H), 2.75-3.56 (br m, 4H), 6.09 (s,
1H), 6.64-7.43 (m, 13H); MS (ES) 39S (M+23), 374 (M-H). HPLC shows 96% purity.
Example 91
Ethanesulfonic acid [3-(10,ll-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-
phenyl)-amide

Following procedures essentially as described in Example 90, 3-(10,l 1-dihydro-
dibenzo[a,d]cyclohepten-5-ylidencmethyl)-phenylamine and cthanesulfonyl chloride gives
the title compound in 74% yield as a brown solid, mp 1S0.2°C. 'h NMR (CDCI3) 5 1.25
(t, 3H), 2.80-3.60 (br m, 6H), 6.06 (br s, 1H), 6.71-7.51 (m, 13H);MS (ES)412 (M+Na),
388 (M-H). HPLC shows 99% purity.
Example 92
Propanc-2-sulfonic acid [3-(10,l l-dihydro-diben2o[a,d]cyclohq3ten-5-ylidenemethyl)-
phenylj-amide
Following procedures essentially as described in Example 90,3-(10,l l-dihydro-
dibenzo[a,d]cycIohepten-5-yUdenemethyl)-phenylaniine and isopropylsulfonyl chloride
gives the title compound in 22% yield as a white solid, mp 187.7°C. 'H NMR (CDCIj) 6
1.28 (d, 6H), 2.80-3.60 (or m, 5H), 6.47 (s, 1H), 6.75-7.50 (m, 13H); MS (ES) 426
(M+Na), 402 (M-H). HPLC shows 94% purity.
Example 93
N-[3-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phcnyl]-
benzenesulfonamide

Following procedures essentially as described in Example 90,2-(10,l l-dihydro-
dibenzo[a,d]cyclohepten-5-ylideneinethyl)-phenylamine and benzenesulfonyl chlonde
gives the title compound in 82% yield as a white solid, mp 121.9SC. lK HMR (CDC13) 6
2.76-3.56 (br m, 4H), 6.64-7.77 (m, 19H); MS (ES) 460 (M+Na), 436 (M-H). HPLC
shows 9S% purity.
Example 94
3,5-DimethyI-isoxazole-4-sulfonic acid [3-00,1 l-dihydro-dibenzo[a,djcyclohepten-5-
ylidenemethyl)-phenyl]-amide

Following procedures essentially as described in Example 90,2-(10,ll-dihydro-
dibenzora,d]cyclohepten-5-yh'denememyI>phenylamine and 3,5-dimetbyl-isoxazole-4-
sulfonyl chloride gives the title compound in 80% yield as a white solid, mp 149.3°C. lH
NMR. (CDClj) 6 2.21 (s? 3H), 2.40 (s, 3H), 2.77-3.54 (br m, 4H), 6.57 (s, 1H), 6.69 (d,
2H), 6.86-7.48 (m, 1 IE); MS (ES) 479 (M+Na) 455 (M-H). HPLC shows 95% purity.
Example 95
l-Methy!-lH-imidazole-4-sulfonic acid [3-< 10,11-dJhydro-dibenzo[a,d]cyclohepten-5-
ylidenemethyl)-phenyl]-aniide

Following procedures essentially as described in Example 90, 2-(10,l 1-dihydro-
dibenzora,d}cyclobepten-5-ylidenemetb.yl)-phenylamine and 1 -methyl- lH-kmdazole-4-
sulfonyl chloride gives the title compound in 40% yield as a white solid, mp 257.0°C. 'H
NMR (DMSO-d6) 6 2.90 (br s, 2H), 3.35 (br s, 2H), 3.64 (s, 3H), 6.46 (d, 1H), 6.67 (s,
III), 6.S0-7.46 (m, 11H), 7.79 (d, 2H), 6.11 (s, 1H); MS (ES) 464 (M+Ka). HPLC snows
100% purity.
Example 96
1,2-Dimethyl-lH-imidazoJc-4-sulfonic acid [3-(l0,l l-dihydro-diben?.o[a,d5cyclohepten-
5-ylidenemethyl)-phenylj-anaide

Following procedures essentially as described in Example 90,2-{10,l 1 -dihydro-
dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and 1,2-dimethyl-lH-iraidazole-
4-sulfonyl chloride gives the title compound in 1% yield as a white solid. MS (ES) 456
(M+H). HPLC shows 100% purity.
Example 97
N-fS^lOjll-Dihyo^ro-dibenzofajdJcyclohepten-S-yhdenemethy^^-methoxy-phenyl]-
memanesulfonanude

Following procedures essentially as described in Example 90-, 5-(10,l 1-dihydro-
dibenzo[a,d]cycIohepten-5-yIidenemethyl)-2-methoxy-phenylamine and methanesulfonyl
chloride gives the title compound in 77% yield as a tan foam, mp 192.1°C. 'H NMR
(CDCI3) 8 2.74 (s, 3H), 2.80-4.61 (br m, 4H), 4.81 (s, 3H), 6.67-7.50 (m, 13H); MS (ES)
423 (M+Nrit), 404 (M-H). HPLC shows 100% purity.
Example 99
N-[4-(l0>ll-Dihydro-dibcnzo[a,d]cyclobcptcn-5-ylidenemethyl)-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 90,4-{l 0,11 -dihydro-
dibenzo[a,d]cyclobepten-5-ylidenemethyl)-phenylamine and methanesulfonyj chloride
gives the title compound in 48% yield as a tan solid, mp 210.7°C. 'H NMR (CDC13) 8
2.72-3.5S (br m, 7H), 6.49 (s, 1H), 6.74 (s, 1H), 6.96-7.49 (m, 12H); MS (ES) 398
(M+Na), 374 (M-H). HPLC shows 98% purity.
Example 104
Propane-1-sulfonic acid [3-(10,ll-dihydro-dibenzo[a,d]cyclohepten-5-yIidenemethyl)-
phenyl]-amide

Following procedures essentially as described in Example 90,3-(l 0,11-dihydro-
dibcnzo[a,d]cyclohepten-5-yIidenemethyl)-phenylamine (50mg, 0.168mmol) and 1-
propanesulfonyl chloride (144mg, l.Olmmol) affords 34mg (50%) of me title compound
as a white foam. MS (ES) 426 (M+Na), 402 (M-H); HPLC shows 99% purity.
Example 105
Butane-1-sulfonic acid [3-(10,n-dihydro-dibenzo[a,d)cyclohepten-5-ylidcncmeihy!)-
phenylj-amide

Following procedures essentially as described in Example 90,3-(10,l 1-dihydro-
dibenzo[a,dJcyclohepten-5-yiidenemethyl}-plienylamnie (50mg, 0.168mmol) and 1-
butanesulfonyl chloride (158mg, l.Olmmol) affords 41mg (58%) of the title compound as
a colorless oil. MS (ES) 440 (M+Na); HPLC shows 99% purity.
Example 106
Ethanesulfomc acid [4-{10,l l-Klihydro-dibenzo[a,d]cycIohepten-5-ylidenemethyl)-
phenylj-amide
Following procedures essentially as described in Example 90,4-(l0,l 1-dihydro-
diben7o[a,d]cyclohepten-5-yIidenemethyl)-phenylamiiie (lOOmg, 0.336mmol) and
ethanesulfonyl chloride (129mg, l.Olmmol) affords 74mg (57%) of the title compound as
a colorless oil. MS (ES) 412 (M+Na), 388 (M-H); HPLC shows 97% purity.
Example 107
Propane-2-suIfonic acid [4-(10,l l-dihydro-dibenzo[a,d]cyclohepten-5-yhdenemethyl)-
phenylj-amide

Following procedures essentially as described in Example 90,4-(10,l 1-dihydro-
dJbenzo[a,d]cyclohepten-5-yUdenemethyl)-phenylarnine (lOOmg, 0.336mmol) and 2-
propanesulfonyl chloride (144mg, l.Olmmol) affords the title compound. MS (ES) 426
(M+Na), 402 (M-H); HPLC shows 93% purity.
Example 108
Propane-1-sulfonic acid [4-(10,ll-dihydro-dibenzo[a,d]cyclohepten-5-ybdenemethyl)-
phenylj-amide

Following procedures essentially as described in Example 90,4-{10,l 1-dihydro-
diben2o[a,d]cyclohepten-5-yhdenememyl)-phenylarnine (lOOmg, O.336mmol) and 1-
propanesulfonyl chloride (144mg, l.Olmmol) affords 69mg (51%) of the title compound
as a colorless oil. MS (ES) 426 (M+Na), 402 (M-H); HPLC shows 99% purity.
Example 109
Butane-1-sulfonic acid [4-(10,l l-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemelhyl)-
phenylj -amide

Following procedures essentially as described in Example 90,4-<10,l 1-dihydro-
diben2o[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (lOOmg, 0.336mmol) and 1-
butanesulfonyl chloride (158mg, l.Oltomol) affords 88mg (63%) of the title compound as
a yellow oil. MS (ES) 440 (M+Na), 416 (M-H); HPLC shows 98% purity.
Example 110
2-Methyl-propane-l -sulfonic acid [3-(10,ll-dihydro-dibenzo[a,d]cyclohepten-5-
ylidenemetbyl)-phenyl]-amide
Following procedures essentially as described in Example 90, 3-(10,l 1-dihydro-
dibenzo[a,d]cyclohepten-5-yhdenemethy1)-phenylaniine (50mg, 0.168mmol) and 2-
methyl-propane-1-sulfonyl chloride (53mg, 0.336mmol) (prepared as described in Quast,
H., Synthesis (1974), (7), 489-90) affords 15mg (21%) of the title compound as a brown
oil. MS (ES) 435 (M+NH4), 416 (M-H); HPLC shows 100% purity.
Example 112
Dimethylsulfamic acid [3-(10,11 -dihydro-dibenzo[a,d]cyclohepten-5-ylidcnemethyl)-
phenylj-amidc

Following procedures essentially as described in Example 90,3-(l 0,11 -dihydrc-
dibenzo[a,d]cyclohepten-5-ylidencmethyl)-phenyiamine (lOOmg, 0.336mrool) and
dirnethylsulfamoyl chloride (144mg, l.Olmmol) affords 92rog (68%) of the title
compound as a yellow oil. MS (ES) 427 (M+Na), 403 (M-H); HPLC shows 93% purity.
Example 113
Diraethylsulfamic acid [4-{10,l lniihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-
phenylj-amide

Following procedures essentially as described in Example 90,4-(10,l 1-dibydro-
dibenzo[a,d]c7clob^tm-5-yhdenemethyI)-phenylaininc (lOOmg, 0.336mmol) and
dirnethylsulfamoyl chloride (144mg, l.Olmmol) affords 83mg (61%) of the title
compound as a white solid. MS (ES) 427 (M+Na), 403 (M-H); HPLC shows 87% purity.
Example 114
N-[3-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylideneniethyl)-phenyl]-acetainide

Following procedures essentially as described in Example 90, 3-(10,l 1-dihydro-
diben2o[a,d]cyclohepten-5-yh"denemethyl)-phenylamine and acetyl chloride give the title
compound in 25% yield as a white solid. lH NMR (CDC13) 5 2.12 (s, 3H}, 2.76-3.61 (br
m, 4H), 6.71 (d, 1H), 6.75 (s, 1H), 6.96-7.50 (m, 13H); MS (ES) 340 (M+H). HPLC
shows 100% purity.
Example 115
N-[2-(10,1 l-Dihydn>-dibenzo[a,d]cyclohC4)ten-5-ylidenemethyl)-phen)d]-acetainide

Following procedures essentially as described in. Example 90,2-(l0,l 1-dihydro-
dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylanrine and acetyl chloride give the title
compound in 70% yield as a yellow solid, mp 189.7°C. lH NMR (CDC13) 5 2.16 (s, 3H),
3.26 (br s, 4H), 6.78 (s, 1H), 6.84-7.50 (m, 11H), 7.82 (d, 1H); MS (ES) 340 (M+H) 338
(M-H). HPLC shows 94% purity.
Example 116
N-[4-{10,ll-Dmydro-diberxro[a,d]<^lohepten-5-yUdenemethyl)-phenyl]-acetamide

Following procedures essentially as described in Example 90,4-(10,l 1-dihydro-
dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and acetyl chloride give the title
compound in 51% yield as an off-white solid, mp 134 S°C. JH NMR (CDCh) 6 2.12 (s,
3H), 2.78-3.61 (br m, 4H), 6.75 (s, 1H), 6.95-7.52 (m, I3H); MS (ES) 340 (M+H). HPLC
shows 95% purity.
Example 117
N-[4-(10,ll-Dmvdro-dibenzo[a,d]cyclohepten-5-yUdencmcmy))-pheDyl]-isonicotinamide

Following procedures essentially as described in Example 90,4-(10,l 1-dihydro-
dibenzo[a,d]cyclohepten-5-yhdenemethyl)-phenylamine and isonicotinoyl chloride give
the title compound in 17% yield as a yellow solid, tap 252.1 °C. 'H NMR (DMSO-d«) 8
2.94 (br s, 2H), 3.87 (br s, 2H), 6.82 (s, 1H), 6.90-7.62 (m, 12H), 7.83 (d, 2H), 8.79 (d,
2H), 10.47 (s, 1H); MS (ES) 403 (M+H), 401 (M-H). HPLC shows 93% purity.
Example 118
[3-(l 0,1 l-Dihydro-dibetizo[a,d]<^lohepten-5-yudencTEethyl)-phenyl]-methyl-aniine

and
Example 119
[3-(l 0,1 l-DihydrcHdb'benzo[a,d]cycloheptcn-5-ylidenemethyl)-phenyl]-dimethyl-aniine

Using a procedure described b Syn. Coram. 1129-1135 (1991), dissolve 3-(10,l 1-
dihydro-dibenzo[a,d]cycloheptcn-5-ylidenemethyl)-phenylamine (lOOmg, 0.336mmol) m
toluene (5mL) and add (Bu)aNBr (2mg, 0.006mmo]), K2C03 (46mg, 0.336), and NaOH
(54mg, 1.34mmol). Stir for 1 h at 35°C, and then add Me2S04 (33L, 44mg, 0.353mmol).
Stir for 2 h, then warm up to 55°C. Stir overnight, then add 20 DL Me2SC>4 (26mg,
0.21 lmmol). Stir at 55°C for 6 h, then cool to room temperature. Dilute reaction with
H2O and ethyl acetate. Separate layers and extract aqueous layer with ethyl acetate.
Combine organics, dry (MgSO<), and concentrate to an oil containing the two title
compounds. Separation and purification of the title compounds is effected via silica gel
chromatography (1:19 ethyl acetatemexanes).
[3-(10,l l-Dmydro-diben2ota,d]cyclohepten-5-yhdenememyl)-phenyl]-methyl-aniine
(Example 118) is obtained in 17% yield (18mg) as a colorless oil. 'H NMR (CDC)3) 5
2.59 (s, 3H), 2.70-3.65 (br m, 5H), 6.26 (s, 1H), 6.40 (d, 1H), 6.46 (d, 1H), 6.74 (s, 1H),
6.97-7.53 (m, 9H); MS (ES) 312 (M+H). HPLC shows 99% purity.
[3-(10,ll-Dmydro^iberjzo[a,dJ(^loliepten-5-yhdeneinemyl)-phenyl]Klimemyl-aniine
(Example 119) is obtained in 14% yield (15mg) as a colorless oil. 'H NMR (CDC13) 5
2.62 (s, 6H), 2.68-3.58 (br m, 4H), 6.33 (s, 1H), 6.44 (m, 2H), 6.67 (s, 1H), 6.95-7.44 (m,
9H); MS (ES) 326 (M+H). HPLC shows 98% purity.
Example 120
[2-{ 10,11 -Dmydro^ibenzo[a,d}c^lohepten-5-yhdenememyl)-phenyl}-methyl-amine

and
Example 12]
[2-(l 0,1 l-Dihydro-dibenzo[a,d]cyclohepten-5-ylideneraethyl)-pheny]J-cimethyl-amine

Following procedures essentially as described in Examples 118 and 119,2-{10,l 1-
dihydro-diben2o[a,d]cyclohepten-5-ylidenemethyl)-pheriylamine gives the title
compounds.
[2-(10JI-Dihya^-dibenzo[a,d]cyclohepten-5-yIidenemethyl)-phenyl]-rnethyl-aniine
(Example 85) is obtained in 21 % yield as a yellow oil. lH NMR (CDC13) 6 2.91 (s, 3H),
3.26 (br s, 4H), 3.94 (br s, 1H), 6.47 (t, 1H), 6.62 (d, 1H), 6.70 (s, 1H), 6.71 (d, 1H), 6.86-
7.51 (m, 9H); MS (ES) 312 (M+H). HPLC shows 98% purity.
[2-(10,ll-Dihyo^c-dibexm)[a,d]cyclohepten-5-yUdenemethy0i)henyl]-d^cthyl-amJne
(Example 86) is obtained in 16% yield as a colorless oil. 'H NMR (CDC13) 5 2.96 (s, 6H),
3.24 (br s, 4H), 6.66 (m, 2H), 6.94-728 (m, 10H), 7.57 (d, 1H); MS (ES) 326 (M+H).
HPLC shows 96% purity.
Example 122
[4-(10Jl-DihyaVcHdiT)enzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methyl-aDiine
and
Example 123
[4-(10Jl-Dihydro-diben2ofa,d]cycIoheptcn-5-ylidenemetfayl)-phenyl]-dimethy]-ainuie

Following procedures essentially as described in Examples 118 and 119,4-{10,11-
dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine gives the title
compounds.
[4-(10,ll-DihydroKiiben2o[a,dJcyclohepten-5-yUdenemethyl)-phenyl]-meiJ3yl-amine
fExample 122) is obtained in 47% yield as a yellow solid. 'H NMR (CDC13) 5 2.66-3.55
(br m, 4H), 2.72 (s, 3H), 4.60 (s, 1H), 6.33 (d, 2H), 6.61 (s, 1H), 6.80 (d, 2H), 6.96-7.43
(m, SH); MS (ES) 312 (M+H). HPLC shows 98% purity.
[4-(1041-Dmydro^T)eiizo[a,d]cyxlohepten-5-ylidenemethyl>pb^iiyl]-diniethyl-
aminefExample 1231 is obtained in 2% yield as a white solid. 'H NMR (CDCb) 5 2.71 -
3.65 (brm, 4H), 2.90 (s, 6H), 6.51 (d, 2H), 6.69 (s, 1H), 6.92 (d, 2H), 7.04-7.50 (m, 8H);
MS (ES) 326 (M+H). HPLC shows 99% purity.
Example 124
N-[3-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-N"-methyl-
metbanesulfonamide

Dissolve N-[3-{10,l l-dihyiidene methyl phenylamine (297mg, l.Ommol) and
1-methyl-lH-iraidazole-4-sulfonyl chloride (lSOmg, l.Ommol) to give the title compound
44mg (10%) after being purified by mass guided reverse-phase HPLC. MS (ES) 442
(M+l). HPLC shows 97% purity.
Example 144
3-(10,l 1 -Dftvdro-a'ibeazo[a,d]cydohepten-5-ylidra

Dissolve l.Og (3.25mmoI) of the corresponding nitrile (prepared as described in Example
81) in diethyl ether (70mL). Add lithium aluminum hydride (250mg, 6.6mmoI) and stir at
room temperature for 3 h. Quench the reaction by adding S drops water. S drops 5N
NaOH and 16 drops water. Filter the inorganic solids and wash with ether. After drying
(MgS04) and concentration, the title compound was obtained in 9S% yield as a colorless
oil, MS (ES) 312 (M+l). HPLC shows 9S% purity.
Example 145
N-[3-(l 0,11 -Dihydro-dibenzo[ a.d]cyc]oheptcn-5-ylidenemethyl)-benzyl)-
methanesulfonamide

Following procedures essentially as described in Example 90, reaction of the
benzylamine (70mg, 0.225mmol) prepared in Example 144 and methanesulfonyl chloride
(52 DL, 0.68mmol) affords 40mg of the title compound in 46% yield as a colorless oil
after puri6cation using column chromatography (30% ethyl acetate/hexane). MS (ES) 38S
(M-l). HPLC shows 97% purity.
Example 146
2-[3-(l 0,1 l-Dihydm-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-4-
trifluoromethyl-lH-unidazole
According to Matthews et a], J. Med. Chem. 33 317 (1990). mix l,l-dibromo-!\l',r-
trifiuoroacetone (216mg, O.Smmol). NaOAc (112mg, 1.4mmol) and water (2mL). Warm
the solution at 60°C for 0.5h. Cool the solution in an ice bath and add 3-(10,l 1-dihydro-
dibenzo[a,d]cyc]ohepten-5-y]idsnemethyI)-benzaldehyde(145mg,0.47mmol) in methanol
(2mL) and concentrated NHjOH (2mL) and stir overnight at room temperature.
Concentrate and collect the solid. Purify by column chromatography (30% ethyl
acetate/hexane) to give 19% title compound. MS (ES) 417 (M+l), 415 (M-1). HPLC
shows 86% purity.
Example 147
2-[4-(10^1-Dihydro^ibaazo[a,d]cyclohC4)ten-5-ylidenemeth3rl)-phenyl]-4-
trifiuoromethyl-lH-imidazole
Prepare using procedures as described in Example 146 to give the title compound as a
pale yellow powder, MS (ES) 417 (M+l), 415 (M-l). HPLC shows 95% purity.
Example 148
5-(4-Euoro-3-methoxy-benzylidene)-10,l 1 -dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Example 28 and using 4-fluoro-3-
methoxybenzaldchyde(1.59g, 10.3mmol), diben20suberane(1.94g, lOmmol, provides
1.66g of title compound in 49% yield as a light tan oil that slowly crystallized.
HPLC shows 93% purity.
Example 149
5-(l 0,1 l-Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-fluoro-phenol

Demethylation of the corresponding methoxy derivative of Example 148 using the
procedures as described in Example 57, provides 1.28g (90%) of title compound as a pale
tan oil. MS (ES) 315 (M-l). HPLC shows 95% purity.
Example 150
5-(2-Fluorc^5-methoxy-bCTizyhdene)-I0Jl^ihydn>5H-diberizo[a,d]cvcloheptene

Following procedures essentially as described in Example 28 and using 2-fluoro-5-
methoxybenzaldehyde (1.59g, 10.3 mmol) and dibenzosuberane (1.94g, 10 mmol),
provides 21 Omg of title compound as white crystals, mp 110.7°C (hexane). HPLC shows
99% purity.
Example 151
3-(l 0,11 -Dihydro-diben2o[a,d]cyclohepten-5-yIJdencmethyl)-4-fluoro-phenol

Demethylation of the corresponding methoxy derivative of Example 150 using the
procedures as described in Example 57, provides 1 lOmg of title compound in 46% yield
as a colorless oil. MS (ES) 315 (M-l). HPLC shows 94% purity.
Example 152
5-(2-Fluoro-3-methoxy-benzylidene)-l 0,1 l-dihydro-5H-dibcnzo[a,d]cycloheptene

Following procedures essentially as described in Example 28 and using 2-fluoro-3-
methoxybenzaldehyde (2.4g, 15.4mmoI) and dibenzosuberane (3.0g, 15.4mmoI), provides
1.5g of title compound as white crystals, mp 148.9°C. HPLC shows 96% purity.
Example 153
3-(10,ll-Dmydro-dibenzo[a,d]cyclohcpten-5-yIidenemethyl)-2-fluoro-phcnoI

Demethylation of the corresponding methoxy derivative of Example 152 using the
procedures as described in Example 57, provides 410mg (47%) of title as light tan
crystals, mp 143.2°C. MS (ES) 315 (M-l). HPLC shows 94% punty.
Example 154
5-(3-Fluoro-5-methoxy-benzylidene)-10,ll-dihydro-5H-dibenzo[a,d]cyclohcptene

Following procedures essentially as described in Example 219, below, and using 3-fluoro-
5-methoxypbenylboronic acid (300mg, 1.76mmol) and 5-bromomethylene-10,l 1-dihydro-
5H-dibenzo[a,d]cyclobeptene (450mg, 1.6mmol)provides 275mg of title compound in
52% yield as a pale yellow oil. HPLC shows 97% purity.
Example 155
3-(l 0,1 l-Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-5-fluoro-phenol

Demethylation of the corresponding methoxy derivative of Example 154 using BBr3
provides the title compound in 62% yield as a colorless, viscous oil. MS (ES) 315(M-1).
HPLC sbows 94% purity.
Example 156
5-(4-Chloro-3-methoxy-benzylidene)-10,11 -dihydro-5H-dibenzo[a,dJcyc!obcptene

Following procedures essentially as described in Example 219, below, and using 4-
chloro-5-metboxyphenylboroiuc acid (160mg, 0.78mmol) and 5-bromomethylenc-10,ll-
dihydro5H-dibcnzo[a,d]cyclobeptene (222mg, 0.85mmol) provides 80mg of title
compound in 23% yield as a colorless oil. HPLC shows 92% purity.
Example 157
2-Chloro-5-(l 0,11 -dihydro-diben2o[a,d]cyclohepten-5-ylideoemethyl)-phenol

Demethylation of the corresponding methoxy derivative of Example 154 using BBr3
provides the title compound in 42% yield as a colorless, oil. MS (ES) 333 (M+l), 331
(M-I).
Preparation 23
5-Methy! ene-10,11 -dihydro- 5H-dibenzo[a,d]cycloheptene

Add incthylmagnesium bromide (3M solution in Et20,4S.0mL, 144mmoI) dropwise to a
cookd (03C) solution of dibenzosuberone (20.0g, 96.03mmol) in THF (140mL) under N2
(exothermic). Let solution warm up to room temperature and continue stirring for 2h.
Cool solution to 0°C and quench with saturated aqueous NH4CI (exothermic, emits gas).
Extract into ethyl acetate, dry organics (MgSCu) and concentrate in-vacuo. Dissolve
residue in 4N KCI/dioxane (40mL) and stir at room temperature overnight. Concentrate
and dilute with H2O. Extract into ethyl acetate, dry organics (MgSCX:) and concentrate to
a yellow oil. Purify crude product by loading onto a 30g plug of silica gel and eluting
with hexanes until eluent shows no UV activity. Combine and concentrate hexane washes
to afford 16.72g (84%) of the title compound as a white solid, mp 65.1°C. HPLC shows
98% purity.
Preparation 24
5-Bromomethylcne-l 0,1 l-dihydro-5H-dibcnzo[a,d]cycloheptene

Dissolve 5-rnethylcne-I0,ll-ll-dihydro-5H-dibenzo[a,d]cycloheptcne(E/Z
mixrure,700mg, 2.22mmol) (Prepared from 2-methoxydibenzosuberone as described in
Preparations 23 and 24 ) with 3-methanesulfonylaminophenylboronic acid (522mg,
2.4mmol) to give 485mg (54%) of an E/Z mixture of isomers. Use UV guided reverse-
phase HPLC with 1/1 acetonitrile/0.1 % aqueous trifluoroacetic acid to separate the
isomers. The E isomer comes off the column first. MS (ES) 406 (M+l), 404 (M-l).
HPLC purity is 99.6%. The second isomer off the column is the Z-isomer, MS (ES) 406
(M+l), 404 (M-l). HPLC purity is 98%.
Example 162
N-[3-(2-Hyo^xy-10,llHimydrcKu"benzo[a,d]cycIohepten-5-yIidenemethyl)-phenyl]-
methanesulfonamide (E/Z mixture)

Demethylate the corresponding methoxy mixture of Example 161 using BBr3 to give the
title compound in 69% yield. MS (ES) 392 (M+l), 390 (M-l). HPLC shows 48% of the
faster eluting isomer and 45% of the slower isomer.
Example 163
Ethanesulfonic acid [3-(2-methoxy-10,l l-dihydro-dibenzo[a,d]cyck>hepten-5-
ylidenemethyl)-phenyl]-amide (E/Z mixture)

Following the procedures essentially as described in Example 219, below, and using 5-
bromomcthyIene-2-methoxy-10,l l-dihydro-5H-dibenzo[a,d]cycloheptcne (E/Z mixture,
97mg, 0.31mmol) with 3-ethanesulfonylammophenylbordnic acid (7Smg, 0.34mmol) to
give 57mg (44%) of an E/Z mixture of the title compound. MS (ES) 420 (M+I) weak,
418 (M-l). HPLC shows 45% of the E isomer and 53% of the Z isomer.
Example 165
N-[2-(2-Methoxy-1041-dihydro^beii2o[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-
methanesulfonamide (E/Z mixture)

Following the procedures essentially as described in Example 219, below, and using 5-
bromomethylene-2-methoxy-10,l l-dihydro-5H-dibenzo[a,d]cycloheptene (E/Z
mixture.lOOmg, 0.32mmol) with 4-methanesutfonylanunophenylboronic acid (75mg,
0J5mmol) to give 35mg (27%) of an E/Z mixture of the title compound. MS (ES) 406
(M+l), 404 (M-l). HPLC shows 53% of the E isomer and 44% of the Z isomer.
Example 166
4^2-Memoxy-10,ll-dihydro^benzo[a,dJcyclohepten-5-yhdenemethyl)-phenylainirie
(E/Z mixture)

Isolate the title compound, which is derived from an impurity in the starting 4-
mcthancsulfonylaminophcnylboronic acid in the above reaction. MS (ES) 328 (M+l).
HPLC shows 41% of the faster eluting isomer and 58% of the slower isomer.
Example 167
3-(2-Metboxy-l 0,11 -dihydro-dibenzo[a,d]cyclohC4)ten-5-ylidenemethyl>-phenol

Following the procedures essentially as described in Example 219, below, and using 5-
bromomethylene-2-me1hoxy-10,l lnlihydro-5H-dibenzo[a,d]cycloheptcnc (E/Z
mixture, lOOmg, 0.32mmol) with 3-hydroxyphenyIboronic acid (48mg, 0.35mmol) to give
43mg (41%) of an E/Z mixture of the title compound as a tan foam. MS (ES) 327 (M-l).
HPLC shows 42% of the E isomer and 55% of the Z isomer.
Example 168
4-(2-Memoxy-10,l l-dihydro^T)enzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (E/Z
mixture)
Following the procedures essentially as described in Example 219, below, and using 5-
bromomethy!ene-2-methoxy-I0,l l-dihydro-5H-dibenzo[a,d]cycloheptcnc (E/Z
mixture,220mg, 0.7mmol) with 4-hydroxyphenylboronic acid (llOrag, 0.8mmol) to give
117mg (51%) of an E/Z mixture of the title compound as a tan foam. MS (ES) 327 (M-
1). HPLC shows 40% of the E isomer and 54% of the Z isomer.
Example 169
5-(4-H>droxy-benzylidene>10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-2-ol(E/Z
mixture)

Dernethylate the corresponding methoxy derivative mixture from Example 168 using
BBr3 to give the title compound in 80% yield. MS (ES) 315 (M+l), 313 (M-l). HPLC
shows 44% of the faster during isomer and 52% of the slower isomer.
Example 170 fa) and (b)
N-[3-(2,3-Dimethoxy-10,1 l-o^ydro-pheny!]-methanesiilforiainide(Z-isomer)

Following procedures essentially as described in Example 239. below, the title
compounds are prepared from the corresponding dimethoxydibenzosuberone and m-
bromobenzylmagnesium bromide. These bromo derivatives are converted to the ammo
derivatives using procedures described in Example S6. The intermediate E and Z amines
are reacted with mcthanesulfonyl chloride as described fa Procedure M. The title
compounds are purified on silica gel using 33% ethyl acctate/hexane to give 1 ?0mg E/Z
mixture. Use column chromatography (20% ethyl acetateliexanc) to give 50mg of the E
isomer (Example 170(a)); MS (ES) 434 (M-l), HPLC 92% and 35mg of the Z isomer
(Example 170(b)); MS (ES) 434 (M-l), HPLC 95%.
Example 171
N-[3-(2,3-Dihydroxy-10,l l-dihydrodibenzo[a,dJcycIohC4)ten-5-ylideneniethyl}-pheny]]-
raethanesulfonamide (E/Z mixture)

Deraethylate N^-[3-(2,3-dimethoxy-10,l l-dihydro-dibenzo[a,d]cyclohepten-5-
ylidencmethyl)-phenyl]-methanesulfoiiamide (60mg, 0.14mmol) fonn Example 170 using
BBr3 to give 53mg (93%) the title compound as a tan semi-solid. MS (ES) 408 M+l),
406 (M-l). HPLC shows 47% fester eluting isomer and 53% slower isomer.
Example 172
1 -ChJoro-5-(4-chloro-3-methoxy-benzyIidene)-10,11 -dihydro-5H-
dibenzo[a,d]cyclohcptene (mixture of E/Z isomers)

Following procedures essentially as described in Example 219, below, and using 4-
chJoro-3-methoxyphenylboronic acid (160mg,0.85mmol) with 5-bromomcthyleae-l-
chloro-10,1 l-d&ydro-5H-dibenzo[a,d]cyc2oheptene (249mg, 0.78mmol) to give 440mg
crude product. Purify by chromatography to give 210mg (71%) colorless oil. HPLC
(ISO90-10M) shows 51% at t=7.62min and 45% at t=9.86min.
Example 173
2-CMoro-5-(l^h]oro-10,ll-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol
(Z-isomer, LY2054560, ER0-A01846-65B) and 2-Chloro-5-(l-chloro-10,l l-dihydra-
dibenzo[a,d]cyclohepten-5-yIidencmetbyl)-phenoI(E-isomer)

Demethylate l-chJoro-5-(4-cbdoro-3-methoxy-benzylidene)-10,l l-dihydro-5H-
m"benzo[a,d]cyclohcptcnc (mixture of E/Z isomers) (215mg, 0.56mmol) from Example
172 using BBr3. Separate the isomers using a chromatatron (2% EtOAc/hexane) to give
47mg Z isomer. MS (ES) 365 (M-l). HPLC shows 98% purity. The lower spot is the E
isomer, 33mg. MS (ES) 365 (M-l). HPLC shows 96% purity.
Example 174
2-Chloro-5-(2-trifluoromethyl-benzy]idene)-l 0,11 -dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Example 219, below, and using 2-
(trifluoromethyl)phenylboronic acid (59mg, 0.31mmol) and 5-bromomethylene-2-chJoro-
10,1 l-dihydro-5H-dibenzo[a,d]cyclohcptene (91mg, 0.28mmol) provides 97mg (90%)
title compound. GC/MS data: retention times in minutes (MS data for M*' ion): 18.19
(384), 18.38(384)Mass Spec (EI+) 384
Example 175
2-Chloro-5-(2-methyl-benzyhdene)-10,11 -dihydro-5H-dibenzo[a,d]cycloheptene

Following procedures essentially as described in Example 219, below, and using o-
tolylboronic acid (91mg, 0.67mmol) and 5-bromomethylene-2-chloro-10,ll-dihydro-5H-
dibenzo[a,d]cycloheptene (178mg, 0.56mmol) provides the title compound. GC/MS data:
retention times in minutes (MS data for M4- ion): 19.62 (330), 19.83(330) Mass Spec
(Eh-) 330.
Example 177
2-ChloiXH5^3-memyI-o«nzybdene)-10,ll-ll-^mydro-dibenzo[a,d]cyclohepten-5-j'lidenemethyl)-phenol

Following procedures essentially as described in Example 219, below, and using 3-
hydroxyphenylboronic acid (98mg, 0.71mrool) and 5-bromomethy]ene-10,l 1-dihydro-5H-
2,8-dichlorodibenzo[a,d]cycloheptenc (230mg, 0.65mmol) (prepared from 2,S-
dichlorodibenzosuberone (M. R. Pavia et al, J. Med. Chem. (35) 423S-424S (1992)) using
procedures as described in Preparations 23 and 24) provides 178mg title compound in
75% yield as a pale yellow oil. MS (ES) 365 (M-l). HPLC shows 93% purity.
Example 184
N-[3-(l-Fluoro-10,ll-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-
methanesulfonamide (Z-isomer) and N-[3-(2-Fluoro-10,l 1-dihydro-
diben2»[a,d]cyclohepten-5-yUdenemethyl)-phenyl]-methanesulfonaraide(E-isomCT^

Following procedures essentially as described in Example 219, below, and using 3-
melhanesulfonamidophenylboronic acid (388mg, l.Smmol) and 5-bromomethylene-1-
fluoro-10,llKluiydro-5H-dibenzo[a,d]cyclobeptene (E/Z mixture,500mg, 1.65mmol)
(Prepared from 1-fluorodibenzosuberone (Chem. Abstr. 70 106272a (1969) using
procedures as described in Preparations 23 and 24 ) provides the title compound. Separate
the isomers using column chromatography (gradient of 10% EtOAc/hexane to 25%
EtOAc/hexane) to give 66mg Z isomer as a white powder, mp 153.5°C, MS (ES) 392 (M-
1). HPLC shows 100% purity. Isolate 18mg E isomer as the slower moving spot, MS
(ES)392(M-1). HPLC shows 97% purity.
Example 185
3-(l -Fluoro-10,1 l-dihydro-dibenzo[a,d]cyclohcpten-5-ylicenemethyl)-phenol (E-isomer)
and 3-(l-Fluoro-10,1 l-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemcthyl)-phcnol (Z-
isomer)

Following procedures essentially as described in Example 219, below, and using
3-hydroxypbenyIboronic acid (250mg, 1.8mmol) and 5-bromomethylene-l-fiuoro-10,l 1-
dihydro-5H-dibenzo[a,d]cycloheptene (E/Z mixture,500mg, 1.65mmol) (Prepared from 1-
fluorodibenzosuberonc (Chan. Abstr. 70 106272a (1969) using procedures as described
in Preparations 23 and 24) provides 750mg crude product of the title compound. Separate
the isomers using radial chromatography (hexane-^3% EtOAc/hexane) to give 115mg Z-
isomer as a pale yellow foam, mp 119.9°CMS(ES)315 (M-l). HPLC shows >95%
purity. The E-isomer is the slower moving material, 69mg yellow foam, mp 158.1°C.
MS (ES) 315 (M-1). HPLC shows 99% purity.
Example 186
3-(l -Fluoro-10,1 l-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylmethyl)-phenol

Dissolve 3-( 1 -fluoro-3 0,11 -dihydro-dibenzo[a,d]cyclohcpten-5-ylidenemethyl)-phenol
(370mg, 0.54inmol) in EtOH (5mL) and add 10% Pd/C (50mg). Stir for ISh under an
atmosphere of hydrogen. Filter and concentrate. Purify the crude product using column
chromatography (10% EtOAc/hexane -> 25% EtOA^exane) to give 98mg (57%)
product as a colorless oil. MS (ES) 317 (M-l). HPLC shows 99% purity.
Example 187
N-[3-(l-Fluoro-10,ll-dihydro-5H- 25% EtOAc/hexane) to
give 6mg product as a colorless oil. MS (ES) 394 (M-l). HPLC shows 99% purity.
Example 188
N-[3-(3-Chloro-10,l 1 -dihyd^x>^bcnzo[a,d]cycloheptcn-5-yUdcnemethyi)-pbenyl]-
methanesulfonamide (Z-isomer) and N-[3-(3-Chloro-l 0,11 -dihydro-
dibenzo[a,d]cycloheptei^5-yUdenemelhyl)-phenyl]-methariesulfonamide (E-isomcr)
cGq cOct
cr""^ Jj Jj ci
N K
\ I
o=s=o o=s=o
I I
E-isomer Z-ismoer
Following procedures essentially as described in Exampie 219, below, and using 3-
methanesulfonamidophenyl boronic acid (473mg, 2.2mraol) with 5-bromomediylene-3-
chloro-10,1 l-dihydro-5H-dibenzo[a,d]cyclohcptene (640mg, 2rnmol) provides 1.17 crude
product as a brown oil. Purify the crude product using column chromatography ehitmg
with 5% EtOAc/hexane to 25%. EtOAc/hexane to give 315mg of the Z-isomer, rap
cr""^ Jj Jj ci
N K
\ I
o=s=o o=s=o
I I
E-isomer Z-ismoer
177.1°C, (MS (ES) 408 (M-l), HPLC 99% purity) and 115mg E-isomer, mp 130.5°C,
(MS (ES) 408 (M-l), HPLC 90% purity).
Example 189
N-[3<3-Chloro-10,31-dihydrc>-5H-dibenzo[a,d]cyclohC4)ten-5-ylrnethyl)-phenyl]-
methanesulfonamide

Dissolve N-[3-(3-chloro-10,l l-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-
phenylj-methanesulfonamide (200mg, 0.49mmol) in EtOAc (30mL) and add 5%Pt/C
(150mg). Stir for ISh under an atmosphere of hydrogen. Add 5%Pt/C (200mg). Stir for
24h under an atmosphere of hydrogen. Filter and concentrate to give 140mg crude
product Purify using reverse-phase UV guided HPLC to give 28mg viscous tan oil, MS
(ES) 410 (M-l). HPLC shows 99% purity.
Example 190
3-{3-Chloro-10,l l-dibydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (Z-isomer)
and 3-(3-Qiloro-10.11-dihydro-dibcnzo[2,d]cyclohepten-5-ylidencmeQiyl)-phenol (E-
isomer)
Following procedures essentially as described in Example 219, below, and using 3-
hydroxyphenyl boronic acid (300mg,2.2mmol) with 5-bromomethylene-3-chloro-10,ll-
dihydro5H-dibenzo[a,d]cycloheptene (640mg, 2mmoI) to give 880mg crude product.
Purify using reverse-phase UV guided HPLC (1/1 CH3CN/ 0.1% TFA) to give I63mg Z-
isomer as a pink foam (HPLC shows 99% purity at t=4.96rain) and 43mg E-isomer (MS
(ES) 331 (M-l), HPLC shows 95% purity at t=5.22min).
Example 191
N-[3-(2,8-Dimethoxy-10,11 ^iihydro-'clobeptcnc (690mg, 2mmol) to give 990mg crude
product. Purify the crude product using column chromatography eluling with 8%
EtOAc/hexane to 25% EtOAc/hexane to give 240mg (33%) product as a colorless oil.
MS (ES) 357 (M-l). HPLC shows 99% purity at t=3.33min.
Example 194
5-(3-Hydioxy-benzylidOTc)-10,ll-^hydrc>-5H-dibenzo[a,d]cycloheptene-2,8-dio]

Demethylate 3-(2,8-dimedioxy-10,l l-dihydro-dibenzo[a,d]cycIohcpten-5-ylidencinethyl)-
phenol (91mg, C25mmoI) with BBr3 to give crude title compound. Purify on silica gel
elating with 25% EtOAc/hexane to 35% EtOAc/hexane to &ve 80mg (96%) as a light
pink solid, MS (ES) 331 (m+1), 329 (M-l). HPLC shows 96% purity.
Example 195
3-[2-(2-Morpholin-4-yi-ethoxy)-10,11 -dihydro-dibenzo [a,d]cyclohepten-5-
ylidencmcthylj-phenol (E-isomer) and 3-[2-{2-Morpholin-4-yl-ethoxy)-10,l 1-dihydro-
diben20[a,d]cyclohepten-5-ylideneinethyl]-phenoI(Z-isomer)

Following procedures essentially as described in Example 219, below, and using 4-[2-(5-
bromomcthylene-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-cthyl]-morpholinc
(220mg, 0.53mmol) and 3-hydroxyphenyIboronic acid (SOmg, (0.58mmol). Attempted
purification on silica gel eluting with 70% EtOAc/hexane to 100% EtOAc/hexane gave
136mg of an E/Z mixture. Separate the isomers using UV guided reverse-phase using
34% CH3CN/66% 0.1% aq. TFA. Pool the pure fractions and neutralize with aq.
NaHC03. Concentrate to remove the organic solvent and extract the product into EtOAc.
After drying (MgSCM) and concentration, 40mg of the E-isomer was obtained as a tan
foam, MS (ES) 428 (M+1). HPLC 95% purity at r=L88min. Similarly, 72mg of the Z-
isomer was obtained as a viscous oil, MS (ES) 428 (M+l). HPLC 96% purity at
t=2.27min.
Example 196
N- {3-[2-(2-Moipbolm-4-yl-ethoxy)-l 0,11 -dihydro-diben2o[a,d3cyclohepten-5-
ylidenemethyl] -phenyl} -methanesulfonamide

Following procedures essentially as described in Example 219, below, and using 4-[2-{5-
bromomethyiene-10,11 -dihydro-5H^rierizo[a1d]cyclohepten-2-ylox'y)-ethyl]-morpholine
(220mg, 0.53mmol) and 3-metlumesulfonaniidophenylboronic acid (125mg, 0.58mmol).
Purification on silica gel eluting with EtOAc then EtOAc/I% MeOH/NH3, gave 57mg of
pure E-isomer. MS (ES)505 (M+l), 503(M-1). HPLC shows 92% purity at t=l .79min.
Example 197
N-[3-( 1,2-Dichioro-l 0,11-dihydro-dibenzo[a,d]cycloheptcn-5-ylidenemethyl)-pheny]]-
methanesulfonamide (Z-isomer) and K-[3-(l,2-Dichloro-10,ll-dihydro-
diben2o[a,d]cyclohepten-5-ylidenemethyl)-phcnyl]-methanesulfonamJdc (E-isomer)
Following procedures essentially as described in Example 219, below, and using 3-
methanesulfonamidophenyl boronic acid (473mg, 2.2mmol) with 5-bromomethylene-l,2-
dichloro-10,1 l~dihydro-5H-dibenzo[a,d]cycloheptene (700mg, 2mmol) to give 1.29g
crude product. Purify the crude product using column chromatography eluting with 10%
EtOAc/hexanc to 20% EtOAc/hexane, to give the Z-isomer, 330mg yellow foam, mp
190.1°C, MS (ES) 442 (M-l). HPLC shows 98% purity at t=3.55min. Continue to elute
and obtain 126mg E-isomer, mp 168.6°C, MS (ES) 442 (M-l). HPLC shows 97% purity
at t=3.84min.
Example 198
3-(l,2-Dichloro-10,l l-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemcthyI)-phenol (Z-
isomer) and 3-(l,2-Dichloro-10,l l-dihydro-dibenzo[a,d]cyclohepten-5-yIidenemethyl>-
phenol (E-isomer)
Following procedures essentially as described in Example 219, below, and using 3-
hydroxyphenyl boronic acid (310mg, 2.2mmol) with 5-bromomethylene-l,2-dichloro-
10,11 -dihydro-5H-dibenzo[a,d]cycloheptene (700mg, 2mmol) to give 1.39g crude
product. Purify the crude product using column chromatography during with 5%
EtOAc/bexane to 15% EtOAc/hexane to give the Z-isomer, 330mg yellow foam, mp
67.6°C, MS (ES) 365 (M-l). HPLC shows 94% purity at t^.05min. Continue to elute
and obtain 190mg E-isomer, MS (ES) 365 (M-l). HPLC shows 94% purity at t=434min
Example 199
N-[3-(2-Fluoro-10,l 1 -dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-
methanesulfonamide (Z-isomer) and N-[3-(2-Fluoro-10,l 1-dihydro-
diberizo[a,d]cyclob^ten-5-yUdenemethyl)-phenyl]-memanesulfonarnide (E-isomer)

Following procedures essentially as described in Example 219, below, and using 3-
methanesulfonamidophenyl boronic acid (596mg, 2.77mmol) with 5-bromomethylene-2-
fluoro-10,Il-dihydro-5H-dibenzo[a,d]cycloheptene (765mg, 2.52mmol) to give 1.49g
crude product. Purify the crude product using column chromatography (15%
EtOAc/hexane -> 25% EtOAc/hexane) to give 212mg Z-isomer as a colorless foam, mp
150.6°C. MS (ES) 392 (M-l). HPLC (ISO60-15M) shows 94% purity at t=12.34imn.
Continue to elute and obtain 203mg E-isomer as a white foam, mp 145.7°C. MS (ES)
392 (M-l). HPLC (ISO60-15M) shows 94% purity at r=I 1.86min.
Example 200
3-(2-Fluoro-104lKiihydxchCiib€nzo[a,d]cyclohepten-5-yUdenemethyl>phenol(Z-isomer)
and 3-(2-Fluoro-10,l l-dihydro-dibenzo[a,d]cyclohepten-5-ylJdcnemethyl)-phenol (E-
isomer)

Following procedures essentially as described in Example 219, below, and using 3-
bydroxyphenyl boronic acid (415mg, 3.0mmol) witb 5-bromomethylcne-2-fluoro-10,ll-
dihydro-5H-dibenzo[a,d]cycloheptene (825mg, 2.72mraol) to give 1.07g crude product.
Purify the crude product using column chromatography eluting with 5% EtOAc/bexane
to 15% EtOAc/hexane to give 120mg pure Z-isomer as a tan viscous oil, MS (ES) 315
(M-l). HPLC (IOS80-10M) shows 94% purity at t=4.02min. Continue to elute and obtain
120mg E-isomer as tan oil, MS (ES) 315 (M-l). HPLC (IOSS0-10M) shows 94% purity
at t=3.86min.
Example 201
N-[3-(l,9-Difluoro-10,lln[iihydro-diberi2o[a,d]cyclohepten-5-yUdenemcthyl)-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 219, below, and using 3-
methanesulfonamidopbenyl boronic acid (592mg, 2.75mmoI) and 5-bromomethylene-l.,9-
difluoro-10,1 l-dihydro-5H-dibcnzo[a,d]cycloheptene (803mg, 2.75mmol), provides 1.52g
of the title compound crude product The crude product is purified using column
chromatography {15% EtOAc/hexane to 30% EtOAc/hexane) to give 690 mg (67%) white
solid. MS (ES) 410 (M-l). HPLC (ISO90-10M) shows 92% purity at t=2.64min.
Example 202
3-( 1,9-Diiluoro-10,11 -dihydro-dibenzo[a,d]cycIohepten-5-yIidenenjethyl )-phenol

Following procedures essentially as described in Example 219, below, and using 3-
hydroxyphcnyl boronic acid (380mg, 2.75mmol) and 5-bromomethylene-l,9-difluoro-
10,ll-dihydro-5H-dibenzo[a,d]cycloheptene (803mg, 2.75mmoI), provides to 1.04 g of
the title compound as crude product The crude product is purified using column
chromatography eluting with 15% EtOAc/hexane to 30% EtOAc/hexane to give 500mg
(60%) product as a light yellow foam, rap 129.5°C. MS (ES) 333 (M-l). HPLC (1SO90-
10M) shows 98% at t=2.90min.
Example 203
3-(l-Chloro-diben2o[a,d]cyclohcpten-5-ylidenemethyl)-pheEylamkie

Heat a suspension of NaH (60% suspension in mineral oil, 49mg, 1.2mmol) in DMSO
(6mL) to 80°C under N2 until evolution of H2 stops. Dissolve (3-nitro-benzyl)-
phosphonic acid diethyl ester (prepared according to procedures as described in Okamoto
eL al., Bull. Chem. Soc. Jpn. (1987),60(1), 277-82) (338mg, 1.2mmol) inDMSO (lmL)
and add to reaction mixture. Add 1 -chloro-10,1 l-dihydro-dibenzo[a,d]cycIohepten-5-one
(prepared according to procedures as described in Humber et al., J. Med. Chem. (1978),
21(12), 1225-31) (200mg, 0.824mmol) at once and heat to 100CC for 48h. Cool to room
temperature. Dilute reaction mixture with ethyl acetate (50mL) and wash twice with H2O.
Dry (MgSC^) and concentrate organics to a brown oil. Chromatograph on silica gel
(IOg), eluting with 2% to 4% ethyl acetate/hexanes to afford a mixture of compounds.
Dissolve this mixture in ethanol (lOmL) and add SnCk (dihydrate, 508mg, 2J25mmol).
Heat to reflux for 3h and cool to room temperature. Concentrate reaction mixture, then
dissolve residue in diethyl ether. Wash organics with H20,1.00N aqueous NaOH, then
twice with H2O. Dry (MgS04) and concentrate organics to a yellow oil. Chromatograph
on silica gel (IOg), eluting with 5% to 10% ethyl acetate/hexanes to afford 28ing (10%) of
the title compound as a colorless oil. MS (ES) 330 (M+H); HPLC reveals 36:64 mixture
of geometric isomers - 36% at 4.977min, 64% at 5.218min - overall 100% purity.
Example 204
N-[3^1-Chlorc-^ibeiizo[a?d]cyclohepten-5-yUdcnememyl)-phenyl]-methanesulfonarnide

Following procedures essentially as described in Example 90, and using 3-(l-chloro-
dibenzo[a,d]cycIohepten-5-ylidenemethy])-phenylamine (63mg, 0.190mmol), affords
26mg (33%) of the title compound as a white foam. MS (ES) 425 (M+NH4), 406 (M-H);
HPLC reveals a mixture of geometric isomers - 41% at 2.S79min, 59% at 2.9S5min -
overall 100% purity.
Example 205(a), (b), and (c)
N-[3-( 1 -Chloro-10,11 -dibydro-diben2o[a,d] cyclohepten-5-yiidenemethyl)-phenylJ-
methanesulfonamide

Following procedures essentially as described in Example 219, below, and using 5-
bromomethylene-l-chloro-10,1 l-dibydro-5H-dibenzo[a,d]cycloheptene (lOOmg,
0.313mmol) and 3-methanesulfonylamino-phenyIboronic acid (74mg, 0.344mmol),
affords 102mg (79%) of the title compound (Example 205(a)) as a mixture of geometric
isomers. MS (ES) 408 (M-H); HPLC reveals a 57:43 mixture of geometric isomers -
54% at 3.061min, 40% at3.197min- overall 94% purity. Separate geometric isomers on
a 1000 micron silica gel chromatatron rotor, (10% to 13% ethyl acetate/hexanes) to afford
22mg (17%) of the Z-isomer of the title compound (Example 205(b), (MS (ES) 410
(M+H). HPLC shows 98% purity. Continue to elute to give 1 lmg (9%) of the E-isomer
of the title compound (Example 205(c)) (MS (ES) 410 (M+H), 408 (M-H); HPLC shows
94% purity).
Example 206(a) and (b)
N-[3-(2-Chloro-10,ll-dihydrc-dibenzo[a,d]cyclohcptcn-5-ylidenemethyl)-phcnyl]-
methanesulfonamide (Z isomer and E isomer)

Following procedures essentially as described in Example 219, below, and using 5-
bromomethylene-2-chloro-10,l l-dihydro-5H-dibenzo[a,d]cycloheptene (lOOmg,
O.313mrool) and 3-methanesulfonyIaminophenylboronic acid (74mg, 0.344mmol),
affords 37mg (29%) of the Z-isomer (Example 206(a)) of the title compound as a
colorless oil (MS (ES) 408 (M-H). HPLC shows 99% purity. Continue to elute and
obtain 23mg (18%) of the E-isomer (Example (b)) of the title compound as a colorless oil
(MS (ES) 408 (M-H); HPLC shows 92% purity).
Example 207
N-[3-(2-Chloro-10,11 -dmydro-5H-dibenzo[a,d]cycloheptenyImethyI)-phenyl]-
methanesulfonamide

Dissolve N-[3-(2-chloro-10,11 -dihydro-diben2o[a,d]cyclohcpten-5-ylidencmcthyl)-
phenyl]-methanesulfonamide (mixture of geometric isomers, lOOrng, 0.243mmol) in
ethanol (15mL) and add 5% Pt/C (20rag). Stir at room temperature under a H2 balloon for
72h. Filter reaction mixture through a pad of Celite, and concentrate filtrate to a colorless
oil. Cbxomatograph on silica gel (lOg), eluting with 15% to 25% ethyl acetatc/hexanes.
Re-purify by UV-guided semi-preparatory reverse-phase HPLC to afford 44mg (44%) of
the title compound as a colorless oil. MS (ES) 429 (M+NH4), 410 (M-H); HPLC shows
98% purity.
Example 208(a). (b). and (c)
Ethancsulfonic acid [3-(l-chloro-10,l l-4ihydro-dibenzo[a,d]cyclohepten-5-
ylidenememyl)-phenyi]-arnide

Following procedures essentially as described in Example 219, below, and using 5-
brornomethyiene-1-chloro-I0,11 -d&ydro-5H-dibenzo[a,d]cycloheptene (1 OOmg,
0.313mmol) and 3-ethanesulfonylaminophenyIboronic acid (79mg, 0344mmol), affords
112mg (84%) of a mixture of geometric isomers of the title compound (Example 208(a))
as a yellow solid (MS (ES) 424 (M+H); HPLC shows 94% purity). Separate geometric
isomers using a chromalatron rotor (10% ethyl acetate/hexanes) to afford 13mg (10%) of
the Z-isomer (Example 208(b)) of the title compound as a white solid, (MS (ES) 424
(M+H), 422 (M-H). HPLC shows 96% purity). Continue to elute and isolate 6mg (5%) of
the E-isomer (Example 208(c))of the title compound as a white solid (MS (ES) 424
(M+H), 422 (M-H); HPLC shows 97% purity).
Example 210
N-[4-{l-Chloro-10,ll-dihydro-djben2o[a,d]cyclohepten-5ylidenemetliyl)-phenylj-
methanesulfonamide

Following procedures essentially as described in Example 219, below, and using 5-
bromomethylene-1 -chloro-10,11 -dihydro-5H-dibeazo[a,dJcycloheptene (1 OOmg,
0.313mmol) and 4-metbanesulfoDylarninopbenylboronic acid (74mg, 0.344mmol),
affords 55mg (43%) of a mixture of geometric isomers of the title compound as a brown
oil. MS (ES) 408 (M-H); HPLC shows 96% purity.
Example 211(a) and (b)
3-(l-Chloro-10,I Wmydro-dibenzo[a,djcyclohepten-5-ylidenemethyl)-phenol

Following procedures essentially as described in Example 219, below, and using 5-
bromomethylene-1-chloro-10,1 l-dihydro-5H-dibenzo[a,d]cyclobeptene (lOOmg,
0.313mmol) and 3-hydroxyphenylboronic acid (47mg, 0.344mmol) affords 8mg (8%) of
the Z-isomer of the title compound (MS (ES) 331 (M-H). HPLC shows 95% purity.
Continue to elute and isolate 27mg (26%) of the E-isomer of the title compound, MS (ES)
331 (M-H). HPLC shows 97% purity.
Example 212
4-(l-Chloro-10,11-dihydro-dibcnzo[a,d )cyclohepten-5-ylidenemethy])-phcnol

Following procedures essentially as described in Example 219, below, and using 5-
bromomethylene-l-chloro-10,1 l-dihydro-5H-dibenzo[a,d]cycloheptene (lOOmg,
0.313mmol) and 4-hydroxyphenylboronic acid (47mg, 0.344mmol), affords 84mg (81%)
of a mixture of geometric isomers of the title compound as a brown oil. MS (ES) 331 (M-
H); HPLC shows 97% purity.
Example 213
5-Bromomethylene-3-fluoro-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene

A. Following the procedures essentially as described in Preparation 23, using
3.84g (16.97m) of 3-fluoro-10,l l-dihydro-dibenzo[a,d]cyclohepten-5-one (prepared
according to procedures as described in published PCT Int. Appl. WO 9856752 Al
19981217 (1998)) to obtain 2.88g (75%) of 3-fluoro-5-methylene-10,11 -dihydro-5H-
dibenzo[a,d]cyclohcptene as a white solid.
B. Following the procedures essentially as described in Preparations 24 and 25,
2.62g(11.70mmol) of the material from Step A, above, affords 3.152g (89%) of a mixture
of geometric isomers of the title compound as a yellow oil. MS fEI] 302,304; HPLC
shows 99% purity.
Example 214
N-[3-(3-Fluoro-10,ll-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-
methanesulfonamide

Following the procedures essentially as described in Example 219, below, and using 5-
bromornethyIene-3-fluoro-10,l l-dihydro-5H-dibenzo[a,d]cycloheptene (200mg,
0.660mmol) and 3-methanesulfonylaminopbenylboronic acid (156mg, 0.726mmol),
affords 212mg (82%) of a mixture of geometric isomers of the title compound as a yellow
solid. MS (ES) 411 (M+NH*), 392 (M-H); HPLC shows 98% purity.
Example 215
3-{3-Fluoro-10,11 ^ihydro-dibenzo[a,d]cyclohepten-'5-ylidenemethyl)-phenol

Following the procedures essentially as described in Example 219, below, and using 5-
bromomethylene-3-fluoro-10,13 -dihydro-5H-dibcnzo[a,d]cycloheptene (200mg,
0.660ramol) and 3-hydroxyphcnylboronic acid (lOOmg, 0.726mmol), affords 192mg
(92%) of a mixture of geometric isomers of the title compound as a yellow oil. MS (ES)
339 (M+Na), 315 (M-H); HPLC shows 95% purity.
Section 3 (derivatives of Formula I wherein the "C" ring further represents a heterocyclic
or benzofused heterocyclic ring.)
Example 216
5-(l 0,11 -Dihydro-diben2o[a,d]cyclohepten-5-ylidenernethyl)-3H-benzooxazol-2-one

Add phenyl chlorofonnate (24uL, 0.195mmol) to a suspension of 2-amino-4-{10,l 1-
dihydro-dibcnzo[a,d]cyclohepten-5-yIidenemethyl)-phenol (61mg, 0.195mmol) (see
Example 63) and NaHCX^ (16mg, 0.195mmol) in water (5mL) and methanol (lOmL).
Stir for 30min at room temperature and add aqueous NaOH (1.00N, 195QL). Stir
ovemight and add aqueous HC1 (1.00N, 195DL). Extract with CH2Cl2, dry organics
(MgS04), and concentrate to a brown oil containing the title compound. Purify on silica
gel (lOg) eluting with 10% TO 35% ethyl acetate/hexanes, and then triturate with 50%
CH2Cl2/hexanes to afford Smg (13%) of a white solid. MS (ES) 357 (M+NR,), 338 (M-
H); HPLC shows 94% purity.
Example 217
5-(lO,ll-Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-ben2ooxazole

Dissolve 2-amino-4-(l 0,1 ] -dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phcnol
(see Example 63) (60mg, 0.191mmol) in triethylorthoformate (3mL) and heat to reflux for
4.5h. Cool to room temperature and concentrate in-vacuo to a brown oil. Chromatograph
on lOg silica gel eluting with 5% to 25% ethyl acetate/hexanes to afford 52mg (S4%) of
the title compound as a colorless oil. MS (ES) 324 (M+H), 322 (M-H), HPLC shows
94% purity.
Example 218
5-{l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-yiideiiemethy3)-2-methyl-ben2ooxazole

Dissolve 2-arnino-4-(10,l I-ten-5-ylidenc)-boronic acid
(lOOmg, 0.400mmol) afford 6mg (5%) of the title compound as a colorless oil. 'H-NMR
(CDC13) 6 2.77-3.63 (br m, 4H), 6.79 (s, 1H), 6.97-7.29 (m, 12H), 7.49 (m, 1H). HPLC
shows 96% purity.
Preparation 26
2-Oxo-2t3-dihydro-benzooxazole-5-boronic acid

Add n-BuLi (1.6M in hexanes, 8.76mL, 14.02mmol) portionwise (exotherm) to a solution
of 5-bromo-3H-benzooxazol-2-one (l.OOg, 4.67mmol) in dry THF (28mL) at -78°C under
N2. Stir at -40CC for Ih and add trimethylborate (1.94g, 18.68mmol) at once. Warm up
to room temperature overnight. Add IN aqueous HC1 (50mL) and stir for 3h at room
temperature. Extract into ethyl acetate, dry (MgSO.i) and concentrate organics to a brown
solid. Triturate with hexanes/toluene and collect 766mg (92%) of the title compound as a
brown powder. MS (ES) 179 (M+H), 177 (M-H); HPLC shows 80% purity.
Example 221(a) and (b)
5-(l-ChJoro-10,lI-dmydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-3H-benzooxazoJ-
2-onc (Z isomer and E isomer)

Following procedures essentially as described in Example 219 and using 5-
bromomethylene-1 -chloro-10,11 -dihydro-5H-dibenzo[a,d]cycloheptene (200mg,
0.630mmol) and 2-oxo-2,3-dinydro-benzooxazo}e-5-boronic acid (134mg, 0.750mmol)
provides 29mg (12%) of the Z-isomer (Example 221(a)) of title compound as a tan solid
(MS (ES) 372 (M-H); HPLC shows 99% purity) and O 23mg (10%) of the E-isomer
(Example 221(b)) of the title compound as a tan solid. MS (ES) 372 (M-H); HPLC shows
97% purity.
Example 222(a) and fb)
5-(2-Chloro-10,l 1 -dihydro-dibenzo[a,d}cyclohepten-5-ylidenemethyl)-3H-ben2ooxa2ol-
2-one (Z isomer and E isomer)

Following procedures essentially as described in Example 219 and using 5-
broraomethylenc-2-chloro-10,ll-dihydro-5H-dibenzo[a,d]cyclohcptene(200mg,
0.630mmol) and 2-oxo-2)3-dihydro-bcnzooxazo]e-5-boronic acid (134mg, 0.750mmol),
provides the title compound. Purify by UV-guided semi-prep reverse-phase HPLC to
obtain 14mg (6%) of the Z-isomcr (Example 222(a)) of title compound as a white solid
(MS (ES) 391 (M+:NH0, 372 (M-H); HPLC shows 94% purity) and 5mg (2%) of the E-
isomer (Example 222(b)) of the title compound as a white solid. MS (ES) 391 (M+NEU),
372 (M-H); HPLC shows 96% purity.
Preparation 27
5-Bromo-l ,3-dihydro-benzoimidazol-2-one

Add phenyl chloroformate (922mg, 5.89mmol) to a suspension of 4-brorao-benzcne-l,2-
diamine (l.OOg, 5.35mmol) and NaHCOj (483mg, 5.89mmol) in methanol (20mL) and
H2O (lOmL). Stir at room temperature for 3.5h and add 1.00N aqueous NaOH (6mL,
6.00mmol). Stir overnight at room temperature and filter. Wash the filter cake with H2O
and dry in-vacuo overnight to obtain 386mg (34%) of the title compound as a brown
powder. MS (ES) 213,215 (M+H), 211,213 (M-H); HPLC shows 95% purity.
Example 223
5-(l 0,1 l-Dihydro-diben2o[a,d]cyclohepten-5-ylidenemethyl)-l ,3-dihydro-benzoirnidazol-
2-one

Following procedures essentially as described in Example 230, below, and using (10,11-
dihydro-diben2o[a,d]cycloheptcn-5-yIidcne)-boronic acid (0.0S25M in toluene, lOmL,
0.825mmol) and 5-brorao-l,3-dihydro-benzoimida2ol-2-one (117mg, 0.550mmol),
provides the title compound. Purify by triturating with CH2CI2 to obtain S5mg (45%) of
the title compound as a white powder. MS (ES) 339 (M+H), 337 (M-H); HPLC shows
93% purity.
Preparation 28
4-Bromo-1,3niihydro-indol-2-one

Add a solution of I2 (2.62g, 10.30mmol) in DMF (lQmL) dropwise to a solution of 4-
broraoindole (2.00g, 10.20mmol) and KOH (1.43g, 25.5mmol) in DMF (40mL). Stir for
30min at room temperature and add saturated aqueous Na2SC>3. Stir at room temperature
for 15min, then dilute reaction mixture with ethyl acetate (lOOmL). Wash organics three
times with H2O, dry organics (MgSCu) and concentrate to a brown oil. Dissolve oil in 2-
methoxyethanol (40mL) and heat to 100°C. Add H3PO4 (9mL) and heat to reflux for 4Sh.
Cool to room temperature and dilute with H20 (75mL). Extract into ethyl acetate, dry
(MgSO,j) and concentrate organics to a dark brown oil. Chromatograph on silica gel
(90g), eluting with 20% to 40% ethyl acetate/hexanes to afford 121mg (6%) of the title
compound as a tan solid. MS (ES) 212^14 (M+H), 210,212 (M-H); HPLC shows 76%
purity.
Example 224
4-( 10,11 -Dihydro-dibenzo[a>d]cyclohepten-5-ylidenemethyl)-l ,3-dihydro-indol-2-one

Following procedures essentially as described in Example 229 and using {10,11 -dihydro-
dibenzo[a,dJcyclohepten-5-ylidene)-boronic acid (0.0S25M in toluene, 7.4M1, 0.61mmol)
(coccentrated to dryness before use in reaction). Add 4-bromo-l,3-dihydro-indoi-2-one
(lOSmg, 0.510mrnol) to provide 37mg (22%) of the title compound as a tan solid. MS
(ES) 338 (M+H); HPLC shows 96% purity.
Preparation 29
2-(10,l l-Dihydro-dibenzof^djcyclohepten-S-ylidenemethyO-phenylboronic acid

Add n-BuLi (1.6M in hexanes, 12.98M1,20.76mmol) portionwise (exothermic) to a
solution of 5-(2-bromo-benzylidene)-10,l l-dihydro-5H-dibenzo[a,d3cyclohq3tene (5.00g,
13.84mmol) in dry THF (50MI) at-78°C under N2. Let stir at-78°C for 30min, then add
triisopropyl borate (5.21g, 27.68mmol) and warm up to room temperature overnight. Add
50M1 1 .OON HC1 and stir for 15mm- Extract into ethyl acetate, dry (MgS04) and
concentrate organics to a brown foam, Recrystallize from boiling hexanes, then
chromatograph on silica gel (40g), elutmg with 20% to 50% ethyl acetate/hexanes to
afford the title compound as a white foam, mp 134.1°C. MS (ES) 325 (M-H); HPLC
shows 82% purity.
Example 225
2-[2-(l 0,11 -Dihydro-dibenzo[a,d] cyclohepten-5-ylidenemethyi)-phenyl] -pyrazine

In a 1-dram vial, mix 2-(10,l l-dihydro-dibcnzo[a,dJcyclohepten-5-ylidencmethyl)-
phenylboronic acid (lOOmg, 0.307mmol), chloropyrazine (69mg, 0.460mmol), cesium
fluoride (94mg, 0.614mmol), and [l,r-bis(diphenylphosphino)-
ferrocene]dichloropanadiurn(II) (1:1 complex with CH2CI2,25mg, 0.031mmol) in
dioxanc (2mL). Heat to 85°C for 72h, then remove solvent under nitrogen. Take up the
resulting residue in H2O (lmL) and CH2CI2 (lmL) and load onto a Varian ChemElut
CE1005 solid-phase extraction cartridge. Elute, collect, and concentrate 15mL CH2Ch to
obtain crude product. Purify by mass-guided reverse-phase HPLC to obtain 2.3mg (2%)
of the title compound. MS (ES) 361 (M+H); HPLC shows 93% purity.
Example 226
4-{2-(10Jl-Dihydro-diberizo[a,d]cyclohepten-5-ylidenemethyl)-phcnyl]-3,5-oUraethyI-
isoxazole

Following procedures essentially as described in Example 225 and using 2-(10,ll-
dihydro-dibenzo[a,d]cyclohepten-5-ylidenernethyI)-phenyIboronic acid (lOOmg,
0.307mmol) and 4-bromo-3^-dinaethylisoxazole (81mg, 0.46Qmmol), provides the title
compound in 2% yield. MS (ES) 378 (M+H); HPLC shows 94% purity.
Example 227
2-[2-(10^1-Dmydro-diT>erizo[a,d]cycloheptcn-5-ybdenemethyl)-phenyl]-pyridine

Following procedures essentially as described in Example 225 and using 2-(10,l 1-
dihydro-dibcnzo[a,d]cyclohepten-5-yIidenemethyl)-phenyIboronic acid (1 OOmg,
0.307rnmol) and 2-chloropyridine (52mg, 0.460mmol),provides the title compound.
Purify further via silica gel chromatography to obtain 34.7mg (13%) of material that is
84% pure by HPLC. MS (ES) 360 (M+H).
Example 228
342-(10,ll-Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-pyriciine

Following procedures essentially as described in Example 225 and using 2-(10,l 1 -
dihydro-ridin-2-yIamiiie

Following procedures essentially as described in Example 219 and using 2-amino-6-
bromopyridine (95mg, 0.55Qmmol) and (10,1 l-dibydro-dibenzo[a,d]cyclohepten-5-
ylidene)-boronic acid (0.197M in dioxane, 3.35mL, 0.660mmol), provides 98mg (60%) of
the title compound as a yellow oil. MS (ES) 299 (M+H); HPLC shows 97% purity.
Example 231
N-[6-(l 0,1 l-DmyclrcHnl)enzo[a>d]<^clob^ten-5-yUdenememyl)-pyridin-2-yl]-
methanesulfonamide

Mix 6-(l 0,11 -dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-2-ylamine
(70mg, 0.235mmol), tricthylamine (68uL, 0.470mmol), N,N-dimethylaminopyridine
(3mg, 0.024mmoi), and methanesulfonyl chloride (19uL, 0.247mmoi) in CH2C12 (2mL).
Stir at room temperature overnight and add 150DL triethylaminc and 40uL
methanesulfonyl chloride. Stir at room temperature for 6h and add l.OON aqueous HO
(ImL). Load mixture onto a Varian ChemEIut CE1005 solid-phase extraction cartridge,
then elute, collect, and concentrate 45mL CH2C12. Dissolve crude product in THF (5mL),
add 1.0M tetrabutylammonium fluoride (0.25mL), and heat to reflux for lh. Cool to
room temperature and dilute with H20 and brine. Extract into ethyl acetate, dry (MgSd)
and concentrate organics. Chromatograph on silica gel (lOg), eluting with 20% to 35%
ethyl acetate/hexanes to afford 61mg (69%) of the title compound as a yellow oil. MS
(ES) 377 (M+H), 375 (M-H); HPLC shows 96% purity.
Example 232
6-(l 0,11 -Dihydro^ben2o(a,d)cyclohepten-5-yUdenemethyl)-pyrazin-2-ylamine

Following procedures essentially as described in Example 219 and using 2-amino-6-
chloropyrazinc (71mg, O.550mmol) and (10,ll-dih>dro-dibcnzo[a,d]cyclohepten-5-
ylidene)-boronic acid (0.197M in dioxane, 3.3 5mL, 0.660nunol), provides the title
compound. Purify by recrystallization (ethyl acetate/hexanes) to obtain 48mg (29%) of
the title compound as a yellow solid. MS (ES) 300 (M+H); HPLC shows 96% purity.
Example 233
N-[6-(10,l 1 -Dmydro-diben2o[a,d]cyclohepten-5-ylidenemethyl)-pyrazin-2-yl]-
methanesulfonamide

Mix 6-(l 0,11 -d^hydro 35%
ethyl acetate/hexanes to afford 19mg (43%) of the title compound as a white solid. MS
(ES) 378 (M+H), 376 (M-H); HPLC shows 100% purity.
Example 234
2-( 10,11 -Dmydro^ben2o[a,d]cyclobepten-5-yhdenemcmyl)-pyridirj-4-ylamine

Following procedures essentially as described in Example 225 and using 4-amino-2-
chloropyridine (216mg, 1.68nunol) and (10,ll-dihydro-diberjzo[a,d]cyclohepten-5-
ylidene)-boronic acid (0.197M in dioxane, 10.2mL, 2.01 mmol), provides the title
compound. Chromatograph on silica gel (35g), eluting with 40% to 60% ethyl
acetate/hexanes to afford 250mg (42%) of the title compound as a brown oil. MS (ES)
299 (M+H). HPLC shows 9S% purity.
Example 235
N-[2-(l 0,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-4-yrj-
methanesulfonamide

Mix 2-(10,l l^iihy(ko-diben2»[a,d]cyclohq5tcn-5-ylidenemethyl)-pyridin-4-ylainine
(176mg, 0.590mmol), triethyiamine (600}iL, 4.13mmol), N,N-dimethylarninopyridine
(7mg, O.059mmol), and methanesulfonyl chloride (137jiL, 1.769mmol) in CH2CI2
(lOmL). Stir at room temperature for 3h and dilute with H2O (I5mL). Extract into
CHaCh, dry (MgS04) and concentrate organics. Dissolve crude product in THF (lOmL),
add 1-0M tetrabutylammonium fluoride (O.S9mL), and heat to reflux for 4h. Cool to
room temperature and dilute with H2O. Extract into ethyl acetate, dry (MgS04) and
concentrate organics. Chromatograph on silica gel (lOg), eluting with 80% -> 90% ethyl
acetate/hexanes to afford 150mg (68%) of the title compound as a yellow foam. MS (ES)
377 (M+H), 375 (M-H); HPLC shows 96% purity.
Example 236
5-(l 0,11 -Dmyd^o-d^enzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-3-ol

Following procedures essentially as described in Example 225 and using 5-chloro-2-
pyridinol (77mg, 0.591mmol) and (10,ll-dihydro-dibenzo[a,d]cyclohcpten-5-ylidene)-
boronic acid (0.197M in dioxane, 3.58mL, 0.709mmol), provides the title compound.
Chromatograph on silica gel (lOg), eluting with 60% to 75% ethyl acetate/hexanes to give
40mg of brown oil. Re-cbromatograph on silica gel (5g) eluting with 60% ethyl
acetate/hexanes to afford 1 Smg (8%) of the title compound as a brown oil. MS (ES) 300
(M+H), 298 (M-H); HPLC shows 95% purity.
Example 237
4-(10Jl-Dihydro-dibenzo[a,d]cycloheptcn-5-ylideriemethyl)-lH-pyrazole

Following procedures essentially as described in Example 229 and using 4-iodopyrazole
(107mg, 0.55mmol) and (10,ll-dihydro-diT)enzo[a,d]cyclohepten-5-ylidene>boronic acid
(0.198M in dioxane, 42mL, 0.825mmol), provides 27mg (18%) of the title compound as
a colorless oil. MS (ES) 273 (M+H), 271 (M-H). HPLC shows 98% purity.
Example 238
4- Benzylidene-9,10-dibydro-Aff-l -thia-benzo|y)azulene (E and Z isomer)

A. Add a 1.0 M solution of benzyl magnesium bromide (0.5mL, 0.5mmol) in THF to
a solution of 9,10-dihydro-l-thia-benzo[/]azulene-4-one (20.8mg, 0.97mmol) (prepared
according to procedures of Bollinger, P.; Cooper, P.; Gubler, H. U.; Leutwiler, A.; Payne,
T. Helv. Chvn. Acta 1990, 73,1197) in 1.0 mL of THF under Ar. Stir the resulting
solution for 2h at 25 °C before quenching with ca. 100 uL of saturated, aqueous
ammonium chloride. Filter the mixture and wash the magnesium salts with copious
amounts of diethyl ether. Wash the filtrate with 1-mL portions of water and brine, dry
(Na^SO^ and concentrate under reduced pressure. The tertiary alcohol can be purified
by column chromatography (9:1 hexanes:ethyl acetate).
B. Dissolve the crude oil in 1.5 mL of CHCI3, add ca. 40 uL (2 drops) of
concentrated hydrochloric acid, and then stir the resulting dark solution for 2 h at 25 °C.
Add 1 mL of water and 1 mL of CHCI3, separate the layers, and wash the organic layer
successively with 0.5-mL portions of saturated, aqueous sodium bicarbonate and brine.
Dry (MgSC>4) and concentrate via rotary evaporation. Purify by flash chromatography
(hexanes) to afford 6.7 mg (24%, 2 steps) of a white solid as a 2:1 mixture of E- and Z-
isomers. MS (C1): 289 (M+l). *H NMR (CDCI3,400 MHz) 5 2.90-3.60 (m, 4 H), 6.53
(d, J = 5.4 Hz, 1/3 H), 6.66 (s, 1/3 H), 6.86 (d, J = 5.4 Hz, 1/3 H), 6.94 (s, 2/3 H), 7.01-
7.34 (m, 10 H), 7.39-7.41 (m, 2/3 H); HPLC shows >95 % purity: tR = 5.S54 min (E + Z;
80:20 MeOH:H20 to MeOH).
Section 4 (derivatives of Formula I wherein the "A" and / or "B" ring represents a
heterocyclic ring.)
Example 239
4^2,4-Dichloio-berazyiidene)-9,LO-d&vdro-4H-l-^ (mixture of E and
Z isomers)
Following the procedures essentially as described in Example 238 and using 9,10-
dihydro-l-thia-benzo[/]azulene-4-one(40.Smg, 0.19mmol) and 2,4-dichlorobenzyl
magnesium chloride (0.575 mmol) in THF.diethyl provides, after dehydration, 30.0 mg
(44%) of the title compound as a 3:1 mixture of E- and Z-isomers. *H NMR (CDG3) 6
2.88-3.40 (rn, 4 H), 6.26 (d, J = 4.8 Hz, 1/4 H), 6.50 (d, J = 8.2 Hz, 3/4 H); 6.63 (s, 1/4 H,
Z), 6.74 (s, 3/4 H), 6.76 (Id, J = 8.6 Hz, 2.0 Hz. 3/4 H), 6.88 (td, J = S.2 Hz, 1.2 Hz, 3/4
H), 6.96 (s, 3/4 H), 6.95-6.98 (m, 1/4 H), 7.06 (d, J = 4.8 Hz, 3/4 H), 7.08-7.20 (m, 14/4
H), 7.28 (d, J = 2.0 Hz, 3/4 H), 7.34 (d, J = 2.4 Hz, 1/4 H), 7.35-7.38 (m, 1/4 H); TLC
shows .95 % purity: Rf = 0.20 (hexanes).
Example 240
^(S.S-DimethyNbenzyUdene^PjlO-dihydro^H-l-thia-benzol/Jazulene (mixture of E- and
Z- isomers)

Following the procedures essentially as described in Example 238 and using 9,10-
dihydro-l-mia-ben2o[/]azulene-4-one (47.0mg (0.22mmol) and solution of 3,5-
dimethylbenzyl magnesium bromide(0.650 mmol) in THF, provides, after dehydration,
39.6 mg (57%) of the title compound as a 1.6:1 mixture of E- and Z-isomers. MS (EI):
316 (M+); *H NMR (CDC13) 5 2.13 (s, IS/5 H), 2.24 (s, 12/5 H), 2.40-3.S0 (m, 4 H),
6.54 (d\J = 5.6 Hz, 2/5 H), 6.53-6.55 (m, 7/5 H), 6.74 (s, 3/5 H), 6.83-6.84 (m, 2/5 H),
6.86 (s, 3/5 H), 6.93 (s, 3/5 H), 7.01-7.02 (m, 1 H), 7.08 (app d, J = 5.6 Hz, 2/5 H), 7.14
(app d, J = 5.6 Hz, 2/5 H), 7.19-7.25 (m, 4 H), 730 (d, J = 8.0 Hz, 3/5 H), 7.37-7.39 (m,
2/5 H).
Example 241
E- and Z-4-Ben2ylidene-9>10-dmydro-4H-3-tbia-bcnzo[/]azulene (mixture of E- and Z-
isomers)
Following the procedures essentially as described in Example 23S and using 9,10-
dihydro-3-thia-benzo[/]azulene-4-one (32.9rng)0.153mmol) (prepared according to
Hallberg, A.; Pedaja, P. Tetrahedron 1983,39, 819) and solution of benzyl magnesium
bromide (0.470 mmol) in THF, provides 15.1 mg (34%) of the title compound as a 4:1
mixture of E- and Z-isomcrs: MS (C1): 289 (M+l); ^NMRtCDC^) 5 2.98-3.12 (m, 4
H), 6.61 (d, J - 5.2 Hz, 1/5 H), 6.65 (s, 1/5 H); 6.66 (d, J = 5.6 Hz, 4/5 H), 6.96 (s, 4/5 H),
6.97 (d, J = 3.2 Hz, 4/5 H), 6.97 (d, J = 32 Hz, 4/5 H), 6.96 (s, 38/5 H), 7.28-731 (m, 4/5
H).
Example 242
4-(2,4-Dichloro-benzylidene)-9,10-dihydro-4H-3-thia-ben2o[/]a2uIene (E- and Z-
isomers)
Following the procedures essentially as described in Example 238 and using 9,10-
dihydro-3-thia-benzo|/]azulene-4-one (23.3mg, O.lOSmmol) and solution of 2,4-
dichlorobenzyl magnesium chloride (0325 mmol) in THF provides, after dehydration,
12.5 mg (32%) of the title compound as a 3:1 mixture of E- and Z-isomers: *H NMR
(CDC13) 5 2.88-3.40 (m, 4 H), 6.26 (d, J = 4.8 Hz, 1/4 H), 6.50 (d, J = 82 Hz, 3/4 H);
6.63 (s, 1/4 H, Z), 6.74 (s, 3/4 H), 6.76 (td, J = 8.6 Hz, 2.0 Hz, 3/4 H), 6.88 (td, J = 8.2
Hz, \2 Hz, 3/4 H), 6.96 (s, 3/4 H), 6.95-6.98 (m, 15/4 H), 7.28 (d, J = 2.0 Hz, 3/4 H),
734 (d, J = 2.4 Hz, 1/4 H), 7.35-738 (m, 1/4 H); TLC shows > 95 % purity. Rf = 020
(hexanes).
Example 243 (a*) and fb)
£-.V-[3-(9,10-Dmydro-l-tm'a-benzoaaulen-4-yIidencmctbyl)-phenyl]-memanesulfonamide
(E-isomer) and Z-7^-[3-(9fl0-Dibydro-l-thia-benzoazulen-4-ylidenemethyl)-phenyl]-
mcthanesulfonamide (Z-isomcr)

Following the procedures essentially as described in Example 219 and using 4-
bromomethylene-9,10-dihydro-4H-l-thia-benzo[/3azulene (54.1mg,0.l86 mmol) and 3-
methylsulfonaminophenyl boronic acid (43.4mg, 0.202mmol), (prepared according to M.
JL Quan, J. Wityak, C. Dominguez, J. V. Duncia, C. A. Kettner, C. D. Ellis, A. Y. Liauw,
J. M. Park, J. B. Santella, R. M. Knabb, M. J. Thoolen, P. C. Weber and R. R. Wexler
Bioorg. Med. Chan. Lett. 1997,13,1595), provides the title compound. Purify the crude
residue by column chromatography (hexanes to 7:3 hexanesrethyi acetate) to give 49.7mg
(ca. 70 %) of the title compound as a 1:1 mixture of E- and Z-isomers. The isomers were
separated via HPLC on a Waters Symmetry CI 8 5-^m 19-mm x 300-mm semi-
preparatory column using a 7:3 MeCN:H20 (0.1 % TFA) eluent and were identified on
the basis of the following spectroscopic properties. E-A-[3-(9,10-Dihydro-l-thia-
benzoa2iilen^ylidenememyl>phenyl]-methanesulfoiiamide (Example 243)a)) : MS
(C1): 382 (M+l); ^H NMR (CDCI3,400 MHz) 6 2.78 (s, 3 H), 2.90-3.45 (m, 4 H), 6.12
(s, 1 H), 6.72 (app s, 1 H), 6.91 (s, NH, 1 H), 6.93-7.03 (m, 3 H), 7.10-7^3 (m, 4 H), 7.32
(d, J = 7.8 Hz, 1 H); HPLC shows >95 % purity: tR = 3.194 min (80:20 MeOH:H20 to
MeOH). Z-AT-[3-(9,10-Dmyd^l-tbJa-berjzoa2ulen-4-ylidenemethyl)-phenyl]-
methanesulfonamide (Example 243(b)): MS (C1): 382 (M+l); !H NMR (CDCI3,400
MHz) 8 2.94 (s, 3 H), 3J24 (br s, 4 H), 6.50 (d, J = 5.0 Hz, 1 H), 6.64 (s, 1 H), 6.88 (d, J =
5.0 Hz, 1 H), 7.08-7.18 (m, 3 H), 7.26-7.30 (m, 4 H), 7.38-7.40 (m, 1 H); HPLC: shows
>95 % purity: tR = 3.194 min (80:20 MeOH:H20 to MeOH).
Example 244
3-(8-Chlon>5,6-dmydYo-beiizo[5,6]cyclohepta{I,2-b]pyridin-ll-ylidenemethyl)-phenol,
(Z-isomer)

A. Prepare 1 l-(3-bromo-benzylidcnc)-8-chloro-6,I l-dihydro-5H-
benzo[5,6]cyclohepta[l,2-b]pyridine according to procedures essentially as described in
Example 2S using m-bromobenzylmagnesiuin bromide (7.5ramol)and 8-chloro-5,6-
dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-l 1-one (600mg, 2.5inmol) in ether (25mL).
Separate the E and Z isomers by column chromatography (15% ethyl acetate/hcxane).
B. Separately, convert each isomer to the bydroxyl derivative by using the following
procedure: Mix ll-(3-bromo-benzyUdene)-8-cMoro-6,ll-dihydro-5H-
benzo[5,6]cyclohepta[l,2-b]pyridine (500mg, (1.26mmol),pinacol diborane (416mg,
1.64mmol),KOAc (375mg, 3.8mmol) in DMSO (lOmL). Sparge with nitrogen for 10
minutes and then add Pd(dppf)Cl2 (160mg, 0.2mmol) and heat at 80°C for 4h. Shake with
water and ethyl acetate. Dry the organic layer (MgSO^) and concentrate to give 650mg
crude product. Purify by column chromatography (15% ethyl acetate/hexane) to give
310mg (56%) 8-chIoro-l l-[3-(4,4^,5-tetramethyl-[U,2]dioxaborolan-2-yl)-
berjL^lidene]^,llHlmydro-5H-benzo[5,6]cyclohepta[1^2-b]pyridine. MS (ES)444
(M+l). Purify by HPLC is 89%.
C. Mix 8^hloro-ll-[3^4,4^,5-tetoimemyl-[13>2]dioxaborolan-2-yl)-benzyudene]-
641-4ihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridme (300mg,0.68mmol), HOAc (lmL),
water (lmL), THF (5mL) and 30% H202 (mL). Stir the reaction at RT for 4L Quench
with aqueous Na2S203 and extract the product into EtOAc. Dry (MgSCk) and concentrate
to give 250mg crude product. Purify by column chromatography (15% ethyl
acetate/hexane) to give 66mg 3-(8-chloro-5,6-dihydro-ben2o[5,6]cyclohepta[l,2-
b]pyridin-l 1 -ylidcnemethyl)-phenol, Z-isomer as a white solid, mp 221.2°C. MS (ES)
334 (M+l), 332 (M-l). HPLC shows 99% purity.
Example 245
3-{8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]p>Tidi.n-ll-ylidencrnethyl)-phenol)
(E-isomcr)

Prepared as described in Example 244, above, to provide 90mg (57%) product as a white
solid, mp >250°C MS (ES) 334 (M+l), 332 (M-l). HPLC shows 94% purity.
Example 246
N-[3-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[ 1,2-b]pyridin-l 1-ylidenemethyl)-
phenyl]-methanesulfonamide (E isomer,)

Following procedures as described in Example 219 and using 1 l-bromomethylene-8-
chloro-6,1 l-dihydro-5H-benzo[5,6]cyclohepta[l ,2-bjpyridine (E-
isomerX820mg,2.56romol) and 3-methanesulfonylaminophenylboronic acid
(605mg^.8mmol), provides the title compound in 53% yield as a white foam after
purification on silica gel using 50% EtOAc/hexane. MS (ES) 411 (M+l), 409 9M-1).
HPLC shows 97% purity.
Example 247
N-[3-(2-Methyl-9,10-dihydro-l-oxa-3-aza-benzo[f]azulen-4-yiidenernethyl)-phenyl]-
methanesulfonamide

Prepare the corresponding ketone (2-memyl-9,10-dmydro-l-oxa-3-aza-benzo[f]azulen-4-
one) as described by E.E. Galantay, et ay. Med. Chem. (17) 1316-1327 (1974) and
convert to the corresponding Z-isomer of the vinyl bromide using procedures essentially
as described in Preparations 23 and 24. Then, following procedures essentially as
described in Example 219, combine the ketone with 3-methanesulfonamidophenyl
boronic acid (325mg, 1.5mmmol). Purify the crude product using column chromatography
(30% EtOAc/hexane to 50% EtOAc/hexane) to provide I80mg (3S%) Z-isomer as a light
tan solid, mp 184.6°C, MS (ES) 381 (M+l), 379 (M-l). HPLC shows 94% purity at
r=1.99min.
Example 248
3-(2-Memyl-9,10-dmydro-l-oxa-3-aza-beo2o[fJazulen-4-ylidenemethyl)-phenol

Prepare the corresponding ketone (2-methyl-9,10-dihydro-l-oxa-3-aza-ben2o[fjazulen-4-
one) as described by E.E. Galantay, et al,J. Med. Chem. (17) 1316-1327 (1974) and
convert to the corresponding Z-isomer of the vinyl bromide using procedures essentially
as described in Preparations 23 and 24. Then, following procedures essentially as
described in Example 219, combine the ketone with 3-hydroxypheny] boronic acid
(207mg, 1.5mmmol). Purify the crude product using column chromatography (15%
EtOAc/hexane to 30% EtOAc/hexane) to give 26mg title compound, MS (ES) 304
(M+l). HPLC shows 93% purity at t=2.48min.
Example 249
(i^-Ar-[3-(5,6^Dihyd^o-benzo[5,6]cyclohepta[l>2-Z7jpyridin-ll-ylidenemethyl)-phenyl]-
methanesulfonamide (LY2076945, JN9-A0I943-65)

Following procedures essentially as described in Example 219, combine 11-
bromomethylene^Jl-dmydn>5//-beii2»[5,6]cyclohepta[l^-fc]pyridine(250mg,
0.87mmol) and 3-methanesulfonamide-phenyl boronic acid (244mg, l.lmmol). Purify the
product via flash chromatography, eluting die product with solutions of increasing
concentrations of ethyl acetate in hexanes (10% to 50%). Combine product fractions,
concentrate and dry to yield 190mg (58%) of product as a white solid. LC/MS (APCI-
pos): 377.1 (M+H). *HNMR (CDC13,400MHz): 58.49 (dd,lH), 7.42 (d,IH), 7.32
(s,lH), 7.29 (d,lH), 7.23-7.11 (rn^H), 7.01 (bd^H), 6.94 (d,lH), 6.86 (s,2H), 3.6-2.9
(bm,4H),2.78(s,3H).
Example 250
(£)-3-(5,6-Dihydro-benzo{5,6]cycIohepta[l,2-6]pyridin-ll-ylidenemcthyl)-pbenol

Following procedures essentially as described in Example 219, combine 11 -
brt>mon]ethylene-6,ll-dihydro-5//-benzo[5,6]cyclohepta[l,2-i]pyridine(250mg.
0.87mmol) and (3-hydroxyphenyl) boronic acid (133mg, 0.96mmol). Purify to provide
product 166mg (63%) as an off-white solid. LC/MS: 300.1 (M+H). 'HNMR(DMSO,
400 MHz): 8922 (s.lH), 8.40 (d,lH), 7.49 (d.lH), 7.34 (d,lH), 7.24 (d,!H), 7.21 (dpH),
7.15 (s,lH), 7.04 (t,lH), 6.92 (d,lH), 6.90 (d,lH), 6.52 (d,lH), 6.40-6.42 (m,2H), 3.4-2.8
(m,4H).
Example 251
(^-^-[S-ClOJJ-Dihydro-benzo^.Slcycloheptafl^-ijpyridin-S-ylidenemethyl^phenyl]-
methanesulfonamide
Following procedures essentially as described in Example 219, combine (Z)-5-
bromomethylene-10,ll-dihydro-benzo[4,5]cyclobepta[l^-6]pyridine (153mg, 0.53mmol)
with 3-metbanesulfonamide-phenyl boronic acid (150mg, 0.7mmol). After work-up,
purify the crude product by flash chromatography (10% ethyl acetate/hexanes to 25%
ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to provide 180mg (90%) of purified
product. LC/MS: 377.1 (M+H) 375 (M-H). Purity by LC/MS 95%.
Example 252
(Z)-3-(l 0,1 l-Dmydro-benzo[4,5]cvclohepta[l^-6]pyridin-5-ylidenemethyl)-phenol

Following procedures essentially as described in Example 219, combine (Z)-5-
bromomethylene-10,11-dihydro-ben2o[4,5]cyclohcpta[l,2-i]pyridinc (153 mg, 0.53
mmol) 3-hydroxyphenyl boronic acid (S5mg, 0.59mmol). After work-up, purify the crude
product by flash chromatography (10% ethyl acetate/hexanes to 25% ethyl
acetate/hexanes to 50% ethyl acetate/hexanes) to provide 68mg (43%) of purified product.
LC/MS: (300.1 (M+H). Purity by HPLC is 95%.
Example 253
(£)-N-[3-(l 0,11 -Dihydro-benzo[4,5]cyclohepta[ 1 ^-fc]pyridia-5-ylidenemethyl)-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 219, combine (E)-5-
bromomemyIene-10,ll-dihydro-benzo[4^]cyclohepta(l^-6]p)Tidine (105mg, 037mmol)
3-methanesulfonamide-phenyl boronic acid (103mg, 0.18mmol). After work-up, purify
the crude product by flash chromatography (10% ethyl acetate/hexanes to 25% ethyl
acetate/hexanes to 50% ethyl acetate/hexanes) to provide 105mg (76%) of purified
product. LC/MS: 377.1 (M+H), 375 (M-H). PuritybyLC/MSis95%. ^NMRfCDCl,,
400 MHz): 88.44 (dd\lH), 7.82 (dd,lH), 7.31 (d^H), 726-7.14 (m,3H), 7.03 (dq,2H),
6.95 (dd,lH), 6.87 (^lohepta[l,2-^]pvriduj-5-ylidenemethyI)-phenol

Following procedures essentially as described in Example 219, combine (E)-5-
bromomethylenc-l 0,11 -dihydro-l-enzo[4,5]cyclohepta[ 1,2-6]pyridine (105mg, 0.37mmol)
3-hydroxyphenyl boronic acid (58mg, 0.4mmol). After work-up, purify the crude product
by flash chromatography (10% ethyl acetate/hexanes to 25% ethyl acetate/hexanes to 50%
ethyl acetate/hexanes) to provide 45mg (41%) of purified product. LC/MS: 300.1 (M+H).
'H NMR (CDC13,400 MHz): 58.25 (d,lH), 7.79 (d,lH), 7.18-7.12 (m,lH), 7.01-6.90
(m,5H), 6.68 (s,lH), 6.58 (dd,lH), 6.54 (d,lH), 6.37 (s,lH), 3.5-2.6 (m,4H).
Section 5 (derivatives of Formula I wherein the bridge depicted by-X—Y- represents a
fused cyclopropyl structure.)
Example 255
N-[3-(8,8-Difluoro-4-ylidine raethyl-2,3,5,6-dibenzobicyclo[5.1.O]octane)-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 219 and using 8,8-difiuoro-4-
bromomethylcne- 2,3,5,6-dibenzobicycIo[5.1.0]octane (163mg, 0.4 mmol) and 3-
(methyIsulfonamido)phenylboronic acid (116mg, 0.54mmol) to provide the title
compound. Evaporate and purify on silica gel (methanol/dichlorometlianc) to obtain 99mg
(48%) of the title compound. Add ethyl acetate to obtain a crystalline material. MS (ES)
423 (M-l).
Example 256
N-[3-(8,8-Difluoro-4-ylidine methvl-2,3,5,6-dibcnzobicyclo[5.1.0]octane)-phenol

Following procedures essentially as described in Example 219 and using 8,8-difluoro-4-
bromomethylene- 2A5,6-dibenzobicyclo[5.1.0]octane (166mg., 0.5mmol) and (3-
hydroxypheny)boronic acid (76mg., O.55mmol). Purify with silica gel (ethyl
acetate/hexanes) chromatography to obtain 103 mg (60%) foam. MS (ES) 346 (M-l).
Example 257
N-[3-(4-Ylidhie methyl-2^,5,6-dibenzobicyclo[5.1.0]octane)-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 219 and using 4-
bromomethylene- 2,3,5,6-dibenzobicyclo[5.1.0]octanc (208 mg, 0.7 mmol) and 3-
(methylsulfonamido)phenylboronic acid (166 rag, 0.77 mmol) to provide the title
compound Purify on silica gel using methanol/dichloromethane and ethyl acctate/hexancs
by radial chromatography. Obtain S3.5mg (31%). MS (ES) 3S7 (M-l).
Example 25S
N-[3-(4-Ylidine raethyl-2,3,5,6-dibcnzobicyclo[5.1.0]octane)-phenol

Following procedures essentially as described in Example 219 and using 4-
bromomethylene- 2,3,5,6-dibenzobicyclo[5.1.0]octane (208mg., 0.7mmol) and (3-
hydroxypheny)boronic acid (106mg, 0.77 mmol) to provide the title compound. Evaporate
the reaction and add to a Celite cartridge using dichloromethane. Elute with
dichloromethane. Evaporate the eluent and purify on silica gel ethyl acetate/hexanes
chromatography to obtaiD 60mg (28%)of the title compound as a foam. GC/MS
t=21.49minMW=310.
Example 259
Ar-[3^8,8-DicbJoro^ylidenemethyl-23»5,6-diberiZobicyclo[5.1.0]octane)-phenyl]-
methanesulfonamide
Following procedures essentially as described in Example 219, combine 8,S-Dicbioro-4-
bromomethylene-2,3,5,6-dibenzobicyclo[5.1.0]octane (160 mg, 0.44 mmol) and
3-methanesulfonamidc-phenyl boronic acid (103 mg, 0.48 mmol to provide the title
compound. Purify the product using radial chromatography eluting the product with
solutions of increasing concentrations of ethyl acetate in hexanes (5,10, 15, 20, and 25%).
Combine product fractions, concentrate and dry to yield 120 mg (60%) of product as a
white solid, mp 199-201 °C. LC/MS (ES): 474 (M+NH/), 456 (M*)-
Example 260
N-[3-(8,8-Dichloro-4-ylidene metbyl-2,3,5,6-dibenzobicyclo[5.1.0]octane)-phenol

Following procedures essentially as described in Example 219, combine S,S-dichloro-4-
bromomethylene-2r3,5>6-dibenzobicyclo[5.1.0]octane (160mg, 0.44mmol) and
(3-hydroxyphenyl)-boronic acid (70mg, 0.4 mmol) to provide the title compound^ Purify
the product radial chromatography eluting the product with solutions of increasing
concentrations of ethyl acetate in hexanes (5,10,15, and 20%). Combine product
fractions, concentrate and dry to yield 59mg (36%) of product as a white solid. LC7MS
(ES*): 397 (M+Nft,4), 379 (M4). 'H NMR (CDCI3, 400 MHz): 57.50 (d, 1H), 7.42 (d,
1H), 7.36 (dd, 1H), 735-726 (m, 3H), 7.12-7.02 (m, 3H), 6.72-6.62 (m, 3H), 6.55 (dd,
IH), 4.89 (s, 1H), 3.46 (d, 1H), 3.35 (d, 1H).
Section 6 (derivatives of Formula I wherein the bridge depicted by -X—Y- contains a
heteroatom or heteroatom containing group at either the X or Y position.)
Example 261
N-[3-(6-Oxo-5]6-dihydro-dibenzo[b,e]azepm-ll-ylidenemethyl)-phenyl]-
methanesulfonamidc
Following procedures essentially as described in Example 158 and using 5H-
dibenzo[b,e]azepine-6,l 1-dione (97mg, 0.31mmol) and methanesulfonyl chloride (260L,
0.34mmol), followed by procedures essentially as described in Example 90, 83g of the
title compound is provided in 68% yield as a white solid H NMR (DMSO) 610.54(s,
IH), 9.67 (s, IH), 7.82 (d, IH), 7.63 (t, 1H), 7.52 (d, 1H), 7.46 (m, IH), 7.25 (m, 2H),
7.15 (m, IH), 7.02 (s, IH), 6.99 (d, IH), 6.98 (m, 2H), 6.80 (m, 2H), 2.81 (s, 3H). MS
[Eh-] 391 (M+H).
Example 262
N-[3KnH-10-Tbia-dibeazo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-
methanesuIfonamide(

Dissolve 3-(l lH-l0^a^benzo[M]cyclohepten-5-yhdenememyl>phenylamine (20mg,
0.06 mmol) in 5mL of methylene chloride under a nitrogen atmosphere. Then, following
procedures essentially as described in Example 90 22.3mg of the title compound is
provided as a white solid. JH NMR (CDC13) 57.49 (m, IH), 7.48 (d, IH), 7.35 (td, IH),
7.25-7.15 (m, 2H), 7.15-7.10 (m, 2H)7 7.10-6.95 (m, 3H), 6.87 (d, IH), 6.79(s, IH), 6.24
(m, IH), 6.10 (s, IH), 5.00 (d, IH), 3.55 (d, IH), 2.80 (s, 3H). MS [EI+] 394 (M+H), 392
(M-H).
Example 263
N-[3-(l 0-Oxo-10,11 -dihydro-10X"-thia-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-
phenyl]-methanesu Lfonamide

In 5mL of acetonitrile add Fe(N03)39H20 (5.1rag, 0.013mmol) and FeBr3 (1.9mg,
.006mmol). Add N-[3-{l lH-10-thia-dibenzo[a,d]cycloheptcn-5-ylidenemethyl)-phcnyl]-
methanesulfonamide (50mg, 0.13mmol) and stir for 2h at ambient temperature. Extract
with methylene chloride, dry (MgSC>4) and concentrate. Purify by recrystallization from
carbon tetrachloride to yield 13.6mg of a yellow solid. JH NMR (CDC13) 87.85 (m, 1H),
7.57 (m, 1H), 7.55 (m, 1H), 7.35 (td, 1H), 7.25-7.15 (ra, 2H), 7.10 (d, 1H), 7.02 (dd, 1H),
7.00-6.95 (m, 3H), 622 (s, 1H), 4.60 (b, 2H), 3.55 (d, 1H), 2.80 (s, 3H). MS [EI+] 410
(M+H)*, 408 (M-H)<
j Example 264
N-[3-
phenyl]-Methanesulfonamide

Dissolve N-[3-(10-oxo-10,ll-dihydro-10?^-thia-dibcnzo[a,d]cyclohepten-5-
ylidenemethyl)-phcnyl]-methanesulfonarnide (35mg, 0.085mmol) in 5mL of methylene
chloride at ambient temperature. Add 300mg of silica gel followed by t-butylperoxide
(0.0l2mL. O.085mmol). Stir overnight, filter and evaporate. Recrystallize from 1 ;1
ethenpentane to obtain 10.6mg of the product as a yellow solid. lH NMR (CDClj) 5 8.91
(b, IH), 7.85 (m, IH), 7.57 (m, IH), 7.55 (m, IH), 7.35 (m, 1H), 7.25-7.15 (m, 2H), 7.10
(m, IH), 7.02 (m, IH), 7.00-6.95 (m, IH), 6.30 (d 2H), 6.15 (d, 1H), 5.25 (t, IH), 4.40 (t,
IH), 2.80 (s, 3H). MS [EI+] 424 (M-H).
Example 265
1 l-(3-Nitro-benzylidene-6,l l-dihydro-dibenzo[b,e]oxq3ine

Following procedures as described in Example 229 combine 1 l-bromomethylcne-67l 1-
dihydydro-dibenzo[b,e]oxepinc (500mg) with m-nitrophenyl boronic acid (290mg). Flash
chromatography eluting widi 1:1 toluene ihexanes gave 310gof a 3:1 mix of both
isomers(54.4% yield). 'H NMR (400 MHz, CDClj) 5 7.96-7.94 (d, IH), 7.87 (s, IH),
7.52-7.47 (m, 2H), 737-7.16 (m, 5H), 7.00-6.95 (t, 3H), 6.85-6.83 (d, IH).
Example 266
3-(6H-Dibenzo [b,e]oxepin-11 -yUdenememyl)-phenylamine

Dissolve ll-(3-Nitro-benzylidene-6.11-dihydro-diben2o[b,e]oxepine (200mg) in cthanol
(lOmL) add tin chloride dihydrate (6S0mg) and reflux for 5h. Concentrate the reaction in
vacuo, re-dissolve in ethyl acetate and wash with IN sodium hydroxide solution.
Separate the layers wash with brine and dry over sodium sulfate. Purity using filter
chromatography during with 10% ethyl acetatertoluene to give 60mg of product (56%
yield).
MSm/z:300(M*+l).
Example 267
N-[3-(6H-Dibenzo{b,e]oxepine-l 1 -ylidenemethyl)-phenyl]-methanesulfonainide

Following the procedures essentially as described in Example 90, the aniline of Example
266 (180mg) is reacted with mcthanesulfonyl chloride (50L) to provide the title
compound. Elute with 1-3-6% ethyl acetatertoluene (silica gel) over a step gradient to give
40mg title product (17.6% yield) !H NMR (400 MHz, CDC13) 8 7.5-7.46 (t, 2H), 7.34-
730 (t, 1H), 7.21-7.15 (m, 3H), 7.06-6.9 (m, 5H), 6.83-6.80 (d, 1H), 6.76 (s, 1H), 6.16 (s,
lH),2.8(s,3H).
MS m/z: 376.1 (M~-l).
Example 268
N-[3-(6H-Dibenzo[b,c]oxepin-1 l-ylidenemethyl)-phenyl]-methanesulfonamide

Following the procedures essentially as described in Example 90, the aniline of Example
266 (180mg) is reacted with methanesulfonyl chloride (50L) to provide 5mg (2.2% yield)
of the title compound. 'H NMR (400 MHz, CDC13) 8 7.48-7.45 (d, 1H), 7.41-7.37 (m,
IH), 7.34-7.32 (m, 2H), 120-1.11 (d, IH), 7.15-6.99 (m, 5H), 6.90-6.88 (d, IH), 6.67-
6.61 (m, 2H), 6.26 (s, IH), 5.33 (broad s, 2H), 2.87 (s, 3H).
MS m/z: 376.1 (M~-l).
Example 269
E-4-Methoxy-l l-(3-nitro-benzylidene)-6,l l-dmydro-dibenzofb,e]oxepinc

Following procedures essentially as described in Example 230,1 l-bromomethylene-4-
metboxy-6,1 l-dihydro-dibenzofb.ejoxepine is combined with m-nitrophenyl boronic acid.
The pure E isomer is isolated by recrystallization with hexanes and diethyl ether to give
311 mg of product (33% yield). *H NMR (400 MHz, CDCfe) 5 7.979-7.949 (d, IH),
7.874 (s, IH), 7.509-7.491 (d, IH), 7.365-7.324 (t, IH), 7.305-7.237 (m, 2H), 7204-7.162
(t, IH), 7.123-7.100 (d, IH), 6.992-6.912 (m, 3H), 6.864-6.840 (d, IH), 5.75 (broad s,
IH), 5.19 (broad s, IH), 3.84 (s, 3H).
Example 270
3-(4-Methoxy-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-phenylaiaine

Prepare the title compound by SnCb reduction of 4-mcthoxy-l 1-(3-nitro-benzylidenc)-
6,11 -dihydro-dibenzofb.ejoxepine (from Example 270) to provide 267mg of product
(93.7% yield). This material is used without further characterization.
Example 271
N-[3-(4-Methoxy-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-phenyl]-
methanesulfonamide

Following procedures essentially as described in Example 90, the title compound is
prepared from 3-(4-Methoxy-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-phenylamine and
methanesulfonyl chloride. Flash chromatography eluting with 5 to 10 to 20% ethyl
acetate:toluene provides 198mg product (60% yield) of the title final product.
'H NMR (400 MHz, CDC13) 8 7.482-7.463 (d, 1H), 7.321-7.237 (m, 2H), 7.193-7.149 (t,
1H), 7.110-7.086(d, 1H), 7.035-6.973 (m, 2H), 6.936-6.881 (m, 3H), 6.840-6.815 (d, IH),
6.763 (s, IH), 6.127 (s, IH), 3.83 (s, 3H), 2.80 (s, 3H).
MS m/z: 406.1 (M~-l).
Example 272
7-Chloro-l l-(3-nitro-benzylidene)-6,l l-dihydro-dibenzo[b,e]oxepine

Following procedures essentially as described in Example 230,1 l-bromomethylcne-7-
chloro-6,ll-dihydro-dibenzo[b,e]oxepine is combined with m-nitrophenyl boronic acid
to provide the title compound. The pure Z isomer is isolated by crystallization (diethyl
ether) to give 1.4g (31.7% yield) product 'H NMR (400 MHz, CDC13) 5 S.038-8.017 (d,
1H), 7.976 (s, 1H), 7.511-7.491 (d, 1H), 7.431-7.410 (d, 1H), 7.369-7.253 (m, 3H), 7.160-
7.121 (t, 1H), 7.041-7.005 (m, 2H), 6.928-6.919 (d, 1H), 6.908-6.898 (d, 1H), 5.60 (s,
2H).
Example 273
3-(7-Chloro-6H-dibenzo[b,e]oxepin-l 1 -ylidenemethyl)-phenylamine

Prepare the title compound by SnCl2 reduction of 7-chloro-ll-(3-nitro-benzylidene)-6,l 1-
dihydro-dibenzo[b,e]oxepine (ftom Example 272) to provide 900mg (98%)of product.
MS m/z: 334.1 (m+ +1).
Example 274
N-[3-(7-CWoro-61I-dibenzon3,e}oxepm-ll-ylidenemethyl)-pheDyl]-methanesulforiainide

Following procedures essentially as described in Example 90, the title compound is
prepared from 3-(7-chloro-6H-dibenzo[b,e]oxepin-l 1-ylidcncmcthy!)-phenylamine and
mcthanesulfonyl chloride. Elute on silica gel with 15% ethyl acetatc:toluene gave 530mg
product (86%). ]H NMR (400 MHz, CDC13) 6 7.463-7.443 (d, 1H)? 7.358-7.337 (d, HI),
7.230-7.155 (m, 2H), 7.116-7.077 (t, 1H), 7.016-6.840 (m, 7H), 6.264 (s, 1H), 5.563 (s,
2H), 2.88 (s, 3H) MS m/z: 410.1 (M~-l).
Section 2
Preparation 30
1 - {2-[4-(2,8-Dimethoxy-l 0,11 -dihydro-dibenzo [a, cQcyclohepten-5-ylideneraethyl)-
phenoxyj-ethyl} -piperidine

Mix 5-bromomeraylene-2,8-dimethoxy-10,l l-dmydro-5H-dibenzo[a,]cycloheptene
(270mg, 0.78mmol) and l-[2-(phenoxy-4-boronic acid)-ethyl]-pipcridine (580mg, 2.35
mmol) in 1,4-dioxane (8mL) and aqueous sodium carbonate (2.0 M, 2mL). Sparge
solution with N2 for 15 min, then add Pd(Ph3P)4 Q40mg, 0.12mmol) and heat to 85°C for
2 h. Cool reaction mixture to room temperature, dilute with dichloromethane (lOOmL),
and wash organic once with saturated aqueous ammonium chloride. Dry (MgSO*) and
concentrate organics to a brown oil. Chromatography on silica gel (40g), eluting with 5 :
1 dichloromethane : methanol affords 180mg (50%) of the title compound as a light
brown oil. MS (ES) 470 (M+H); TLC Rf = 0.40 (5 : 1 dichloromethane : methanol).
Example 275
5-[4-(2-Piperidin- l-yI-cthoxy)-benzylidene]-10,11 -dihydro-5H-dibenzo[a, 'l]-10,ll-dihydro-5H-dJbcnzo[j.rf]cycloheptenc-2,S-
diol hydrochloride
Mix 5-[4-(2-piperidin-l-yl-ethoxy)-ben2ylidene]-10,l l-dihydro-5H-
dibenzo[a,£f)cycloheptene-2,8-diol (25rng, O.Oommol) and 10% palladium on carbon
(lOmg) in ethanol (5mL). Place under ambient hydrogen atmosphere. Stir overnight.
Filter through Celite and concentrate under reduced pressure. Chromatography on silica
gel (40g), eluting with 5 : 1 dichloromethane : methanol yields the product as a light
brown oil. React with ethereal hydrogen chloride (1.0 M, 1 mL) in dichloromethane (5
mL). Concentrate under reduced pressure. Isolate the hydrochloride salt which weighs
25mg (95%) MS (ES) 444 (M+H); TLC Rf« 0.35 (5 :1 dichloromethane: methanol).
Section 7 (derivatives of Formula I wherein R8 is not hydrogen and the bridge depicted by
-X—Y- contains either a heteroatom or heteroatom containing group at either the X or Y
position or both X and Y are CH2.)
Preparation 31
l-[2^5-Methylene-l0jlKlihydn)-5H-dibenzo[a.d]cyclohepten-2-yloxy)-ethy]j-piperidine
Dissolve 5-methylene-lO.l l-dihydro-5H-dibenzo[a,c/]cyc]ohepten-2-ol (200mg,
0.90mmol) in dimethylformamide (5mL). Add sodium hydride (90mg, 2.25mmol)
followed by 2-cWoro-ethyl-l-pipcridine hydrochloride (190mg, 1.03mmol). Stir at room
temperature overnight. Dilute with dichloromethane (50mL) and saturated aqueous
ammonium chloride (15mL). Separate organic, dry over magnesium sulfate, filter and
concentrate under reduced pressure. Chromatograph the residue on silica gel (40g),
eluting with 5 : 1 dichloromethane : methanol. Isolate the product as a light brown oil
which weighs 300mg (100%) MS (ES) 334 (M+H); TLC Rf= 0.45 (5 :1 dichloromethane
: methanol).
Preparation 32
l-[2-(5-Bromomethylene-10,l 1 -dihydro-5H-dibenzo[a,if]cyclobepten-2-yloxy)-ethyl]-
piperidine
Dissolve l-[2-(5-methylene-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-ethyl]-
pipcridine (360mg, 1.08mmol) in dichloromethane (15mL). Add
dimemylaininopyridinium tribromide (390mg, l.OSmmol). Stir at room temperature for
30min. Dilute with dichloromethane (50mL) and 10% aqueous sodium thiosulfite
(15rnL). Separate organic, dry over magnesium sulfate , filter and concentrate under
reduced pressure. Chromatograph the residue on silica gel (40g), eluting with 5 : 1
dichloromethane : methanol. Isolate the product as a light brown oil which weighs 21 Omg
(47%) MS (ES) 414 (M+H); TLC Rf = 0.48 (5 : 1 dichloromethane : methanol).
Example 277
4-[2-(2-Piperidin-l-yl^thoxy)-10,ll-3^]dioxaborolane (1.25 equivalents), 2N Na2C03 (2
equivalents) and tefrafostriphenylphosphine palladium (0.05 equivalents)in a suitable
solvent Purify the product by silica gel chromatography to obtain a 79% yield of the title
compound. MS(ES) = 329(+)
Example 279
5-(3-Memanesulfonyl-benzylidene)-10>ll-dihydro-5H-dibenzo[a,d]cycIoheptene

Mix 5-(3-methylsulfanyl-benzylidene)-10,l l-dihydro-5H-dibcnzo[a,d]cycloheptene (I
equivalent) and sodium perborate hydrate (2.2 equivalents) in 50:50
dichloromethane/glacial acetic acid and stir at room temperature for 18 hours. Then
warm to 45°C for four hours. Partition between dichioromethane and 0. IN NaOH. Dry
and evaporate the organic layer. Purify the product by silica gel chromatography to obtain
a 72% yield of the title compound. MS(ES) = 361(+)
Examples 280-288 contained in Table n, herein, provide yet additional examples
of compounds of Formula I having substitution on the "C ring, but not on the "A" or "B"
rings. These examples, which further illustrate the present invention are prepared
according to the procedures as described generally in the Schemes and literature
references described above.
Additional preparations for, and examples of compounds of Formula I having
having substitution on both the "C" ring and the "A" and/or "B" rings. (Section 2 as
represented by original Examples 161-215)
Preparation 33
E- and Z-5-Bromomethylene-2-chloro-10,l l-dmydro-5H-dibenzo[a,d]cyclobeptene

Cool a mixture of 2.8 equiv of bromomethyltriphenylphospbonium bromide (prepared
asdescribed in G. Vassilikogiannakis, M. Hatzimarinaki, M. Orfanapoulos J. Org. Chem.,
65, 8180) in THF (0.5 M) to -78 °C and add 2.8 equiv of LiHMDS-THF dropwise to give
a bright yellow mixture. Stir for 1 h at -78 °C and then 10 min at 0 °C. Recool the
mixture to -78 °C and add 2-chloro-10,I l-dihydro-dibenzo[a,d]cyclohepten-5-one.
Allow the dark mixture to warm to room temperature and stir for 3.5 h before adding
saturated, aqueous saturated ammonium chloride and diluting with pentane. Filter
through celite, concentrate filtrate and concentrate under reduced pressure. Purify by
column chromatography (1% to 2% to 3% to 5% EtOAc:hexanes) to give title compound
(30 %)as a 1:1 mixture of geometric isomers: GC-MS (GRAD60-280°C) t = 7.23 (90 %).
MS (EI): 320 (M+).
Example 289
3-(2-CWoro40,ll^lihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine

Following procedures essentially as described in Example 219, and using 5-
bromomethylene-2-chloro-10,! l-dihydro-5H-dibenzo[a,d]cycIoheptene and 3-
arninophenylboronic acid, a mixture of the E and Z isomers of the title compound is
prepared.
Preparation 34
5-Memylene-10,n^ihydro-5H-dibenzo[a,d]cyclohepten-2-ol

Prepared from commercially available 2-hydroxy-10,11 -dihydro-
dibenzo[a,d]cyclohepten-5-one following procedures essentially as described in
Preparation 23. MS(ES-)221.
Preparation 35
5-Bromomethylene-l 0,11 -dihydro-5H-dibenzo[a,d]cycIobepten-2-ol
Prepared from 5-methylene-10,l l-dihydro-5H-dibenzo[a,d)cyclohepten-2-ol using
procedures essentially as described in Preparation 24. MS (ES-) 301.
Examples 290-435 contained in Table 13, herein, provide yet additional examples
of compounds of Formula I having substitution on both the "C" ring and the "A" and/or
"B" rings. These examples, which further illustrate the present invention are prepared
according to the procedures as described generally in the Schemes and literature
references described above.
Additional preparations for, and examples of compounds of Formula I wherein
the "C ring represents a heterocyclic or benzofused heterocyclic ring. (Section 3 as
represented by original Examples 216-237)
Preparation 36
1 -(2-moipholin^-yl-ethyl>5-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-l ,3-dihydro-
benzoimidazol-2-one.
Following procedures as described in Scheme DC.
Step A: Preparation of (4-bromo-2-rutrcKphenyl)-(2-morpholm-4-yl-emyl)-arnine.
Mix 5-bromo-2-fluoro-nirrobenzene (lOg, 45mmol) and 4-(2-arninoethyI)morpholine
(] l.SmL, 90mmol) in THF (lOOmL). Stir at room temperature for 18h. Remove the THF
under reduced pressure and partition the residue between water (200mL) and ethyl acetate
(200mL). Dry the organic layer (MgS04) and concentrate to give 15.3g (100%) title
compound. HPLC (ISO80-10M) t=1.83min (94%), MS (ES) 331 (M+l).
Step B: Preparation of 4-bromo-Nl-(2-moipholirh4-yl-emyl)-benzene-l,2-diarnine
Dissolve (4-bromo-2-nitro-phenyl)-(2-morpholin-4-yl-ethyl)-amine (15.3g, 46.4mmoI) in
ethyl acetate (IL) and add 5% Pt/C (suifided) (3S2mg). Place the shiny under 60psi
hydrogen gas at room temperature of 8h. Filter arid concentrate to give 23g crude product
as a dark red oil. Purify using a short plug of silica gel and 10% 2N NH3 in
MeOH/dicbJoromethane to give 13.5gof abrown oil. HPLC (ISO60-10M) t=1.46 (94%),
MS (ES) 301 (M+l).
Step C: Preparation of 5-bromo-1^2-morphoIii>^yl^thyl)-l,3-dihydrcHben2oimidazoI-2-
one.
In a 500-mL round-bottomed flask, mix 4-bromo-Nl-(2-morpholin-4-yl-ethyI)-beri2ene-
1,2-diarnine 13J25g, 44.1mmol),NaHC03 (5.4g, 66.2mmol), water (50mL) and methanol
(250mL). Slowly add phenyl chloroformate (8.3mL,66.2mmol). Stirr the reaction for In at
room temperature and then add 5N NaOH (20mL) and stir overnight at room temperature.
Collect the solid by vacuum filtration and wash with methanol. HPLC (ISO60-10M)
t=l .42 (97%), MS (ES) 326 (M+l).
Step D: Preparation of l-(2-morpholin-4-yI-ethyl)-5-(4,4,5,5-tetramethyl-
[ 1,3,2]dioxaborolan-2-yi)-1,3-dmyfro-benzoiinidazol-2-one.
Under a blanket of nitrogen, cool a THF (150mL) solution of 5-bromo-l-(2-morpholin-4-
yl-ethyl)-13-dihydro-benzoimidazoI-2-one (7.5g, 20mmol) to 5°C and add 3N
ethylmagnesium bromide (8mL, 24mmol). After 'Ah, cool the reaction to -72°C and
slowly add 1.7M t-BuLi (170mL, lOOmmol). Allow the reaction to warm to -55°C, add
dimethyl borate (SOmmol) and allow the reaction to stir at room temperature overnight.
Add 5N HC1 (50mL) and stir for 4h. Adjust the pH to 6-7 and extract the crude boronic
acid into ethyl acetate. Dry (MgS04) and concentrate to give 10.4g crude product. Slurry
with toluene (500mL) and add pinacol (64mmol). Heat briefly and then stir overnight.
Add ethyl acetate and aqueous NaHC03. Wash the organic extract with water and
evaporate the dried (MgS04) organic layer to give 5.0g (67%) title boronic ester as a
white solid. LC/MS (ISO70-10M) 374 (M+l). Rccrystallizc from ethyl acetate/hexane.
'H NMR (CDCU) d 1.34 (s,12H), 2.55 (br s,4H), 2.70 (br s, 2H), 3.68 (br s,4H), 4.02 (br
s,2H), 7.03 (s,lH), 7.52 (s, 1H), 7.56 (d, 1H), 8.78 (br s, 1).
Preparation 37
5-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-y])-1^-dmydro-benzoimidazol-2-one
5-Bromo-13-dibydro-benzoimidazol-2-one (20.0 g, 93.9 mmol) is dissolved in
argon purged anhydrous DMF (150 mL). To this solution is added
bis(pinacolato)diboron (28.6 g, 113 mmol), KOAc (27.6 g, 282 mmol), and PdCl2(dppf),
1:1 complex with CH2CI2 (7-67 g, 9.40 mmol). The reaction is heated to 95 °C overnight
with mechanical stirring then cooled to room temperature and diluted with brine (500 mL)
and EtOAc (750 mL). The mixture is filtered to remove a dark brown solid, which is
washed thoroughly with EtOAc. The layers are separated and the organics washed with
water (3 x 500 mL), then dried (MgSO*), filtered and evaporated under reduced pressure.
Trituration with 1:1 CH2Cl2/hexanes affords the product (10.9 g, 44%).
R/0.52 (silicageL 85:15 OfcCfe/MeOH); mp 313-315 °C (dec); lHNMR (300MHz,
DMSO-40 pi.27 (s, 12 H), 6.92 (-benzoirnidazol-2-onc

Following procedures essentially as described in Example 219, mix l-(2-morpholin-4-yl-
ethyI)-5-(4,4,5,5-terxamethyl-[ 1,3t2]dioxaborolan-2-yI)-1,3-dihydro-benzoimidazol-2-one
(520mg, 1.4mmol), 5-bromomethylene-2,8-difluoro-10,ll-dihydro-5H-
dibenzo[a,d]cycloheptene (510mg, 1.6mmol)(prepared using a procedure essentially as
described for the 2,8-dichloro derivative in Example 182), 2N NajCCb (lmL), dioxane
(lOmL) and (Pb^P^d (67mg, 0.06mmol). Purify the crude product by column
chromatography using MeOH/ethyl acetate to give 310mg colorless oil that solidified
upon drying, HPLC (ISO80-10M) t=2.03 (97%). MS (ES) 488 (M+l), 486 (M-l). H
NMR 10.69 (s, 1H), 7.49 (do, IH, 7=8.4,6.2 Hz), 7.22 (dd, 1H, 7=9.7,2.2 Hz), 7.02 (td,
1H, 7=12.0, 42 Hz), 6.97-6.83 (m, 4H), 6.81 (s, IH), 6.72 (d, IH, 7=7.9 Hz), 6.56 (s, IH),
3.80 (t, 2H, 7=6.2 Hz), 3.47 (t, 4H, 7=4.2 Hz), 3.31 (s, 2H), 2.90 (s, 2H), 2.48 (m, 2H),
2.38 (s, 4H).
Example 437
5-(2,8-difluoro-10>n-dmydro-dibcnzo[a,d]cyclohcpten-5-yljdenememyl)-l,3-dih^
benzoimidazol-2-one

Following procedures essentially as described in Example 219, mix 5-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3-dihydro-benzoimidazol-2-one(535mg,
2.06mmol) (prepared from 5-bromo-l ,3-dihydro-benzoimidazol-2-one (Preparation 27)
according to the procedure reported by M Murata, T Takashi, S Watanabe and Y Yusuru,
J. Org. Chem.; 65 (1) 164-168 (2000)), 5-broroomethylene-2,8-difluoro-10,l i-dihydro-
5H-dibenzo[a,d]cyclobeptene (550mg, 1.71mmol), 2NNa2C03 (2mL), dioxane (14mL)
and (PhsPJ^Pd (200mg, 0.17mmol). Purify the crude product by column chromatography
using dichloromethane/ethyl acetate to give 285mg white solid, mp 257°C. HPLC
(ISO80-I0M) t=2.62 (97%), MS (ES) 373 (M-.l). H NMR 10.55 (s, IH), 10.45 (s, IH),
7.48 (dd, IH,.7=8.4,62 Hz), 721 (dd, IH, 7=9.7,2.2 Hz), 7.01 (td, IH, 7=12.2, 4.2 Hz),
6.94 (dd, 1H, .7=10.1, 22 Hz), 6.90 (d, 2H, 7=6.2 Hz), 6.85 (dd, 1H, 7=8.6,2.4 Hz), 6.78
(s, 1H), 6.72 (d, 1H, 7=8.4 Hz), 6.67 (d, 1H, 7=7.9 Hz), 6.51 (s, 1H), 3.30 (s, 2H), 2.89 (s,
2H), 6.90 (d,lH, 7-6.2 Hz).
Example 438
5-(2,8-difluoro-l 0,11 -dihydro-l -(3-morpholin-
4-yI-propyl)-l ,3-dihydro-benzoirnidazol-2-ooe

Following procedures essentially as described in Example 219, mix l-(2-morpholin-4-yl-
propyty-S-^^^S-tetramethyl-fl 3,2]dioxaborolan-2-yl)-l ,3-dihydro-benzoimidazol-2-
one(458mg, l.lSmmol), 5-bromomethylene-2,8-difluoro-105ll-dihydro-5H-
dibcnzo[a,d]cycloheptene (400mg, l.25mmoI), 2NNa2C03 (1.3mL), dioxane (8mL) and
(Ph3P)4Pd (45mg, 0.04mmol). Purify the crude product by column chromatography using
2% 2N NH3 in MeOH/dichloromethane to give 170mg title compound as a white foam.
HPLC (ISO80-10M) t=1.86 (98%), MS (ES) 502 (M+l), 500 (M-l). H NMR 8.38 (s,
1H), 7.42 (dd, 1H, 7=8.4,5.7 Hz), 7.01 (dd, 1H, 7=9.2,2.6 Hz), 6.95 (dd, 1H, 7=8.4, 5.7
Hz), 6.91 (dd, 1H, 7=8.4,2.6 Hz), 6.85 (d, 1H, 7=8.4 Hz), 6.80 (dd, 1H, 7=9.7,2.2 Hz),
6.71 (dd, LH, 7=8.6,2.4 Hz), 6.64 (s, 1H), 3.89 (t, 2H, 7=6.8 Hz), 3.68 (s, 4H), 3.59-2.71
(m, 4H), 1.60 (s, 2H), 1.94 (s, 2H), 2.40 (s, 4H), 6.76 (m, 2H).
Examples 439-474 contained in Table II, herein, provide yet additional examples
of compounds of Formula I wherein the "C" ring represents a heterocyclic or benzofused
heterocyclic ring. These examples, which further illustrate the present invention are
prepared according to the procedures as described generally in the Schemes and literature
references described above.
Additional preparations for, and examples of compounds of Formula I wherein
the "A" and / or "B" ring represents a heterocyclic ring. (Section 4 as represented by
original Examples 238-254)
Preparation 38
4-Methylene-940-o^ydro-4H-l-thia-benzor/)azulene

Following procedures as described in Scheme X:
Add 3 equiv of a 0.5 M solution of Tebbe reagent in toluene to a solution (-40 °C) 9,10-
dihydro-l-thia-benzo[/]azuleoe-4-one (prepared as described in P. Bollinger, P. Cooper.;
H. U. Gubler, A. Leutwiler, T. Payne Helv. Chim. Acta (1990), 73, 1197) and 3 equiv of
pyridine in THF (0.1 M) under Ar. Stir the resulting dark red mixture for 2 h then allow
to warm to 0 °C over ca. 30 min period before diluting with diethyl ether. Carefully add 5
N sodium hydroxide until bubbling ceases, add solid Na2S04, and then stir for 1 h. Filter
the mixture through Celite®, and concentrate the filtrate by rotary evaporation. Purify the
crude residue by column chromatography (hexanes) to give the title compound as white
crystals (56 %): HPLC (ISO80-20M) t = 1.903 (98 %). MS (APCI): 213 (M+l). *H
NMR (CDC13) 5 3.07-3.12 (m, 2 H), 3.14-3.17 (m, 2 H), 5.32 (s, 1 H), 5.63 (s, 1 H), 7.05
(app d, J = 5.4 Hz, 1 H), 7.0S (d, J = 5.4 Hz, I H), 7.19-7.26 (m, 3 H), 7.35 (dd, J = 7.6
Hz, 1.6 Hz, 1H).

Following procedures essentially as described in Preparation 24 followed by procedures
essentially as described in Example 219, and using 4-methylene-9,l 0-dihydro-4H-l-thia-
benzo[/]azulene, the title compounds are made.
Example 477
3-(9,l O-Dihydro-1 ^hia-benzo[f]azuIen-4-yh^eneraemyl)-phenylaniine '

4-Methylene-940-dihydro-4H-l-thia-benzo[/]azulene is converted to the vinyl bromide as
in Preparation 24 and the vinyl bromide coupled with 3-aminophenylboronic acid using
the procedures essentially as described in Example 219.
Example 478
3-(7-Chloro-9,10-dihydro-1 -tbia-benzo[fjazulen-4-ylidenemethyl)- phenylamine

7-chloro-9,10-dihydro-benzo[4,5]cyclohepta[l,2-b]thiophen-4-one (prepared as described
in Bastian et al, Helv. Chim. Acta; 49 214-234 (1966)) is converted to the title compound
following procedures as described in Scheme VDL
Example 479
3-(2-Chloro-9,10-dihydro-l-thia-benzo[f]azulen-4-ylidenemcthyl)-

Add 2.2 equiv of n-BuLi-hexanes dropwise to a solution of 3-(9,10-dihydro-l-thia-
ben2o[fjazulen-4-yIidenemethyl)-phenylamine in THF (0.1 M) at 0 °C under Ar. Stir the
resultant dark solution for 1 h before adding 2.5 equiv of hexachloroethane in THF. Stir
for 2 h, quench with excess water, and acidify to neutral pH. Extract the aqueous layer
with diethyl ether (3 X) and then dry (MgSO*) and concentrate the combined organic
layers under reduced pressure. Purify the crude residue by column chromatography (0%
to 2% to 20% EtOAc:hexanes) to give title compound as an oil (22 %) along with
recovered starting material: HPLC (ISO80-20A)t = 1.903 (90 %). MS (APCI): 338
(M+l).
Example 480
3^2J-DicUoro-9,10enzo[f]azulen^ylidenemethyl)-phenylamine, the title compound is
prepared.
Example 482
N-[3<2J-Dichloro-9J0-dmydro-l-mia-benzo[f]az^
methanes ulfonamide
Following procedures essentially as described in Example 90 and using 3-(2,7-dichloro-
9,10-dihydro-l-mia-beiKo[f]a2ulen-^ylidenemethyl)-phenylamine, the title compound is
prepared.
Preparation 39
2-Methyl-4-methylene-9,10-dihydro-4H-3-thia-l -aza-benzo[fj azulene

Add 1.2 equiv of w-BuLi-hexanes dropwisc to a solution of 4-methylcnc-9,10-dihydro-
4H-3-tbia-l-aza-bcnzo[f]azulene (prepared from 9,10-dihydro-3-thia-l-aza-
benzo[f)azu]en-4-one (see Scheme XH2(b) as in Preparation 23) in THF (0.0S M) at -78
°C under Ar. Stir the resultant dark green solution for 5 min before adding 1.2 equiv of
iodomethane in THF. AJlow to warm and stir at room temperature for 18 h before
quenching with excess water. Separate layers and extract the aqueous layer with diethyl
ether (3 X) and then dry (MgSC^) and concentrate the combined organic layers under
reduced pressure. Use in the next step without further purification: *H NMR (CDCI3,
400 MHz) 5 2.60 (s, 3 H), 3.03-3.13 (m, 4 H), 5.34 (s, 1 H), 5.53 (s, 1 H), 7.20-7.28 (m, 3
H), 7.33 (m, J = 7.2 Hz, 1 H). TLC R, = 0.30 (10 % EtOAc±exanes).
Example 4S3(a)
N-[3-(2-Methyl-9,10-dihydro-3-thia-1 -aza-benzo[fJazulen-4-ylidenemethyl)-phenyl]-
methanesulfonamide (E-isomer); and
Example 483(b)
N-[3-(2-Methyl-9,10-o^yd^t>-3-tnia-l-a2a-ben2o[fJazuIen-4-ylidenernethyl)-phenyl]-
methanesulfonamide (Z-isonaer)

Following procedures essentiaUy as described in Preparation 24 followed by procedures
essentially as described in Example 219, and using 2-methyl-4-mcthylcne-9,10-dihydro-
4H-3-thia-l-aza-benzo[f]azulene and 3-methanesulfonylaminophenylboronic acid, the
title compounds are made.
Preparation 40
3-Chloro-2-oxo-5-phenyl-pentanoic acid methyl ester

Charge a flask with equimolar methyl dichloroacetate and 3-phenyl-prionaldehyde in
diethyl ether (3.0 M). Cool the solution to 0 °C and add 1.1 equiv of sodium methoxide
in methanol (2.8 M) over a 1 h period. Vigorously stir the mixture for 2 h at 0 C and then
allow to warm to room temperature before adding brine. Separate layers and dry
(MgSC>4) and concentrate organic layer to give the crude residue in 92 % yield. GC-MS
(GRAD60-280<>C) t = 13.01 (90 %). MS (EI): 240 (M-).
Preparation 41
2-Arrmio-5-phenemyl-thiazole-4-carboxylic acid methyl ester

Reflux equimolar 3-chloro-2-oxo-5-phenyl-pentanoic acid methyl ester and thiourea in
MeOH (1.0 M) for 4 h. Basify with ammonia-MeOH and add brine. Extract with ethyl
acetate (4 X). Wash combined organic layers with brine, dry (MgSO^), and concentrate
under reduced pressure to give (91 %) of title compound. HPLC (GRAD80-100M) t =
2.193 (95 %). MS (APCI): 263 (M+l).
Preparation 42
5-Phenethy]-thiazole-4-carboxylic acid methyl ester

Reflux one equiv of 2-amino-5-phenethyl-thiazole-4-carboxylic acid methyl ester and 3
cquiv of isoamyl nitrite in THF (0.13M) for 3 b_ Evaporate volatile components to give
55 % yield of title compound. HPLC (GRADS0-100M) t = 2.410(99%). MS (APCI):
248 (M+l).
Preparation 43
9,10-Dihydro-l-thia-3-aza-benzo[fJazulen-4-one

Rapidly stir and heat a thick slurry of 5-phenethyl-thiazole-4-carboxylic acid methyl ester
and polyphosphoric acid (PPA) at 140 °C for 24 h and then 150 °C for 5 h. Carefully add
hot mixture to ice-cold aqueous sodium hydroxide. Extract well with EtOAc (4 X).
Wash combined organic layers with brine, dry (MgS04), and concentrate under reduced
pressure. Purify the crude residue by column chromatography (10% to 50%
EtOAchexanes) to give title compound as a brown solid (37 %). HPLC (GRAD80-
100M) t = 2.0S8 {99 %). MS (APCI): 216 (M+l).
Preparation 44
9,10-Dihydro-3-thia-1 -aza-benzo[/]azulen-4-one
To a room temperature solution of 2-arrunc-9,10-dihydro-3-tbia-l-aza-
benzo[/]azulen-4-one (531 g, 23.1 mmol) in DMF (50 mL) is added isoamyl nitrite (5.95
g, 50.8 mmol) and the reaction stirred for 30 min. The reaction mixture is heated to SO °C
for 2 h, and then cooled to room temperature. The solvent is removed under reduced
pressure and ice-cold HzO (100 mL) is added. The aqueous layer is extracted with EtOAc
(2 x 150 mL) and the combined organic layers are dried (MgS04), filtered and the solvent
removed under reduced pressure. The dark red oil is subjected to flash chromatography
(silica gel, 75:25 Hex/EtOAc) to afford the slightly impure product as an orange-red solid.
The product is further purified by trituration using Hex/EtOAc (90:10) to afford the title
compound (2.59 g, 52%) as an orange solid: fy0.33 (1:1 EtOAc^Hex); mp 83-86 °C; *H
NMR (300 MHz, CDC13) C8.89 (s, 1H), 7.96 (dd, J= 12,7.7 Hz, 1H), 7.50 (dt,J= 1.4,
7.4 Hz, 1H), 7.37 (m, 1H), 7.30 (d, J= 7.5 Hz, 1H), 3.36 (m, 2H), 3.24 (m, 2H); ESI MS
m/z 216 [C12H9NOS + H]+. Anal. Calcd for C[2H9NOS: C, 66.95;"H, 4.21; N, 6.51.
Found: C, 66.81; H, 3.99; N, 6.48.
Preparation 45
7-Fluoro-9,10-dihydro-3-thia-l -aza-benzo[/]azulen-4-one; and
5-Fluorc~9,10-dihydro-3-thia-1 -aza-benzo[/]azulen-4-one
To a room temperature solution of a 85:15 mixture of 2-amino-7-fluoro-9,10-
dihydro-3-thia-l-aza-benzo[/]azulen-4-one and 2-ammo-5-fluoro-9,10-dibydro-3-thia-l-
aza-benzo[/]azulen-4-one (6.00 g, 24.2 mmol) in DMF (80 mL) is added /-butyl nitrite
(5.48 g, 53.2 mmol). The reaction mixture is then heated to 60 °C for 2 h (gas evolution
may be observed after 5-10 min of heating), then cooled to room temperature. The
solvent is removed under reduced pressure and ice-cold H2O (100 mL) and EtOAc (700
mL) are added. The organic layer is washed with saturated aqueous NaHCCb (100 mL)
and saturated aqueous NaCl (100 mL). The organic layer is dried (MgS04), filtered and
concentrated under reduced pressure. The resulting red oil is subjected to flash
chromatography (silica gel, 80:20 to 70:30 Hex/EtOAc) to afford the products (3.16 g,
56%) as a partially separable mixture of 5- and 7-fluoro regioisomers. The fractions
obtained as a mixture (1.19 g) contain some of the minor isomer (-3:7 5-fluoro/7-fluoro):
'H NMR of 5-fluoro isomer, subtracted from the mixture (300 MHz, CDC13) D 8.88 (s,
1H), 7.41 (m, 1H), 7,12-6.98 (m, 2H), 332 (m, 2H), 3.39-3.19 (m, 2H).
The fractions obtained pure (1.97 g) contain only the major isomer (7-fluoro) which is
isolated as an orange solid: A/0.52 (1:1 EtOAc/Hex); mp 122-125 °C; *H NMR (300
MHz, CDCI3) D 8.89 (s, 1H), 8.02 (dd, J= 8.7,6.0 Hz, 1H), 7.06 (m, 1H), 7.00 (dd, J=
9.1,2.5 Hz, 1H), 337 (m, 2H), 3.22 (m, 2H); APCI MS m/z 232 [C,2HgFNOS - H]Anal. Calcd for C,2HgFNOS: C, 61.79; H, 3.46; N, 6.00. Found: C, 61.70; H, 3.43; N,
6.04.
Preparation 46
4-Meraylene-9,10-dmydro-4H-l-thia-3-aza-Denzo[f]azulene

Following procedures essentially as described in Preparation 23, and using 9,10-dihydro-
l-thia-3-aza-benzo[fJazulen-4-one, the title compound is made.
Example 484 (a)
N-[3-(9,l 0-Dihydro-1 -thia-3-aza-bcnzo[f]azulcn-4-ylidenemethyl)-phenyl]-
methanesulfonamide (E isomer) and
D. Majumder Organometal!icsl9&3,2,230), 1 equiv TMEDA, 2.5 equiv of
tetramethylpiperidine (TMP), and THF at -78 °C. Allow the solution to warm to room
temperature and stir for 3.5 h before quenching with excess water. Extract well with Et20
(4X). Dry (MgS04) and concentrate under reduced pressure. Purify the crude residue by
column chromatography (5% to 10% EtOAcrhexanes) to give pure E-isomer (45 %)and
Z-isomer (24 %). E-isomer: HPLC (GRAD80-100M) t = 4.340 (99 %). MS (APCI): 322
(M+l).
Z-isomer (24 %) HPLC (GRAD80-100M) t = 4.423 (99 %). MS (APCI): 322 (M+l).
Example 485(a)
4
N-[3-(5,6-Dihydro-benzo[d]pyrrolo[l ^-ajazepin-11 -ylidenemethyl)-phenyl]-
methanesulfonamide (E-isomer) and
Example 4850>)
N-[3-(5,6-Dihydro-benzo[d]pyjrolo[l ^-a]azepin-l 1 -ylidenemethyl)-phenyl]-
methanesulfonamide (Z-isomer)

Following procedures essentially as described in Example 219, and using E- and Z-l 1-
(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-ylmethylene)-6,l 1 -dihydro-5H-
benzo[djpyrrolo[l,2-a]azepine and N-(3-iodo-phcnyl)-methanesulfonamide, the E and Z
isomers of the title compound are prepared.
Preparation 48
2-[2-(3-Fluoro-phenyI)-ethyl]-nicotinicacid

Dissolve diisopropylamine (3.8 mL, 27.3 mmol) in diy tetrahydrofuran (75 mL). Chill the
resulting mixture to -78 °C and add butyl lithium (1.6M solution in hexanes, 17.1 mL,
27.3 mmol). Warm the reaction mixture to 0 °C and add a fine slurry of 2-methyI-
nicotinic acid (1.5 g, 10.9 mmol) in THF (25 mL) portionwise during 10 min. Stir the
resulting slurry for lh, then add 3-fluorobenzyl bromide (2.0 mL, 16.4 mmol) and stir 5
min. Quench the reaction with water (100 mL). Extract the reaction mixture with diethyl
ether (100 mL). Adjust the pH of the aqueous layer to 3.1 with concentrated aqueous
hydrochloric acid solution. Treat the resulting slurry with ethyl acetate and stir to dissolve
all solids. Separate the layers and extract the aqueous layer with ethyl acetate.
Concentrate the combined extracts to dryness. LCMS (APCI-pos): 244.1 (M+H).
Preparation 49
8-Fluoro-l 0,11 -dihydro-benzo[4,5]cyclohepta[ 1,2-6}pyridin-5-one

Combine crude 2-[2-{3-fluoro-phenyl)-ethyl]-nicotinic acid (2.06 g, 15.0 mmol) and
polyphosphoric acid (100 g) and heat the mixture to 160 °C for 6 h. Allow slow cooling
of the reaction mixture over 12h, then reheat the mixture to 160 °C and pour it into ice
(200 g). Complete the transfer using water and adjust the pH of the aqueous mixture to
-S.0 with 50% aqueous sodium hydroxide solution. Extract the product with methylene
chloride. Dry the combined organic extracts with magnesium sulfate, filter and
concentrate. Purify the crude product via flash chromatography (25% ethyl
acetate/hexanes to 50% ethyl acetate/hexanes) to provide 1.54 mg (81%) of purified
product. LCMS (APCI-pos): 228.1 (M+H). !HNMR (CDC13,400 MHz): 58.63 (dd, 1H),
8.39 (dd, IH), 8.01 (dd, 1H), 7.31 (dd, 1H)T 7.02 (dt, 1H), 6.95 (dd, IH), 3.46-3.43 (m,
2H), 3.23-3.21 (m, 2H).
(Literature reference: Journal of Heterocyclic Chemistry 1971,73).
Preparation 50
8-nuoro-5-methylene-10,ll-dihydro-benzo[4,5]cyclohepta[l,2-i]pyridine

Chill a mixture of 8-fluoro-10Jl-d£hydro-benzo[4,5]cyclohepta[l,2-6]pyridin-5-orie (1.3
g, 5.7 mrnol) and dry tetrahydrofuran (50 mL) to 0 °C. Treat this mixture with methyl
magnesium broraide(3.0M solution in diethyl ether, 5.7 mL, 17.2 mmol). Remove
cooling and stir the admixture at room temperature for 15 tnin Quench the reaction,
while cooling with an ice-water bath, by adding saturated aqueous ammonium chloride
solution (50 mL). Separate the layers and extract the aqueous layer with methylene
chloride (2x50 mL). Dry the combined organic layers with magnesium sulfate, filter and
concentrate to provide the intermediate product as a thick crude oil.
Without further purification, dissolve this residue in a solution of sulfuric acid in
acetic acid (3% by volume, 50 mL) and stir the resulting mixture at room temperature for
12-18 h. Concentrate the reaction mixture to remove excess solvent and dissolve the
resulting orange residue in IN aqueous sodium hydroxide solution (25 mL) and ethyl
acetate (50 mL). Adjust the pH of the resulting mixture to ~8 with 5N aqueous sodium
hydroxide solution. Separate the layers and extract the aqueous layer with ethyl acetate
(2x50 mL). Dry the combined organic layers with magnesium sulfate, filter and
concentrate to 1.3g (91%) of the title product as an orange-brown oil. LCMS: 226.1
(M+H).
Preparation 51
(£+^-5-Bromomemylene-8-fluoro-10,ll-dmydro-bcnzo[4,5]cyclohcpta[l,2-6]pyridine

Make the title compounds according to Preparation 24, beginning with 8-fluoro-5-
methylene-10,ll-dihydro-benzo[4,5]cyclohepta[l,2-6]pyridine(l.l g, 5.1 mmol). After
workup and purification and separation by flash chromatography (25% ethyl
acetate/hexanes to 50% ethyl acetate/hexanes) isolate 700 mg (44%) of (£}-5-
bromomethylene-10,1 l-dmydro-8-fluoro-benzo[4,5]cydohepta[l,2-b]pyridine and 550
mg (34%) of (2)-5-bromomethylene-10,ll-dihydro-8-fluoro-benzo[4,5]cycIohepta[l^-
b]pyridine. For (Z)-5-bromomethylene-10,l 1 -dmydro-8-fluon>benzo[4,5]cycIohepta[l,2-
£]pyridine, LCMS (APCI-pos): 304,305,306,307. 'HNMR (CDC13,400 MHz): 68.45
(dd, 1H), 7.69 (dd, 1H), 7.18 (dd, 1H), 7.13 (dd, 1H), 6.87-6.83 (m, 2H), 6.61 (s, 1H), 3.6-
2.4 (m, 4H). For (£)-5-bromomcthylene-10,ll-dihydro-benzo[4,5]cyclohepta[1^2-
6]pyridine, LCMS (APCI-pos): 304,305, 306, 307. 'HNMR (CDC13,400 MHz): 58.45
(dd, 1H), 7.56 (dd, 1H), 7.25 (dd, 1H), 7.09 (dd, 1H), 6.99 (dd, 1H), 6.92 (dt, 1H), 6.69 (s,
1H), 3.6-2.8 (m, 4H).
Example 486
(£)-#-[3-(8-fluoro-10Tl I -dihydro-benzo[4,5]cyclohepta( 1 ^-i]pyridin-5-ylidenemethyl)-
phenyl]-methanesulfonamide

Following procedures essentially as described in Example 219, beginning with (E)-5-
bromomethylene-8-fluoro-10,l l-dihydro-benzo[4,5]cyclohepta[l,2-Z7]pyridine (200 rag,
0.66 mmol). After work-up, purify the crude product by flash chromatography (50% ethyl
acetate/hexanes to 75% ethyl acetate/hexanes) to provide 197 mg (76%) of purified
product. LCMS (APCI-pos): 395.1 (M+H). LCMS (APCI-neg): 393.0 (M-H). Puntyby
LCMS (UV Area percent) 99%. 'HNMR (d6-DMSO, 400 MHz): 89.62 (s, 1H), 8.41
(dd, 1H), 7.90 (dd, 1H), 7.28-724 (m, 2H), 7.14 (t, 1H), 6.96-6.87 (m, 5H), 6.75 (d, 1H),
3.6-2.9 (m, 4H), 2.79 (s, 3H).
Example 487
(jE>5-(8-Huoro-10,ll-dihydro-beiizo[4,5]cycloh^
dihydrobenzoimidazol-2-one

Following procedures essentially as desctribed in Example 219, beginning with (£>5-
bromomethylene-8-fluoro-104lHJihydro-benzo[4,5]cyclohepta[l,2-i]pyridine (100 mg,
0.33 mmol) and 5-{4,4,5,5-tetramethyl-[13,2]&oxaborolaQ-2-yl)-l,3^ydrc~
benzoimidazol-2-one (111 mg, 0.43 ramol). After work-up, purify the crude product by
flash chromatography (100% ethyl acetate to 10% ethanol/ethyl acetate) to provide 70 mg
(60%) of purified product. LCMS (APCI-pos): 358.0 (M+H). LCMS (APCI-neg): 356.0
(M-H). Purity by LCMS (UV Area percent): 99%. 'HNMR (d6-DMSO, 400 MHz):
810.56 (s, 1H), 10/46 (s, 1H), 8.38 (dd, 1H), 7.88 (dd, 1H), 7.28 (dd, 1H), 7.23 (dd, 1H),
6.96-6.90 (m, 2H), 6.89 (s, 1H), 6.73 (d, 1H), 6.68 (d, 1H), 6.52 (s, 1H), 3.5-3.3 (m, 2H),
3.1-2.9 (m,2H).
Preparation 52
2-(3-Fluoro-5-nitro-phenyl)-4,4,5,5-tetramethyI-[l,3^]dioxaborolane

Make according to literature precedent (Journal of Organic Chemistry 1995,60, 7508)
beginning with 1 -fluoro-3-iodo-5-nitrobenzene (1.0 g, 3.7 mmol). Purify the crude
product by flash chromatography (1:3- 4% acetic acid in tetrahydrofuran/hexanes) and
combine product fractions. Strip to dryness and add 50 mL ethanol and strip to dryness to
provide 945 mg (94%) of purified product Purity by GCMS: 80%, mass 267.0. lHNMR
(CDCU, 400 MHz): 58.43 (bs, 1H), 7.98 (dt, 1H), 7.80 (dd, 1H), 1.36 (s, 12H)
Preparation 53
3-Fluoro-5-(4,4,5,5-tetraniethyi-[ 1 ,3 ,2]dioxaborolan-2-yl)-phenylainine

Combmel-fluoro-3-iodo-5-nitrobenzene2^3-FluorcH5-nitro-phenyl)^,4,5,54etramethyl-
[l,3,2]dioxaborolane (940 mg, 3.5 mmol), 5% palladium on carbon (-60% H20,200 mg),
and anhydrous ctbanol (25 mL). Purge and fill the reaction vessel with hydrogen three
times. Stir the reaction mixture under 1 arm of hydrogen. When the reaction is complete
by LCMS, filter the reaction mixture through celite to remove the catalyst and wash the
filter cake with ethanol. Strip to dryness and purify the crude product by flash
chromatography (25% ethyl acetate/hexanes) and combine product fractions. Strip to
dryness to provide the crude product. LCMS (APCI-pos): mass 238.2 (M+l), Purity by
LCMS (UV area percent): 85%. lHNMR (CDClj, 400 MHz): 86.88-6.83 (m, 2H), 6.47-
6.43 (m, 1H), 3.55-3.9 (bs, 2H), 1.32 (s, 12H)
Preparation 54
N-[3-Fluoro-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-
methanesulfonamidc

Combine 3-fluoro-5-(4>4,5,5-tetraraetliyl-[l,3r2]dioxaborolan-2-yl)-phenylamine (610 mg,
2.6 mmol), methanesulfonyl chloride (240 uL, 3.09 mmol) in pyridine (25 mL). Stir the
reaction mixture under nitrogen for 18-24L Strip to dryness and partition the crude
product between methylene chloride (100 mL) and brine (100 mL). Separate the layers
and dry the organic layer with magnesium sulfate. Purify the crude product by
crystallization (methylene chloride/hexanes) to provide 625 mg of purified product
LCMS (APCI-pos): mass 333.1 (M+H20), Purity by LCMS (UV area percent): 99%.
'HNMR (CDC13,400 MHz): 5731-720 (m, 3H), 6.44 (s, 1H), 3.03 (s, 3H), 1.34 (s,
12H).
Example 48S
(£>N-[3-Fluoro-5-(8-fluoro-l 0,1 l-dihydro-benzo[4,5]cyclohepta[l ,2-b]pyridin-5-
ylidenememyl)-phenyl]-methanesulfonamide

Following procedures essentially as desctribed in Example 219, beginning with (£)-5-
bromomemylene-S-fluoro-10,ll-^lmydro-benzo[4,5]cyclohepta{l^-6]pyridine (50 mg,
0.16 mmol) and N-(3-fluoro-5-(4,4,5^-tetramethyl-[l,3^]dioxaboroIan-2-yl)-phcnyI]-
methanesulfonamide (62 mg, 0.20 mmol). After work-up, purify the crude product by
flash chromatography (50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) to
provide 44 mg (65%) of purified product. LCMS (APCI-pos): 413.0 (M+H). LCMS
(APCI-neg): 411.0 (M-H). Purity by LCMS (UV Area percent) 98%. 'HNMR (d6-
DMSO, 400 MHz): 89.91 (s, 1H), 8.42 (dd, 1H), 7.91 (dd, 1H), 7.29-7.25 (m, 2H), 6.92
(s, 2H), 6.90 (d, 1H), 6.77-6.74 (m,.2H), 6.52-6.49(m, 1H), 3.4-2.8 (m, 4H), 2.87 (s, 3H).
Examples 489-601 contained in Table H, herein, provide yet additional examples of
compounds of Formula I wherein the "A" and / or "B" ring represents a heterocyclic ring.
These examples, which further illustrate the present invention are prepared according to
the procedures as described generally in the Schemes and literature references described
above.
Examples 602-606 contained in Table H, herein, provide yet additional examples of
compounds of Formula I wherein the bridge depicted by -X—Y- represents a fused
cyclopropyl structure. (Section 5 as represented by original Examples 255-260). These
examples, which further illustrate the present invention are prepared according to the
procedures as described generally in the Schemes and literature references described
above.
Additional preparations for, and examples of compounds of Formula I wherein the
bridge depicted by -X—Y- contains a heteroatom or heteroatom containing group at
either the X or Y position. (Section 6 as represented by original Examples 261-274)
Preparation 55
3,8-difluoro-6H-dibenzo[b,e]oxepin-l 1-one

Prepare starting ketones for oxepine derivatives as described by M Kurokawa, F Sato, Y
Masuda, T Yoshida and Y Ochi, Cbem. Pfaarm. Bull., 39; 10; (1991) 2564-5273.
Example 607
5-(3-Fluoro-6H-dibcrizo[b>e]oxepm-ll-ylidenememyl)-l-(2-morpholin-4-yl-ethyl)-l,3-
dihydro-benzoimidazol-2-onc

Following procedures essentially as described in Example 219, mix l-(2-morpholin-4-yl-
ethyl)-5-(4,4,5,5-tetramethyl-[13^]dioxaborolan-2-yl)-13Klihydro-ben2oimida2ol-2-one
(330mg, l.lmmol), ll-bromomethylene-3-fluoro^,ll--6H-dibenzo(>,e]oxepm-ll-yhdenememyl)-H3-morpholin-4-yl-propyl)-l,3-
dihydro-benzoimidazol-2-one

Following procedures essentially as described in Example 219, mix V(2-morpholin-4-yl-
propyl)-5-(4,4,5,5-tetramemyl-[l,32]dioxaborolan-2-yl)-l,3-dmydro-berizoimidazol-2-
one (205mg, 0.53mmol)(prepared following procedures cssentfelly asdescribedin
Preparation 36), 1 l-bromomcthylene-3-fiuoro-6,l l-dihydro*-dibenzo[b,e]oxcpine (E-
isomer, 150mg, 0.5mmol), 2N Na2C03 (0.5mL), dioxane (5mL) and (PhjP^d (53mg,
0.046mmol). Purify the crude product by column chromatography using 2N NH3 in
MeOH/dichloromethane. Triturate the product obtained (192mg) with hexane to give
170mg pure title compound, HPLC (ISO80-10M) t=l .72 (100%). MS (ES) 486 (M+l),
484 (M-l). H NMR (DMSO-d«)10.6S (s, 1H), 7.57 (m, 2H), 7.35 (t, 1H, 7=7.5 Hz), 7.22
(t, 1H, 7=7.7 Hz), 6.96 (m, 3H), 6.78 (td, 1H, 7=12.0,4.2 Hz), 6.71 (d, 1H, 7=7.5 Hz),
6.60 (in, 2H), 5.31 (br d, 2H), 3.72 (t, 2H, 7=6.6 Hz), 3.46 (1,4H, 7=4.2 Hz), 2.48 (m,
4H), 1.71 (m, 2H), 2.20 (m, 6H).
Example 609
1 -cyclopropyl-5-{3-fluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-1,3-dihydro-
benzoimidazol-2-one

Following procedures essentially as described in Example 219, mix l-cyclopropyl-2-oxo-
2,3-dihydro-lH-benzoinudazole-5-boronic acid (120mg, O.55mmol) (prepared essentially
as described in Preparation 36), 1 l-bromomethylene-3-fluoro-6,l 1 -dihydro-
dibenzo[b,e]oxepine (E and Z mixture, 177mg, 0.58mmol), 2N Na2CC>3 (0.7mL), dioxane
(8mL) and (PhjP^d (38mg, 0.033mmol). Purify the crude product by column
chromatography using THF/hexane to give 65mg title compound as a gray powder.
HPLC (ISO80-10M) t=3.53 (93%), MS (ES) 399 (M+l), 397 (M-l). H NMR 10.58 (s,
1H), 7.58 (m, 3H), 7.35 (t, 1H, 7=7.5 Hz), 7.23 (t, 1H, 7=7.5 Hz), 6.96 (m, 3H), 7.58 (m,
2H), 6.80 (dd, 1H, 7=7.9,2.6 Hz), 6.75 (d, 1H, 7=7.5 Hz), 6.60 (dd, 1H, 7=10.6,2.2 Hz),
6.57 (s, 1H), 5.84-4.79 (m, 2H), 2.75 (m, 1H), 0.93 (m, 2H), 0.77 (m, 2H).
Example 610
5-(3-fluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-1 -(2-morpholin-4-yl-ethyl)-1,3-
dihydro-benzoimidazol-2-one

Following procedures essentially as described in Example 219, mix l-(2-morpholin-4-yl-
ethyl)-5-(4,4,5,5 -tetrametbyl-[ 13,2]dioxaborolan-2-yI)-1,3-dihydro-bcai2oimida2ol-2-one
(300mg, 1.03mmol), ll-bxcm3omethylene-3-fluoro-6,ll-dihydro-dibenzo[b,e]oxepine(E
isomer, 330mg, 1.08mmol), 2NNa2C03 (1.4mL), dioxane (lOmL) and (Pb}P)4Pd (44mg,
0.038mmol). Purify the crude product by column chromatography using 40% THF/hexane
to yield 80mg title compound as a pale yellow powder. HPLC (ISO80-10M) t=1.84
(96%), MS (ES) 472 (M+l), 470 (M-l). H NMR (DMSO-de) 10.72 (s, 1H), 7.57 (m, 2H),
735 (t, 1H, .7=7.5 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.00 (d, 1H, J=7.5 Hz), 6.97 (s, 1H), 6.93
(d, 1H,/-S.4 Hz), 6.79 (td, m,J=ll.9,43 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.60 (m, 2H),
5.82-4.79 (m, 2H), 3.80 (t, 2H, 7=6.4 Hz), 3.46 (t, 4H, J=4.4 Hz), 2.48 (m, 2H), 238 (s,
4H).
Example 611
5^3-Fluoro-6H-dibenzo|^,e]oxepm-ll-yUdenememyl)-l,3-d&ydix)-berj2omiidazol-2^ne

Following procedures essentially as described in Example 219, using 11-
bromomethyiene-3-fluoro-6,ll-dihydro-dibenzo[b,e]oxepine (E-isomer, 1.05 cq.) and 5-
(4,4,5,5-tetrameuiyI-[13,2]dioxaborolan-2-yl)-l,3-dmydro-benzoirnidazol-2-one (1 eq.).
Purify crude product on silica gel, eluting with 60% to 100% ethyl acetate/CHCl3 to
afford a light yellow solid. Triturate with acetone to afford the title compound as a white
solid. HPLC (ISO60-10) t=4.09min, 100%; MS [ES] 357 (M-H), 359 (M+H); 'H-NMR
(DMSO-d<) 6 10.56 (s, 1H), 10.46 (s, 1H), 7.56 (m, 2H), 7.35 (t, 1H, 7=7.5 Hz), 7.23 (t,
1H, 7=7.5 Hz), 6.99 (d, 1H, 7=7.5 Hz), 6.94 (s, 1H), 6.78 (td, 1H, 7=12.0,4.2 Hz), 6.71
(d, 1H, 7=8 4 Hz), 6.66 (d, 1H, 7=8.4 Hz), 6.59 (dd, 1H, 7=10.6,2.6 Hz), 6.57 (s, 1H),
5.83^.71 (brd,2H).
Example 612
5-(3-Fluoro-6H-dibenzo[b,e]oxepin-l l-ylidenemethyl)-l-isopropyI-l ,3-dihydro-
benzoimidazol-2-one

Following procedures essentially as described in Example 219, mix 11-bromomethylene-
3-fluom-6,l l-dihydro-dibenzofb.ejoxepine (150mg, 0.493mmol), l-isopropyl-2-oxo-2,3-
dihydro-lH-benzoimidazole-5-boronic acid (103mg, 0.468mmol)(prepared according to
Scheme IX by using isopropylamine in Step A), Na2C03 (2M in water, 620DL,
1.23mmol), dioxane (4mL), and PaXPPh3)4 (29mg, 0.025mmol). Purify the crude product
on silica gel (24g), eluting with 25% to 50% THF/hexanes to afford 130mg (69%) of the
title compound as a yellow foam. HPLC (ISO80-10) t=3.86min, 98%; MS [ES] 399 (M-
H); 'H-NMR (CDCb) 8 9.10 (s, 1H), 7.44 (m, 2H), 7.32 (t, 1H, 7=7.5 Hz), 7.22 (t, 1H,
7=7.5 Hz), 7.11 (d, 1H, 7=7.5 Hz), 6.93 (d, 1H, 7=8.4 Hz), 6.86 (s, 1H), 6.75 (d, 1H,
7=8.4 Hz), 6.69 (s, 1H), 6.66 (td, 1H, 7=11.7,4.1 Hz), 6.52 (dd, 1H, 7=10.3, 2.4 Hz),
5.92-4.73 (m, 2H), 4.66 (m, 1H), 1.51 (d, 6H, 7=7.0 Hz).
Example 613
5-(3,8-Difluoro^H-diben2o[b,e]oxepm-n-yb'dencmethyI)-l,3-dihydro-benzoimidazoI-2-
one
Following procedures essentially as described in Example 219, mix 11 -bromometbylene-
3,8-difluoro-6,ll-dihydro-dibenzo[b,e]oxepine (E-isomer, 326mg, l.Olmmol), 5-(4,4,5,5-
tetramethyl-[l^^]dioxaborolan-2-yl)-13-dihydro-benzoimidazol-2-one(250mg,
0.96Imxnol), Na2C03 (2M in water, l^OmL, 2.40mmol), dioxane (7mL), and Pd(PPh3)4
(58mg, 0.051mmol). Purify the crude product on silica gel (12g) eluting with 50% to
70% THFVhexanes to afford two lots of yellow solid weighing 180mg and 151mg.
Dissolve the 180mg lot in boiling MeOH (20mL), concentrate to lOmL and cool to -26°C
to precipitate 165mg (46%) of the title compound as a white solid. Repeat the
recrystallization on the 151mg lot to afford 98mg (27%) of the title compound as a white
solid. HPLC (ISOSO-10) t=2.38min, 97%; MS [ES] 375 (M-H), 377 (M+H); 'H-NMR
(DMSO-de) 5 10.57 (s, 1H), 10.46 (s, 1H), 7.57 (dd, 1H, J=*ZA, 7.0 Hz), 7.49 (dd, 1H,
/=9.2,2.6 Hz), 7.08 (td, 1H,>12.5,43 Hz), 7.01 (d, 1H, J=5.1 Hz), 6.97 (s, 1H), 6.79
(td, 1H, J=\2.0,42 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.67 (d, 1H, ^=8.4 Hz), 6.61 (dd, 1H,
.£=10.6,2.6 Hz), 6.52 (s, 1H), 5.78-4.78 (or d, 2H).
Following procedures essentially as described in Example 219, mix 11-bromomethylene-
3-chloro-6,ll-dihydro-dibenzo[b,e]oxepine (E-isomer, 40mg, 0.124mmol) (prepared
essentially as described in Preparation 55), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-
yl)-l,3-dihydro-benzoimidazo!-2-one (31 rag, 0.118mmoI), Na2C03 (2M in water, 148 QL,
0.295mmol), dioxane (lmL), and Pd(PPh3)4 (7mg, 0.006mmol). Purify the crude product
on silica gel (12g) eluting with 2% to 5% (2M NH3/MeOH)/CH2Cl2 to afford 31mg (69%)
of the title compound as a white solid. HPLC (ISO80-10) t=2.85rain, 99%; MS [ES] 373
(M-H); 'H-NMR (DMSO-cU) $10.57 (s, 1H), 10.47 (s, 1H), 7.56 (dd, 2H, >7.8,6.1 Hz),
7.35 (t, IH, >7.5 Hz), 724 (t, 1H,>7.7 Hz), 6.98 (m, 3H), 6.82 (d, 1H, J=2.2 Hz), 6.69
(m, 2H), 6.57 (s, IH), 5.89-4.79 (br d, 2H).
Example 615
5-(3,7-Difluon>-611^1fl>enzo[b,e]oxepm-
1,3-dihydro-benzoimidazol-2-one

Following procedures essentially as described in Example 219, mix 11 -bromomethylene-
3,7-difluoro-6,l l-dmydro-dibenzo[b,e]oxepine (E-isomer, 200mg, 0.619mmol) (prepared
essentially as described in Preparation 55), l-^-morpholm^yl-ethyl)-^-^^^-
tetramethyl-[l ,3,2]dioxaborolan-2-yl)-l,3-dihydro-benzoraiidazol-2-one (220mg,
0.5S9mmol), Na2C03(2M in water, 736DL, 1.47mmoI), dioxane (4mL), and Pd(PPh3)4
(36mg, 0.031mrnol). Purify the crude product on silica gel (64g) during with 2% (2M
NH3yMeOH)/CH2Cl2 to afford 191mg (66%) of the title compound as a white foam.
HPLC (KO80-10) t=l.95min, 98%; MS [ES] 488 (M-H), 490 (M+H); 'H-NMR PMSO-
d«) 6 10.69 (s, IH), 7.58 (dd, IH, .7=8.8, 7.0 Hz), 7.24 (m, 2H), 7.02 (s, IH), 6.96 (d, IH,
>8.4 Hz), 6.80 (m, 3H), 6.64 (m, 2H), 5.56-5.20 (br d, 2H), 3.81 (t, 2H, .7=6.4 Hz), 3.46
(t, 4H, J=4.4 Hz), 2.48 (m, 2H), 2.37 (s, 4H).
Example 616
^-(S^-Difluorc^H-dfterizol^jeJoxepm-ll-ylidcnemethyl^l^-dAydro-benzoimidazol^-
one

Following procedures essentially as described in Example 219, mix 11 -bromomethylene-
3,7-difluoro-6,ll-dihydro-diben2o[b,e]oxepine (E-isomer, 68mg, 0.21mmol), 5-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)-l ,3-dmydro-benzoiniidazol-2-one (52mg,
0-20mmol), Na2C03 (2M in water, 25 ljiL, 0.503mmol), dioxane (2mL), and Pd(PPh3)4
(12rag, O.OlOmmol). Purify on silica gel (12g) eluting with THF to afford a brown solid.
Triturate with acetone to afford 56mg (74%) of the title compound as a white solid.
HPLC (ISOSO-10) r=2.42min, 96%; MS [ES] 375 (M-H); 'H-NMR (DMSO-d6) 6 10.58
(s, 1H), 10.46 (s, 1H), 7.57 (dd, 1H, 7=8.8,7.0 Hz), 724 (m, 2H), 7.00 (s, 1H), 6.81 (m,
2H), 6.72 (m, 2H), 6.64 (dd, 1H, .7=10.6,2.6 Hz), 6.59 (s, 1H), 5.55-5.19 (br d, 2H).
Example 617
5-(3,8-Difluoro-6H^ibenzor>,e]oxepm-ll-yUdenemethyl)-H2-morpholin-4-yl-ethyl)-
1,3-dmydro-benzoimidazoI-2-one

Following procedures essentially as described in Example 219, mix 1 l-bromornethylene-
3,8-difluoro-6,ll-dihydro-dibenzo[b,e]oxepine (E-isomer, 40rag, 0.12mmol), l-(2-
morphoIin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-1,3-dihydro-
bcn2oimidazoI-2-one (44rog, 0.12mmol), Na2C03 (2M in water, 155ML, OJlOmmol),
dioxane (lmL), and Pd(PPh3)4 (7mg, 0.006mmol). Purify on silica gel (12g), eluting with
2% to 5% (2M NH3/MeOH)/CH2Cl2 to afford 45mg (78%) of the tide compound as a
white foam. HPLC (ISOSO-10) t=1.86min, 99%; MS [ES] 488 (M-H), 490 (M+H); 'H-
NMR (DMSO-dt) 8 10.70 (s, 1H), 7.59 (dd, 1H, 7=8.5, 7.1 Hz), 7.51 (dd, 1H,>8.8,2.6
Hz), 7.08 (td, 1H, ^=12.5,4.3 Hz), 7.01 (m, 2H), 6.96 (d, 1H, 7=7.9 Hz), 6.80 (td, 1H,
J=12.0,4.2 Hz), 6.73 (d, 1H, J=1.9 Hz), 6.62 (dd, 1H, 7=10.3,2.4 Hz), 6.58 (s, 1H), 5.72-
4.85 (br d, 2H), 3.81 (t, 2H, J=6.4 Hz), 3.47 (t, 4H, 7=4.4 Hz), 2.48 (m, 2H), 2.38 (s, 4H).
Preparation 56
8-Fluoro-l lH-10-oxa-l -aza-dibenzo[a,d3cycIohepteD-5-one

Prepare according to literature precedent: Journal of Medicinal Chemistry 1990,33,
3095.
Preparation 57
8-Fluoro-5-methylene-5,11 -dihydro-10-oxa-l-aza-dibenzo[a,d]cycloheptenc

Combine 8-fluoro-l lH-10-oxa-l-aza-dJbcnzo[a,d]cyclohepten-5-one (567 mg, 2.47
rnmol) and anhydrous tetrahydrofuran (25 mL). Chill the solution to 0 °C and add Tebbe
reagent (0.5M/L solution in toluene, 5.4 mL, 2.72 mmol). Remove cooling and stir the
admixture for 10 min. Quench the reaction by adding saturated aqueous Rochelle's salt
solution (75 mL). Stir the biphasic mixture rapidly for 10 rain, then separate the layers
and extract the aqueous layer with ethyl acetate. Dry the combined organic layers with
magnesium sulfate, filter and strip. Purify the crude product by flash chromatography
(25% ethyl acetate/hexanes) to provide 416 mg (74%) of purified product. LCMS (APC1-
pos): 228.1 (M+H). LCMS (APCI-neg): 226.9 (M-H).
Preparation 58
(E+Z)- 5-Bromomethylene-8-fluoro-5,Il-dihydro-10-oxa-l-aza-dibenzo[a,d]cycloheptene
Make the title compounds according to proceduresessentiaHy as described in Preparation
24, beginning with 8-fluoro-5-methylene-5,l 1-dihydro-lO-oxa-l-aza-
dibenzo[a,d]cycloheptene (416 mg, 1.83 mmol). After workup and purification and
separation by flash chromatography (25% ethyl acetate/hexanes) isolate 383 mg (68%) of
(£)-5-bromomethylene-8-fluoro-5,l 1 -dihydro-10-oxa-1 -a2a-dibenzo[a,d]cycloheptene
and 125 mg (23%) of (2)-5-bromomethylcne-8-fluoro-5,l 1-dihydro-10-oxa-l-aza-
dibenzo[a,dJcycloheptene. For(£>5-bromomethylene-8-fluoro-5,ll-dihydro-10-oxa-l-
aza-dibenzo[a,d]cyclob.eptene, LCMS (APCl-pos): 306,308. 'HNMR (d6-DMSO, 400
MHz): 68.55 (d, 1H), 7.86 (d, 1H), 7.49 (dd, IH), 7.40 (dd, 1H), 7.25 (s, 1H), 6.84 (dt,
IH), 6.73 (dd, 1H), 523 (bs, 2H). For(Z>5-bromomethylene-8-fluoro-5Jll-dihydro-10-
oxa-l-aza-dibenzo[a,d]cycloheptene, LCMS (APCI-pos): 306,308. lHNMR (d6-DMSO,
400 MHz): 58.50 (dd, IH), 7.81 (d, IH), 7.50 (dd, IH), 7.40 (dd, IH), 7.09 (s, IH), 6.99-
6.93 (m,2H), 5.22 (bs,2H).
Example 618
(£>5-(8-Fluoro-llH-10^xa-l-aza-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-l-(2-
morpholm^yI-ethyI)-l,3-dihydro-benzoiniidazol-2-one

Following procedures essentially as described in Example 219, beginning with (£)-5-
bromomethyIene-8-fluoro-5,l l-dihydro-10-oxa-l-aza-dibenzo[a,d]cycloheptene (192 mg,
0.63 mmoI)and l-(2-morpho]in-4-yl-ethyl>5-(dihyroxyborolan-2-yl)-l ,3-dihydro-
benzoimidazol-2-one (219 mg, 0.75 mmol). Partition the reaction mixture between ethyl
acetate (50 mL) and IN aqueous hydrochloric acid solution (50 mL). Separate the layers
chromatography to give 2 as a yellow solid (2.59 g, 10.25 mmol, 82 % yield). ]H NMR
(300 MHz, CDC13) 5 8.37 (m, 1 H), 8.21 (m, 1 H), 7.82 (m, 1 H), 7.60 - 7.32 (m, 5 H),
4.94 (d, J - 5.9 Hz, 2 H), 1.97 (t, J= 2.3 Hz, 1 H). Yu, H. RG6-R6H-070.

To a mixture of 2-bronio-5-fluorophenol (3.77 g, 19.8 mmol) and the alkyne from Step A,
above (5.0 g, 19.8 mmol) in 125 mL of anhydrous THF is added triphenylphosphine (7.8
g, 29.6 mmol) at rt. The reaction mixture is cooled to 0 CC and
diisopropylazodicarboxylate (5.99 g, 29.6 mmol) is added dropwise under N2. The
reaction mixture is wanned up to rt and stirred at rt for 2h. 200 mL of water isadded
followed by 200 mL of EtOAc. The layers are separated and the aqueous layer further
extracted with 200 mL of EtOAc. The combined organic layer is dried and concentrated
to give a brown residue. The residue is purified by column chromatography (5%
EtOAc/hexane) to give the product (6.70 g, 15.7 mmol, 79 % yield) as an off-white solid.
'H NMR (300 MHz, CDC13) 8 8.30 (m, 1 H), 820 (m, 1 H), 7.78 (m, 1 H), 7.69 - 7.35
(mr 6 H), 6.78 (m, 1 H), 6.61 (m, 1 H), 5.18 (s, 2H). Yu, H, RG6-R6H-087.

A mixture of the product of Step B, above (56 mg, 0.131 mrnol), Pd (OAc)2 (3 mg, 0.013
mmol) and tri-O-tolylphosphine (8.0 mg, 0.026 mmol) in 0.7 mL of acetonitrile is stirred
under N2 at rt. Formic acid (96 %, 18.2 mmol, 0.394 mmol) is added dropwise followed
by pipcridine (45 mg, 0.526 mmol). The reaction mixture is heated at 70 °C overnight.
TLC shows starting material still remains. Additional Pd (OAc)2 (3 mg, 0.013 mmol), tri-
O-tolylphosphine (8.0 mg, 0.026 mmol), formic acid (96 %, 18.2 mmol, 0.394 mmol) and
piperidine (45 mg, 0.526 mmol) are added in this sequence. The reaction mixture is
heated at 70 °C for additional 4 h with until no starting observed by TLC. The reaction
mixture is concentrated to a black residue and purified through 5 g of silica gel to give the
aniline product (17 mg, 0.054 mmol, 41% yield) as a beige solid. 'H NMR (300 MHz,
CDClj) 5 7.42 (m, 2 H), 7.31 (dt, J= 9.6 Hz,/= 1.3 Hz, 1 H), 7.21 (dt, J = 9.6 Hz, J=
1.3 Hz, 1 H), 7.11 (m, 1 H), 6.93 (t, J= 9.6 Hz, 1 H), 6.78 (s, 1 H), 6.65 (m, 1 H), 6.53 -
6.29 (m, 4 H), 3.46 (bs, 2 H). Yu, H. RG6-R6H-074.
D. Preparation of Final Title Compound:
To a mixture of the aniline of Step C (1.0 mg, 0.0132 mmol) in 0.1 mL of methylene
chloride is added pyridine (0.3 mg, 0.0038 mmol) followed by mcthanesulfonylchloride
(0.4 mg, 0.0035 mmol) at rt under N2. The reaction mixture is stirred at rt for 2L The
reaction mixture is concentrated to dry and the residue is purified by column
chromatogrphy to give Title Compound as a solid. 'H NMR (300 MHz, CDCI3) 5 7.44
(m, 2 H), 7.32 (t, 7= 7.5 Hz, 1 H), 7.17 (m, 2 H), 7.00 (m, 2 H), 6.87 (m, 2 H), 6.78 (m, 1
H),6.67(dt,7= 11.7 Hz, .7=4.1 Hz, 1 H),6.53 (dd,J= 10.6Hz, J= 2.5 Hz, 1 H), 6.07
(s, 1H), 2.81 (s, 3 H).
Examples 619-751 contained in Table IL herein, provide yet additional examples of
compounds of Formula I wherein the bridge depicted by-X—Y— contains a heteroatom
or heteroatom containing group at either the X or Y position.. These examples, which
further illustrate the present invention are prepared according to the procedures as
described generally in the Schemes and literature references described above.
Additional preparations for, and examples of compounds of Formula I wherein
R8 is other than hydrogen and the bridge depicted by-X—Y- contains either a
heteroatom or heteroatom containing group at cither the X or Y position or both X and Y
are CH2. (Section 7)
Example 752
N-{3-[l-(8-Metboxy-6,l l-dihydro-dibenzo[b,e]oxepin-l l-yl)-ethyl]-pbenyl}-
methanesulfonamide

Mix N-{3-[l-(8-methoxy-6H-dibenzo[b,e]oxepin-l l-ylidene)-ethyl] -phenyl} -
methanesulfonamide (prepared essentially a sdescribed in Example 271) (1.0 eC4) with
10% Pd/C (652 weight %) in EtOH and heat at 60°C overnight under 500 psi hydrogen.
Remove the solvent and purify by chromatography (ISCO Combi Flash, 3/1 hexane/ethyl
acetate) to give 29% of the title compound as a racemic mixture. HPLC (Xterra CI 8
2.1x50fim 3.5/iM, 5-100% acetonitrile with 02% formic acid.) t= 4.55 (100%). MS (ES)
424 (M+l), 422 (M-l).
Preparation 59
(10,ll-dihydro-dibenzo[a,J]cyclohepten-5-ylidine)-acetic acid ethyl ester

Prepared as described in Bergmann, E.D., Solomonovici, A., Synthesis, 1970, 183-189.
Preparation 60
Bromo-(10,1 l-dihydro-dibenzo[a,-acetic acid mediyl
ester (1 equivalent) in a suitable dry solvent and cool to 0°C under a dry atmosphere. Add
1M diisobutylaluminun hydride solution in toluene (3 equivalents) dropwise and stir the
mixture for one hour. Quench with aqueous citric acid solution and partition between
water and ethyl acetate. Dry and evaporate the organic layer to obtain the title compound
in 87% yield.
Preparation 63
2-Chloro-5-(2-methoxy-ethylidene)-10,l l-dihydro-5H-dibenzo[a,d]cycloheptene

Treat 2-(2-chloro-10,l l^iihydro-dibenzo[a,d]cyclohepten-5-ylidene)-ethanol (1
equivalent) with sodium hydride (2 equivalents) in. a suitable dry solvent at 0°C and stir
for 15~minutes. Add dimethyl sulfate dropwise (2 equivalents) and stir at 0°C for one
hour. Quench with aqueous citric acid solution and partition between water and ethyl
acetate. Dry and evaporate the organic layer. Purify the residue by silica gel
chromatography to give the title compound in 82% yield
Preparation 64
5-(l-Bromo-2-memoxy-ethylidene)-2^hloro-10,ll-dihydro-5H-dibenzo[a,d]cycloheptene

Treat 2-chloro-5-(2-rnethoxy-ethylidene)-l 0,1 l-dihydro-5H-dibcnzo[a,d]cyclobeptene
essentially as described in Preparation 24 to give the title compound in 43% yield.
Example 756
N-{3-[l-(2-Chloro-10Jl-dihydro^benzo[a,d]cyclohepten-5-ylidene)-2-methoxy-ethyI]-
phenyl} -methanesulfonamide

Following procedures essentially as described in Example 219, mix 5-( 1 -bromo-2-
methoxy-ethylidene)-2-chloro-10,l l-dihydro-5H-dibenzo[a,d]cycloheptene (1
equivalent), N-[3-(4,4,5,5-tetramethyl-[ 1 ,3 ,2]dioxaborolan-2-yl)-phenyl]-
methanesulfonamide (1.25 equivalents), 2N Na2C03 (2 equivalents) and
terratotriphenylphosphine palladium (0.05 equivalents)in a suitable solvent. Purify the
product by silica gel chromatography to obtain a 62% yield of the title compound
MS(ES>=452(-)
Preparation 65
1I-Fluoromethylene-6,1 l-dihydro-dibenzo[b,e]oxepine

Dissolve ll-Bromomethylene-6,ll-dihydro-dibenzo[b,e]oxepijac (1 eq.) in dryTHF (0.1
M). Cool the solution to - 78C in a dry ice/acetone bath. Slowly add s-butyl lithium (1.2
eq., 3.3 M in cyclohexane) to the above solution. Stir the dark brown solution at - 78 C
for two hours. Add a solution of N-fluorobenzene sulfonimide (1.2 eq.) in dry THF (0.4
M) over 2 minutes. Remove the cold bath and allow the reaction mixture to warm to
ambient temperature. Stir the reaction mixture at room temperature for 1 hour. Quench
the reaction with water. Wash the resulting mixture with saturated aqueous NaHCC>3.
Separate the organic phase and dry over sodium sulfate. Filter the mixture and
concentrate under reduced pressure to afford a crude product Purify the crude product by
chromatography on silica gel, eluting with 30% CH2CI2 in hexanes. MS (EI) = 226 (M).
Preparation 66
1 l-Bromo-fiuoro-rnethylene-6,11-dihydro-dibenzo[b,e]oxepine