Title of Invention

A BENZAZEPINE COMPOUND

Abstract The present invention provides 6-substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepines of Formula I as selective 5-HT2C receptor agonists for the treatment of 5-HT2C associated disorders including obesity, obsessive/compulsive disorder, depression, and anxiety: I where: R6 is -C=C-R10, -O-R12, -S-R14, or -NR24R25; and other substituents are as defined in the specification
Full Text The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich
pharmacology arising from a heterogeneous population of at least seven receptor classes.
The serotonin 5-HT2 class is further subdivided into at least three subtypes, designated 5-
HT2A, 5-HT2B, and 5-HT2C- The 5-HT2C receptor has been isolated and characterized
(Julius, et al., U.S. Patent No. 4,985,352), and transgenic mice lacking the 5-HT2c
receptor have been reported to exhibit seizures and an eating disorder resulting in
increased consumption of food (Julius etal., U.S. Patent No. 5,698,766). The 5-HT2C
receptor has also been linked to various other neurological disorders including obesity
(Vickers et al, Psychopharmacology, 167: 274-280 (2003)), hyperphagia (Tecott et al,
Nature, 374: 542-546 (1995)), obsessive compulsive disorder (Martin et al, Pharmacol.
Biochem. Behav., 71: 615 (2002); Chou-Green et al, Physiology & Behavior, 78: 641-
649 (2003)), depression (Leysen, Kelder, Trends in Drug Research II, 29: 49-61 (1998)),
anxiety (Curr. Opin. Invest. Drugs 2(4), p. 317 (1993)), substance abuse, sleep disorder
(Frank et al, Neuropsychopharmacology 27: 869-873 (2002)), hot flashes (EP 1213017
A2), epilepsy (Upton et al, Eur. J. Pharmacol., 359: 33 (1998); Fitzgerald, Ennis, Annual
Reports in Medicinal Chemistry, 37:21-30 (2002)), and hypogonadism (Curr. Opin.
Invest. Drugs 2(4), p. 317 (1993)).
Certain substituted 2,3,4,5-tetrahydro-lH-benzo[d]azepine compounds have been
disclosed as useful therapeutics as for example:
US 4,265,890 describes certain substituted 2,3,4,5-tetrahydro-lH-benzo[d]azepine
compounds as dopaminergic receptor antagonists for use as antipsychotics and
antiemetics, inter alia.
EP 0 285 287 describes certain substituted 2,3,4,5-tetrahydro-lH-benzo[d]azepine
compounds for use as agents to treat gastrointestinal motility disorders, inter alia.

WO 93/03015 and WO 93/04686 describe certain substituted 2,3,4,5-tetrahydro-
lH-benzo[d]azepine compounds as alpha-adrenergic receptor antagonists for use as
agents to treat hypertension and cardiovascular diseases in which changes in vascular
resistance are desirable, inter alia.
WO 02/074746 Al describes certain substituted 2,3,4,5-tetrahydro-lH-
benzo[d]azepine compounds as 5-HT2C agonists for the treatment of hypogonadism,
obesity, hyperphagia, anxiety, depression, sleep disorder, inter alia.
WO 03/006466 Al describes certain substituted tricyclic hexahydroazepinoindole
and indoline compounds as 5-HT ligands and consequently their usefulness for treating
diseases wherein modulation of 5-HT activity is desired.
High affinity 5-HT2c receptor agonists would provide useful therapeutics for the
treatment of the above mentioned 5-HT2c receptor-associated disorders including obesity,
hyperphagia, obsessive/compulsive disorder, depression, anxiety, substance abuse, sleep
disorder, hot flashes, and hypogonadism. High affinity 5-HT2c receptor agonists that are
also selective for the 5-HT2c receptor, would provide such therapeutic benefit without the
undesirable adverse events associated with current therapies. Achieving selectivity for the
5-HT2c receptor, particularly as against the 5-HT2A and 5-HT2B receptors, has proven
difficult in designing 5-HT2c agonists. 5-HT2A receptor agonists have been associated
with problematic hallucinogenic adverse events. (Nelson et al, Naunyn-Schmiedeberg's
Arch. Pharm., 359: 1-6 (1999)). 5-HT2B receptor agonists have been associated with
cardiovascular related adverse events, such as valvulopathy. (V. Setola et al., Mol.
Pharmacology, 63: 1223-1279 (2003), and ref. cited therein).
Previous references to substituted 2,3,4,5-tetrahydro-lH-benzo[d]azepine
compounds as potential therapeutics have predominately recited their uses as alpha
adrenergic and/or dopaminergic modulators. Adrenergic modulators are often associated
with the treatment of cardiovascular diseases (Frishman, Kotob, Journal of Clinical
Pharmacology, 39: 7-16 (1999)). Dopaminergic receptors are primary targets in the
treatment of schizophrenia and Parkinson's disease (Seeman, Van Tol, Trends in

Pharmacological Sciences, 15: 264-270 (1994)). It will be appreciated by those skilled in
the art that selectivity as against these and other physiologically important receptors will
generally also be preferred characteristics for therapeutics for the specific treatment of
5-HT2C associated disorders as described above.
The present invention provides selective 5-HT2C agonist compounds of Formula I:

where:
R1 is hydrogen, fluoro, or (C1-C3)alkyl;
R2, R3, and R4 are each independently hydrogen, methyl, or ethyl;
R5 is hydrogen, fluoro, methyl, or ethyl;
R6 is -C=C-R10, -O-R12, -S-R14, or -NR24R25;
7 \*
R is hydrogen, halo, cyano, (Ci-Ce)alkyl optionally substituted with 1 to 6 fluoro \substituents, (C2-C6)alkenyl optionally substituted with 1 to 6 fluoro substituents, \(C3-C7)cycloalkyl, (C1-C6)alkoxy optionally substituted with 1 to 6 fluoro I substituents, (C1-C6)alky!thio optionally substituted with 1 to 6 fluoro substituents, 1 Ph'-(Co-C3)alkyl, Ph1-(C0-C3)alkyl-O-, or Ph'-CCo-C^alkyl-S-; if
R8 is hydrogen, halo, cyano, or -SCF3;
R9 is hydrogen, halo, cyano, -CF3, -SCF3, or (C1-C3)alkoxy optionally substituted with 1
to 6 fluoro substituents;
R10 is -CF3, ethyl substituted with 1 to 5 fluoro substituents, (C3-C6) alkyl optionally
substituted with 1 to 6 fluoro substituents, (C3-C7)cycloalkyl(Co-C3)alkyl,
Ar'-CQ-CsJalkyl, Ph1-(C0-C3)alkyl, or 3-(C1-C4)alkyl-2-oxo-imidazolidin-l-yl-
(CrC3)alkyl;

R12 is Ph2-(C,-C3)alkyl, Ar2-(C,-C3)alkyl, (C,-C6)alkyl-S-(C2-C6)alkyl,
(C3-C7)cycloalkyl-S-(C2-C6)alkyl,phenyl-S-(C2-C6)alkyl,Ph2-S-(C2-C6)alkyl,
phenylcarbonyl-(C,-C3)alkyl,Ph2-C(O)-(C,-C3)alkyl,
(C1 -C6)alkoxycarbonyl(C3-C6)alkyl, (C3-C7)cycloalkyl-OC(O)-(C3-C6)alkyl,
phenyloxycarbonyl-(C3-C6)alkyl)Ph2-OC(O)-(C3-C6)alkyl,Ar2-OC(O)-(C3-C6)alkyl,
(C3-C7)cycloalkyl-NH-C(O)-(C2-C4)alkyl->Ph1-NH-C(O)-(C2-C4)alkyl-5
Ar2-NH-C(O)-(C2-C4)alkyl-, or R13-C(O)NH-(C2-C4)alkyU
R13 is (C3-C7)cyc1oalkyl(Co-C3)alkyl, Ph1, Ar2, or (Ci-C3)alkoxy optionally substituted
with 1 to 6 fluoro substituents, Ph'-NH- or N-linked Het1;
R14 is Ar2 which is not N-linked to the sulfur atom, Ph2, R15-L-, tetrahydrofuranyl,
tetrahydropyranyl, or phenyl-methyl substituted on the methyl moiety with a
substituent selected from the group consisting of (Ci-C3)-«-alkyl substituted with
hydroxy, (CrC3)alkyl-O-(Ci-C2)-«-alkyl, (Ci-C3)alkyl-C(0)-(Co-C2)-»-alkyl, and
(Ci-C3)alkyl-O-C(O)-(C0-C2)-n-alkyl,
wherein when R14 is Ph2 or Ar2, wherein Ar2 is pyridyl, then R14 may also,
optionally be substituted with phenyl-CH=CH- or phenyl-C=C-,
said phenyl-CH=CH- or phenyl-OC- being optionally further
substituted with 1 to 3 substituents independently selected from the
group consisting of halo, cyano, -SCF3, (Ci-C6)alkyl optionally
further substituted with 1 to 6 fluoro substituents, and
(Ci-C6)alkoxy optionally further substituted with 1 to 6 fluoro
substituents, and
wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally be
substituted with R28R2*N-C(O)-, and optionally further substituted with
one methyl, -CF3, cyano, or -SCF3 substituent, or with 1 to 2 halo
substituents, and
wherein the tetrahydrofuranyl and tetrahydropyranyl may optionally be
substituted with an oxo substituent, or with one or two groups
independently selected from methyl and -CF3;
R15 is -OR16, cyano, -SCF3, Ph2, Ar2, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,
phthalimido, benzothiophenyl optionally substituted at the 2-position with phenyl or
benzyl, benzothiazolyl optionally substituted at the 2-position with phenyl or benzyl,

benzothiadiazolyl optionally substituted with phenyl or benzyl, 2-oxo-dihydroindol-l-
yl optionally substituted at the 3 position with gem dimethyl or (C1-C6)alkyl
optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-dihydroindol-5-yl
optionally substituted at the 3 position with gem dimethyl or (C1-C6)alkyl optionally
further substituted with 1 to 6 fluoro substituents, 2-oxo-imidazolidin-l-yl optionally
substituted at the 3 position with gem dimethyl or (C1-C6)alkyl optionally further
substituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydropyrimidinyl optionally
substituted at the 3 or 4 position with gem dimethyl or (C1-C6)alkyl optionally further
substituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydroquinolin-l-yl optionally
substituted at the 3 position with gem dimethyl or (C1-C6)alkyl optionally further
substituted with 1 to 6 fluoro substituents, 2-oxo- dihydrobenzimidazol-1-yl
optionally substituted at the 3 position with gem dimethyl or (C1-C6)alkyl optionally
further substituted with 1 to 6 fluoro substituents, -NRI7R18, -C(O)R22, or a saturated
heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl,
morpholinyl, and thiomorpholinyl, tetrahydrofuranyl, and tetrahydropyranyl,
wherein Ph2 and Ar2 when Ar2 is pyridyl, may also optionally be substituted
with phenyl-CH=CH- or phenyl-OC-,
said phenyl-CH=CH- and phenyl-OC- being optionally further
substituted on the phenyl moiety with 1 to 3 substituents
independently selected from the group consisting of halo, cyano,
-SCF3, (CrC6)alkyl optionally further substituted with 1 to 6 fluoro
substituents, and (C1-C5)alkoxy optionally further substituted with
1 to 6 fluoro substituents, and
wherein Ar2 may alternatively, optionally be substituted with a substituent
selected from the group consisting of (C3-C7)cycloalkyl-(Co-C3)alkyl,
Het'-(Co-C3)alkyl, pyridyl-(C0-C3)alkyl, and phenyl-(C0-C3)alkyl, and
optionally further substituted with one methyl, -CF3, cyano, or -SCF3
substituent, or with 1 to 2 halo substituents,
said pyridyl-(Co-C3)alkyl and phenyl-(Co-C3)alkyl optionally being
further substituted with 1-3 substituents independently selected
from halo, -CH3, -OCH3, -CF3, -OCF3, -CN, and -SCF3, and

wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally be
substituted with R28R29N-C(O)-, or (C1-C6)alkyl-C(O)- optionally
substituted with 1 to 6 fluoro substituents, and may be optionally further
substituted with one methyl, -CF3, cyano, or -SCF3 substituent, or with 1 to
2 halo substituents, and
wherein when Ar2 is thiazolyl, the thiazolyl may alternatively, optionally be
substituted with (C3-C7)cycloalkyl-(C0-C3)alkyl-NH-, and
wherein the pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl is
substituted with oxo- on a carbon atom adjacent to the ring nitrogen atom,
or is N-substituted with a substituent selected from the group consisting
of
(C1 -C6)alkylcarbonyl, (C1-C6)alkylsulfonyl,
(C3-C7)cycloalkyl(C0-C3)alkyl-C(O)-,
(C3-C7)cycloalkyl(Co-C3)alkyl-S(0)2-,Ph1-(Co-C3)alkyl-C(0)-,and
Ph1-(C0-C3)alkyl-S(O)2-, and
may optionally be further substituted with 1 or 2 methyl or -CF3
substituents, and when oxo-substituted, may optionally be further N-
substituted with a substituent selected from the group consisting of
(C|-C6)alkyl optionally farther substituted with 1 to 6 fluoro
substituents, (C3-C7)cycloalkyl(C0-C3)alkyl, and Ph'-(Co-C3)alkyl, and
wherein tetrahydrofuranyl and tetrahydropyranyl may optionally be substituted
with an oxo substituent, and/or with one or two groups independently
selected from methyl and -CF3;
L is branched or unbranched (C1-C6)alkylene, except when R15 is -NR17R18 or
Ar2-N-linked to L, in which case L is branched or unbranched (C2-C6)alkylene, and
when L is methylene or ethylene, L may optionally be substituted with gem-ethano or
with 1 to 2 fluoro substituents, and when R15 is Ph2, Ar2, or a saturated heterocycle, L
may alternatively, optionally be substituted with a substituent selected from the group
consisting of hydroxy, cyano, -SCF3, (CrC6)alkoxy optionally further substituted with
1 to 6 fluoro substituents, (C1-C6)alkoxycarbonyl optionally further substituted with 1
to 6 fluoro substituents, (Ci-Ce)alkylcarbonyloxy optionally further substituted with 1
to 6 fluoro substituents, (C3-C7)cycloalkyl-(C0-C3)alkyl-O-,

(C3-C7)cycloalkyl-(Co-C3)alkyl-0-C(0)-,and(C3-C7)cycloalkyl-(Co-C3)alkyl-C(0)-0-
R16 is hydrogen, (C1-C6)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl(Co-C3)alkyl,
(C3-C7)cycloalkyl(Co-C3)alkyl-C(0)-,Phl-(Co-C3)alkyl>Ph1-(Co-C3)alkyl-C(0)-,
Ar2-(C0-C3)alkyl, or Ar2-(C0-C3)alkyl-C(O)-,
R17 is (C1-C4)alkyl optionally substituted with 1 to 6 fluoro substituents, /-butylsulfonyl,
(C3-C7)cycloalkyl(Co-C3)alkyl-C(0)-, (C3-C7)cycloalkyl(C0-C3)alkyl-sulfonyl,
Ph1-(C0-C3)alkyl. Ph'-(C0-C3)alkyl-C(O)-, Ph'-(C0-C3)alkylsulfonyl, Ar2-(C0-C3)alkyl,
Ar2-(C0-C3)alkyl-C(O)-, Ar2-(C0-C3)alkylsulfonyi, R19OC(O)-, or R20R21NC(O)-;
R18 is hydrogen or (C|-C4)alkyl optionally substituted with 1 to 6 fluoro substituents, or
R17 and R18, taken together with the nitrogen atom to which they are attached form
Het1 where Het1 is substituted with oxo- on a carbon atom adjacent to the ring
nitrogen atom, or
R17 and R18, taken together with the nitrogen atom to which they are attached, form an
aromatic heterocycle selected from the group consisting of pyrolyl, pyrazolyl,
imidazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl,
said aromatic heterocycle optionally being substituted with 1 to 2 halo
substituents, or substituted with 1 to 2 (Ci-GOalkyl substituents optionally
further substituted with 1 to 3 fluoro substituents, or mono-substituted with
fluoro, nitro, cyano, -SCF3, or (Ci-Gt)alkoxy optionally further substituted
with 1 to 3 fluoro substituents, and optionally further substituted with a
(C1-C4)alkyl substituent optionally further substituted with 1 to 3 fluoro
substituents;
R19 is (C1-C6)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(Co-C3)alkyl, Ar2-(CO-C3)alkyl, or Ph1-(C0-C3)alkyl,
R20 is (C1-C6)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(Co-C3)alkyl, Ar2-(C0-C3)alkyl, or Ph'-(Co-C3)alkyl,
R21 is hydrogen or (C1-C4)alkyl optionally substituted with 1 to 6 fluoro substituents, or
R20 and R21, taken together with the nitrogen atom to which they are attached, form
Het1;

R22 is (C1-C6)alkyl optionally substituted with 1 to 6 tluoro substituents,
(C3-C7)cycloalkyl(Co-C3)alkyl, R23-O, Ph'-(C0-C3)alkyl, Ar2-(C0-C3)alkyl, or
R32R33N-;
R23 is (CrC6)alkyI optionally substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(C0-C3)alkyl, Ph'-(C0-C3)alkyl, or Ar^Co-QOalkyl;
R24 is (C1-C6)alkoxy(C2-C5)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C1-C6)alkylthio(C2-C5)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(Co-C,)alkyl-0-(Ci-C5)alkyl,
(C3-C7)cycloalkyl(Co-C,)alkyl-S-(Ci-C5)alkyl, phenyl(C1-C3)M-alkyl,
/ph2-(C1-C3)-w-alkyl, Ar^Co-C;,) w-alkyl, phenyl(C0-Ci)alkyl-O-(Ci-C5)alkyl,
V phenyKG^^Tkyl-S^^aKyirPh'KCo-COalkyl-CCOJNH-CCz-C^alkyl,
Ph' -(Co-C, )alkyl-NH-C(O)NH-(C2-C4)alkyl,
pyridyl-(Co-Ci)alkyl-C(0)NH-(C2-C4)alkyl,
pyridyl-(C0-C,)alkyl-NH-C(O)NH-(C2-C4)alkyl, or Ar3(C1-C2)alkyl,
where Ar3 is a bi-cyclic moiety selected from a group consisting of indanyl, indolyl,
dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzo[l,3]dioxolyl, naphthyl, dihydrobenzopyranyl, quinolinyl,
isoquinolinyl, and benzo[l,2,3]thiadiazolyl,
said Ar3 optionally being substituted with (C1-C6)alkyl optionally further
substituted with 1 to 6 fluoro substituents, phenyl(C0-Ci)alkyl optionally
further substituted with 1 to 6 fluoro substituents, or substituted with
(C3-C7)cycloalkyl(Co-C3)alkyl, or substituted with 1-3 substituents
independently selected from the group consisting of halo, oxo, methyl, and
-CF3,
said phenyl(C1-C3) n-alkyl, Ph2-(C1-C3) n-alkyl, or Ar^Co-C;,) n-alkyl
optionally being substituted on the n-alkyl moiety when present with
(C1-C3)alkyl, dimethyl, gem-ethano, 1 to 2 fluoro substituents, or (Ci-
C6)alkyl-C(O)-,
said Ar2(Co-C3) «-alkyl being alternatively optionally substituted with a
substituent selected from the group consisting of (C3-C7)cycloalkyl-
(C0-C3)alkyl, Het'-(C0-C3)alkyl, pyridyl-(C0-C3)alkyl, phenyl-(C0-C3)alkyl,
pyridyl-(C0-C3)alkyl-NH-, phenyl-(C0-C3)alkyl-NH-, (C1-C6)alkyl-S-, and

(C3-C7)cycloalkyl-(Co-C3)alkyl-S-, and optionally further substituted with
one methyl, -CF3, cyano, or -SCF3 substituent, or with 1 to 2 halo
substituents,
said pyridyl-(Co-C3)alkyl and phenyl-(Co-C3)alkyl optionally being
further substituted with 1-3 substituents independently selected
from halo, -CH3, -OCH3, -CF3, -OCF3, -CN, and -SCF3, and
said Ph2-(C1-C3) w-alkyl and Ar2(Co-C3) «-alkyl where Ar2 is pyridyl, also
optionally being substituted on the phenyl or Ar2 moiety, respectively, with
phenyl-CH=CH- or phenyl-OC-,
said phenyl-CH=CH- or phenyl-C=C- being optionally further
substituted with 1 to 3 substituents independently selected from the
group consisting of halo, cyano, -SCF3, (C1-C6)alkyl optionally
further substituted with 1 to 6 fluoro substituents, and
(Ci-Ce)alkoxy optionally further substituted with 1 to 6 fluoro
substituents, and
said Ar^Co-Cy «-alkyl where Ar2 is pyridyl, alternatively, optionally being
substituted with (C1-C6)alkyl-C(O)-W R28R29N-C(O)-, and optionally
further substituted with one methyl, -CF3, cyano, or -SCF3 substituent, or
with 1 to 2 halo substituents,
said phenyI(C0-Ci)alkyl-O-(Ci-C5)alkyl, or phenyl(C0-Ci)aIkyl-S-(Ci-C5)alkyl
optionally being substituted on the phenyl moiety with (Ci-C2>S(O)2-, or
with 1 to 5 independently selected halo substituents, or with 1 to 3
substituents independently selected from the group consisting of halo,
cyano, -SCF3, (C]-C6)alkyl optionally further substituted with 1 to 6 fluoro
substituents, and (C|-C6)alkoxy optionally further substituted with 1 to 6
fluoro substituents, and
said pyridyl-(Co-C1)alkyl-C(0)NH-(C2-C4)alkyl and
pyridyl-(Co-Ci)alkyl-NH-C(0)NH-(C2-C4)alkyl optionally being
substituted on the pyridyl moiety with methyl, -CF3, or 1 to 3 halo
/Substituents;
/R25 is hydrogen, (d-C3)alkyl optionally substituted with 1 to 6 fluoro substituents, OJ^
^ allyl; ' " '

R26 is hydrogen, (C]-C6)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(Co-C3)alkyl;
R27 is hydrogen or (C|-C4)alkyl optionally substituted with 1 to 6 fluoro substituents, or
R and R , taken together with the nitrogen atom to which they are attached, form
Het1;
R is (Ci-Cg)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C3-C8)cycloalkyl(C0-C3)alkyl, tetrahydropyran-3-yl(C0-C3)alkyl,
tetrahydropyran-4-yl(Co-C3)aIkyl, tetrahydrofuranyI(C0-C3)alkyl, Ph'-(C0-C2) n-alkyl,
or Ar2-^^) n-alkyl,
said Ph'-(Co-C2) «-alkyl and Ar^Co-Ci) rc-alkyl optionally being substituted
on the alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano;
R29 is hydrogen or (CrC3)alkyl;
R30 is hydrogen, (C1-C6)alkyl optionally substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(C0-C3)alkyl, Ph1-(C0-C3)alkyl, or Ar2(C0-C3)alkyl,
R31 is hydrogen or (C1-C6)alkyl optionally substituted with 1 to 6 fluoro substituents, or
R30 and R31, taken together with the nitrogen atom to which they are attached, form
Het1,
said Het1 also optionally being substituted with phenyl optionally further
substituted with 1 to 3 halo substituents;
R32 and R33 are each independently hydrogen or (C1-C6)alkyl optionally substituted with 1
to 6 fluoro substituents, or R32 and R33, taken together with the nitrogen atom to
which they are attached, form Het1, or R32 is Ph'(C0-Ci)alkyl provided that R33 is
hydrogen;
Ar1 is an aromatic heterocycle substituent selected from the group consisting of furanyl,
thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, and pyridazinyl, any of which may
optionally be substituted with 1 to 3 substituents independently selected from the
group consisting of halo, (C1-C3)alkyl, (C1-C3)alkoxy, -CF3, -O-CF3, nitro, cyano, and
trifluoromethylthio;
Ar2 is an aromatic heterocycle substituent selected from the group consisting of pyrrolyl,
pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,
isothiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, and

benzimidazolyl, any of which may optionally be substituted with 1 to 3 substituents
independently selected from the group consisting of halo, cyano, -SCF3, (C1-C6)alkyl
optionally further substituted with 1 to 6 fluoro substituents, and (C1-C6)alkoxy
optionally further substituted with 1 to 6 fluoro substituents, and wherein pyridyl and
pyridazinyl may also optionally be substituted with (C1-C6)alkylamino optionally
further substituted with 1 to 6 fluoro substituents, (C3-C7)cycloalkyl(Co-C3)alkyl, or
(C3-C7)cycloalkyl(Co-C3)alkyl-amino;
Het' is a saturated, nitrogen-containing heterocycle substituent selected from the group
consisting of azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,
thiomorpholinyl, homomorpholinyl, and homothiomorpholinyl, any of which may
optionally be substituted with (Ci-Ce)alkyl or with 2 methyl substituents;
Het2 is a saturated, oxygen-containing heterocycle substituent selected from the group
consisting of tetrahydrofuranyl and tetrahydropyranyl, any of which may optionally be
substituted with (Ci-Ce)alkyl or with 2 methyl substituents;
Ph1 is phenyl optionally substituted with 1 to 5 independently selected halo substituents,
or with 1 to 3 substituents independently selected from the group consisting of halo,
cyano, -SCF3, (C1-C6)alkyl optionally further substituted with 1 to 6 fluoro
substituents, and (C1-C6)alkoxy optionally further substituted with 1 to 6 fluoro
substituents;
Ph2 is phenyl substituted with:
a) 1 to 5 independently selected halo substituents; or
b) 1 to 3 substituents independently selected from the group consisting of halo, cyano,
-SCF3, nitro, hydroxy, (C1-C6)alkyl optionally further substituted with 1 to 6
fluoro substituents, and (Ci-Ce)alkoxy optionally further substituted with 1 to 6
fluoro substituents; or
c) 0, 1, or 2 substituents independently selected from the group consisting of halo,
cyano, -SCF3, methyl, -CF3, methoxy, -OCF3, nitro, and hydroxy, together with
one substituent selected from the group consisting of
i) (Ci-Cio)alkyl optionally further substituted with 1 to 6 fluoro
substituents or mono-substituted with hydroxy, (Ci-Ce)alkoxy,
(C3-C7)cycloalkyl(C0-C3)alkyloxy, Het2-(C0-C3)alkyloxy, Ph1 -(Co-
C3)alkyloxy,

ii) (Ci-C!o)alkoxy-(Co-C3)alkyl optionally further substituted with 1 to 6
fluoro substituents, and optionally further substituted with hydroxy,
iii) (C1-C6)alkyl-C(0)-(Co-C5)alkyl optionally further substituted with I
to 6 fluoro substituents,
iv) carboxy,
v) (C1-C6)alkoxycarbonyl optionally further substituted with 1 to 6
fluoro substituents,
vi) (C1-C6)alkyl-C(O)-(C0-C3)-O- optionally further substituted with 1 to
6 fluoro substituents,
vii) (C1-C6)alkylthio-(Co-Cs)alkyl optionally further substituted with 1 to
6 fluoro substituents,
viii) (C1-C6)alkylsulfinyl-(Co-C5)alkyl optionally further substituted with
1 to 6 fluoro substituents,
ix) (C1-C6)alkylsulfonyl-(Co-C5)alkyl optionally further substituted with
1 to 6 fluoro substituents,
x) (C i -C6)alkylsulfonyl-(Co-C3)alkyl-0- optionally further substituted
with 1 to 6 fluoro substituents,
xi) (C3-C7)cycloalkyl(Co-C3)alkyl, optionally further substituted on the
cycloalkyl with 1 to 4 substituents selected from methyl and fluoro,
xii) (C3-C7)cycloalkyl(Co-C3)alkyl-0-, optionally further substituted on
the cycloalkyl with 1 to 4 substituents selected from methyl and
fluoro,
xiii) (C3-C7)cycloalkyl(Co-C3)alkyl-C(0)-,
xiv) (C3-C7)cycloalkyl(Co-C3)alkyl-0-C(0)-,
xv) (C3-C7)cycloalkyl(Co-C3)alkyl-S-,
xvi) (C3-C7)cycloalkyl(C0-C3)alkyl-S(O)-,
xvii) (C3-C7)cycloalkyl(Co-C3)alkyl-S(0)2-,
xviii) Ph'-(Co-C3)alkyl, optionally substituted on the alkyl moiety with 1 to
2 fluoro substituents,
xix) Ph1-(Co-C3)alkyl-0-, optionally substituted on the alkyl moiety with
1 to 2 fluoro substituents
xx) Ph1-(C0-C3)alkyl-C(O)-,

xxi) Ph1-(C0-CJ)alkyl-O-C(O)-,
xxii) Phl-(Co-C3)a[kyl-C(0)-(Co-C3)alkyl-0-,
xxiii) Ph'-CCo-Cyatkylthio,
xxiv) Ph'-(CO-C3)alkylsulfinyl,
xxv) Ph'-(C0-C3)alkylsulfonyl,
xxvi) Ar2(C0-C3)alkyl,
xxvii) Ar2(C0-C3)alkyl-O-
xxviii) Ar2-(Co-C3)allcyl-S-,
xxix) Ar2(C0-C3)alkyl-C(O)-,
xxx) Ar2(C0-C3)aIkyl-C(S)-,
xxxi) Ar2-(C0-C3)alkylsulfmyl,
xxxii) Ar2-(Co-C3)alkylsulfonyl,
xxxiii) Het1 (Co-C3)alkyl-C(0)- optionally substituted on the Het1 moiety
withPh1,
xxxiv) Het1 (C0-C3)alkyI-C(S)- optionally substituted on the Het1 moiety
with Ph1,
xxxv) N-linked Het'-C(O)-(C0-C3)alkyl-O-,
xxxvi) Het2-(C0-C3)alkyloxy,
xxxvii) R26R27N-,
xxxviii) R2SR29-N-(C1-C3)alkoxy,
xxxix) R28R29N-C(O)-,
xl) R28R29N-C(O)-(C1-C3)alkyl-O-(
xli) R28R29N-C(S)-,
xlii) R30R31N-S(O)2-,
xliii) HON=C(CH3)-, and
xliv) HON=C(Ph')-,
or a pharmaceutically acceptable salt thereof, subject to the following provisos:
a) no more than two of R1, R2, R3, R4, and R5 may be other than hydrogen;
b) when R2 is methyl, then R1, R3, R4, and R5 are each hydrogen;
c) when R3 is methyl, then R2 and R4 are each hydrogen;

d) when R3 is methyl, R7 and R8 are each -OH, and R1, R2, R4, R5, and R9 are
each hydrogen, then R6 is other than cyclohexylthio, fiiranylthio, or
phenylthio; and
e) When R12 is Ar2-(C1-C3)alkyl, then R7 is other than hydrogen or R9 is other
than chloro.
This invention also provides pharmaceutical compositions which comprise a
compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with
a pharmaceutically acceptable carrier, diluent, or excipient.
In another aspect of the present invention, there is provided a method for
increasing activation of the 5-HT2c receptor in mammals comprising administering to a
mammal in need of such activation an effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
The present invention also provides a method for treating obesity in mammals
comprising administering to a mammal in need of such treatment an effective amount of a
compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for treating obsessive/compulsive
disorder in mammals comprising administering to a mammal in need of such treatment an
effective amount of a compound of Formula I, or a pharmaceutically acceptable salt
thereof.
Furthermore, the present invention provides a method for treating depression in
mammals comprising administering to a mammal in need of such treatment an effective
amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides a method for treating anxiety in
mammals comprising administering to a mammal in need of such treatment an effective
amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In preferred embodiments of the above methods of treatment utilizing a compound
of Formula I, or a pharmaceutically acceptable salt thereof, the mammal is a human.
In another aspect of the present invention, there is provided a compound of
Formula I for use in selectively increasing activation of the 5-HT2c receptor and/or for
use in treating a variety of disorders associated with decreased activation of 5-HT2c
receptors. Preferred embodiments of this aspect of the invention include a compound of
Formula I for use in the treatment of obesity, hyperphagia, obsessive/compulsive
disorder, depression, anxiety, substance abuse, sleep disorder, hot flashes, and/or
hypogonadism. Particularly preferred embodiments of this aspect of the invention
include the treatment of obesity, obsessive/compulsive disorder, depression, and/or
anxiety.
In another aspect of the present invention, there is provided the use of one or more
compounds of Formula I in the manufacture of a medicament for the activation of 5-HT2C
receptors in a mammal. In preferred embodiments of this aspect of the invention, there is
provided the use of one or more compounds of Formula I in the manufacture of a
medicament for the treatment of obesity, hyperphagia, obsessive/compulsive disorder,
depression, anxiety, substance abuse, sleep disorder, hot flashes, and/or hypogonadism.
Particularly preferred embodiments of this aspect of the invention include the use of one
or more compounds of Formula I in the manufacture of medicaments for the treatment of
obesity, obsessive/compulsive disorder, depression, and/or anxiety.
Additionally, the present invention provides a pharmaceutical formulation adapted
for the treatment of obesity, or for the treatment of obsessive/compulsive disorder, or for
the treatment of depression, or for the treatment of anxiety, each of which comprise a
compound of Formula I in association with a pharmaceutically acceptable carrier, diluent
or excipient.
In those instances where the disorders which can be treated by 5-HT2c agonists are
known by established and accepted classifications, their classifications can be found in
various sources. For example, at present, the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric

Association, Washington, D.C.), provides a diagnostic tool for identifying many of the
disorders described herein. Also, the International Classification of Diseases, Tenth
Revision (ICD-10), provides classifications for many of the disorders described herein.
The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and
classification systems for disorders described herein, including those as described in the
DSM-IV and ICD-10, and that terminology and classification systems evolve with
medical scientific progress.
The general chemical terms used throughout have their usual meanings. For
example, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon
group. The term "w-alkyl" refers to an unbranched alkyl group. By way of illustration,
but without limitation, the term "(C]-C2)alkyP' refers to methyl and ethyl. The term "(Cr
C3) M-alkyl" refers to methyl, ethyl, and propyl. The term "(Ci-Cj)alkyF' refers to methyl,
ethyl, propyl, and isopropyl. The term "(C1-C4) n-alkyl" refers to methyl, ethyl, n-propyl,
and w-butyl. The term "(C1-C4)alkyl" refers to methyl, ethyl, propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, and tert-butyl. The term "(C1-C6)alkyl" refers to all branched and
unbranched alkyl groups having from one to six carbon atoms. The term "(C3-C6)alkyl"
refers to all branched and unbranched alkyl groups having from three to six carbon atoms.
The term "(C2-C6)alkyl" refers to all branched and unbranched alkyl groups having from
two to six carbon atoms.
(Cx-Cy)alkyl may also be used in conjunction with other substituents to indicate a
branched or unbranched saturated hydrocarbon linker for the substituent, where x and y
indicate the range of carbon atoms permitted in the linker moiety. By way of illustration,
but without limitation, -(Co-Ci)alkyl refers to a single bond or a methylene linker moiety;
-(Co-C2)alkyl refers to a single bond, methylene, methyl-methylene, or ethylene linker
moiety; -(Co-C3)alkyl further includes trimethylene, alpha- or beta-methyl ethylene, or
ethyl methylene. -(C1-C2)alkyl, -(C1-C3)alkyl, -(C1-C4)alkyl, and -(CrC6)alkyl refer to
branched or unbranched alkylene linkers having from 1 to 2, 3, 4, or 6 carbons,
respectively.

The term "alkenyl" refers to a branched or unbranched unsaturated hydrocarbon
group. By way of illustration, but without limitation, the term "(C2-C6)alkenyl" refers to a
branched or unbranched hydrocarbon group having from 2 to 6 carbon atoms and 1 or
more carbon-carbon double bonds. Allyl means a propyl-2-en-1-yl moiety
(CH2=CH-CH2-).
The term "(C3-C7)cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl. Cycloalkylalkyl refers to a cycloalkyl moiety linked through
a branched or unbranched alkylene linker, as for example, but without limitation, -CH2-,
-CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH(CH2CH3)-,
and the like. (C3-C7)cycloalkyl(Co-Ci, 2or3)alkyl, refers to cycloalkyls linked through a
single bond (i.e. Co-alkyl) or an alkylene linker. Each alkyl, cycloalkyl, and
cycloalkylalkyl group may be optionally substituted as provided for herein.
The terms "alkoxy", "phenyloxy", "sulfonyloxy", and "carbonyloxy" refer to an
alkyl group, phenyl group, sulfonyl group, or carbonyl group, respectively, that is bonded
through an oxygen atom.
The terms "alkylthio", "trifluoromethylthio", "cycloalkylthio" ("cyclohexylthio"),
"phenylthio", and "furanylthio" refer to an alkyl group, trifluoromethyl group, cycloalkyl
(cyclohexyl) group, phenyl group, or furanyl group, respectively, that is bonded through a
sulfur atom.
The terms "alkylcarbonyl", "alkoxycarbonyl", "phenylcarbonyl", and
"phenyloxycarbonyl", refer to an alkyl, alkoxy, phenyl, or phenyloxy group bonded
through a carbonyl moiety.
The term "alkylcarbonyloxy" refers to an alkylcarbonyl group bonded through an
oxygen atom.

The terms "(C1-C6)alkylsulfinyl", "Ph1-(Co-C3)alkylsulfinyl", and
"Ar2-(Co-C3)alkylsulfinyl", refer to an alkyl, Ph'-(Co-C3)alkyl, or Ar2-(CO-C3)alkyl,
respectively, group bonded through a sulfinyl moiety (-SO-).
The terms "alkylsulfonyl" (/-butylsulfonyl), "(CrC7)cycloaIkylsulfonyl",
"phenylsulfonyl", "Ph'-(C0-C3)alkylsulfonyr', and "Ar2-(C0-C3)alkylsulfonyl", refer to an
alkyl (/-butyl), (C3-C7)cycloalkyl, phenyl, Ph'-(C0-C3)alkyl, or Ar2-(C0-C3)alkyl group
bonded through a sulfonyl moiety ( -SO2-).
The term "phenylamino" refers to a phenyl group bonded through a nitrogen atom.
The term "N-linked" means that the referenced moiety is linked through its
nitrogen atom, by way of illustration, but without limitation, N-Iinked Het1 means the
Het moiety is linked through a nitrogen atom in the ring of the Het moiety, and N-linked
Ar2 means the Ar2 moiety is linked through a nitrogen atom in the ring of the Ar2 moiety.
The term "halo" refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are
fluoro, chloro, and bromo. More preferred halo groups are fluoro and chloro.
The term "heterocycle" is taken to mean a saturated or unsaturated 4 to 7
membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and
sulfur, said ring optionally being benzofused. Exemplary saturated heterocycles, for the
purposes of the present invention, include azetidinyl, pyrrolidinyl, piperidinyl,
homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,
piperazinyl, and the like. Exemplary unsaturated heterocycles include, but are not limited
to, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl,
isoxazolyl, 1,2,3-oxadiazoIyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,
isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl,
and the like. Exemplary benzofused heterocyclic rings include, but are not limited to,
indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl,
dihydrobenzofuranyl, benzoxazolyl, benzo[l,3]dioxolyl, benzothiophenyl, benzothiazolyl,
quinolinyl, isoquinolinyl, benzopyranyl, dihydrobenzopyranyl, cinnolinyl, quinazolinyl

and the like, all of which may be optionally substituted as provided for herein, which also
includes optionally substituted on the benzene ring when the heterocycle is benzofused.
In one embodiment, preferred heterocycles include pyrrolidinyl, piperidinyl,
homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl,
furanyl, isoxazolyl, 1,2,4-oxadiazolyl, thiophenyl, thiazoiyl, 1,2,3-thiadiazolyl, pyridyl,
pyridazinyl, indolyl, dihydroindolyl, benzimidazolyl, benzofuranyl, dihydrobenzoruranyl,
benzoxazolyl, benzo[l,3]dioxolyl, benzothiophenyl, benzothiazolyl, quinolinyl,
isoquinolinyl, and benzopyranyl, all of which may be optionally substituted as provided
for herein.
In yet another embodiment, preferred heterocycles include pyridyl, pyridazinyl,
and thiophenyl.
The terms "gem-", "geminal", or "geminate" refer to two identical substituents
bonded to a common carbon atom, as for example, but without limitation, gem-methyl,
meaning two methyl groups bound to a common carbon atom, as for instance in a 3,3-
dimethyltetrahydrobenzofiiranyl group. For the purposes of this application, gem-ethano
means an ethylene substituent wherein both carbons are bound to the same carbon atom of
the substituted group to form a cyclopropyl moiety, as for example, but without limitation,
the ethano substituent on the 2-phenyl-(l,l-ethano)ethyIamino group below:

It is to be understood that when a basic definition of a group lists optionally
allowable substituents, and in another place that group is said to also optionally be
substituted with other recited substituents, then those other recited substituents are
intended to be added to the list of optionally allowable substituents listed in the basic
definition of the group. Conversely, if in another place that group is said to be
alternatively, optionally substituted with other recited substituents, then those other
recited substituents are intended to replace the list of optionally allowable substituents

recited in the basic definition of the substituent. For example, but without limitation, Ar2
has a basic definition that recites that any of the listed heteroaromatic groups may
"optionally be substituted with 1 to 3 substituents independently selected from the group
consisting of halo, cyano, -SCF3, (C1-C6)alkyl optionally further substituted with 1 to 6
fluoro substituents, and (C1-C6)alkoxy optionally further substituted with 1 to 6 fluoro
substituents, and wherein pyridyl and pyridazinyl may also optionally be substituted with
(C1-C6)alkylamino optionally further substituted with 1 to 6 fluoro substituents,
(C3-C7)cycloalkyl(C0-C3)alkyl, or (C3-C7)cycloalkyl(Co-C3)alkyl-amino." This is to be
understood to mean that any of the listed heteroaromatic groups may optionally be
substituted with [1 to 3 substituents independently selected from the group consisting of
halo, cyano, -SCF3, (CrC6)alkyl optionally further substituted with 1 to 6 fluoro
substituents, and (C1-C6)alkoxy optionally further substituted with 1 to 6 fluoro
substituents], and that when Ar2 is selected to be pyridyl or pyridazinyl, the list of
substituents selectable for the 1 to 3 substituents is expanded to also include
[(C1-C6)alkylamino optionally further substituted with 1 to 6 fluoro substituents, (C3-
C7)cycloalkyl(Co-C3)alkyl, and (C3-C7)cycloalkyl(Co-C3)alkyl-amino]. Likewise, in the
definition of R14, the terminology "wherein ... Ar2, wherein Ar2 is pyridyl, then R14 may
also, optionally be substituted with phenyl-CH=CH- or phenyl-C=C- ..." is understood to
mean that the list of substituents selectable for the 1 to 3 substituents optionally allowed
on Ar2 = pyridyl is again expanded to also include [phenyl-CH=CH- or phenyl-C=C- • • •]•
Conversely, later in the definition of R14, the terminology "wherein when Ar2 is pyridyl,
the pyridyl may alternatively, optionally be substituted with R28R29N-C(O)- and
optionally further substituted with one methyl, -CF3, cyano, or -SCF3 substituent, or with
1 to 2 halo substituents", is understood to mean that when R14 is selected to be Ar2 =
pyridyl, then the list of 1 to 3 independently selected substituents optionally allowable in
the basic definition of Ar2 may be superceded by "R28R29N-C(O)- and optionally further
substituted with one methyl, -CF3, cyano, or -SCF3 substituent, or with 1 to 2 halo
substituents."
The term "amino protecting group" as used in this specification refers to a
substituent commonly employed to block or protect the amino functionality while reacting
other functional groups on the compound. Examples of such amino protecting groups

include the formyl group, the trityl group, the acetyl group, the trichloroacetyl group, the
trifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, carbamoyl-
type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl
("FMOC"), t-butoxycarbonyl (t-BOC), and like amino protecting groups. The species of
amino protecting group employed is not critical so long as the derivatized amino group is
stable to the conditions of subsequent reactions on other positions of the molecule and can
be removed at the appropriate point without disrupting the remainder of the molecule.
The selection and use (addition and subsequent removal) of amino protecting groups is
well known within the ordinary skill of the art. Further examples of groups referred to by
the above terms are described by T. W. Greene and P. G. M. Wuts, "Protective Groups in
Organic Synthesis", 3rd edition, John Wiley and Sons, New York, NY, 1999, chapter 7,
hereafter referred to as "Greene".
The term "pharmaceutical" or "pharmaceutically acceptable" when used herein as
an adjective, means substantially non-toxic and substantially non-deleterious to the
recipient.
By "pharmaceutical composition" it is further meant that the carrier, solvent,
excipients and/or salt must be compatible with the active ingredient of the composition
(e.g. a compound of Formula I). It is understood by those of ordinary skill in this art that
the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally
interchangeable, and they are so used for the purposes of this application.
The term "effective amount" means an amount of a compound of Formula I which
is capable of activating 5-HT2C receptors and/or elicit a given pharmacological effect.
The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to
the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
It is understood that compounds of the present invention may exist as
stereoisomers. As such, all enantiomers, diastereomers, and mixtures thereof, are
included within the scope of the present invention. Where specific stereochemistries are

identified in this application, the Cahn-Prelog-Ingold designations of (R)- and (S)- and the
cis and trans designation of relative stereochemistry are used to refer to specific isomers
and relative stereochemistry. Known optical rotations are designated by (+) and (-) for
dextrorotatary and levorotatary, respectively. Where a chiral compound is resolved into
its isomers, but absolute configurations or optical rotations are not determined, the
isomers are arbitrarily designated as isomer 1, isomer 2, etc. While all enantiomers,
diastereomers, and mixtures thereof, are contemplated within the present invention,
preferred embodiments are single enantiomers and single diastereomers.
It is generally understood by those skilled in this art, that compounds intended for
use in pharmaceutical compositions are routinely, though not necessarily, converted to a
salt form in efforts to optimize such characteristics as the handling properties, stability,
pharmacokinetic, and/or bioavailability, etc. Methods for converting a compound to a
given salt form are well known in the art (see for example, Berge, S.M, Bighley, L.D., and
Monkhouse, D.C., J. Pharm. Sci., 66:1, (1977)). In that the compounds of the present
invention are amines and therefore basic in nature, they readily react with a wide variety
of pharmaceutically acceptable organic and inorganic acids to form pharmaceuticalIy
acceptable acid addition salts therewith. Such salts are also embodiments of this
invention.
Typical inorganic acids used to form such salts include hydrochloric,
hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric,
pyrophosphoric acid, and the like. Salts derived from organic acids, such as aliphatic
mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and
hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also
be used. Such pharmaceutically acceptable salts thus include chloride, bromide, iodide,
nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-
acetoxybenzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-1,4-
dicarboxylate, hexyne-l,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate,
fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,
malonate, mandelate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate,

propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,
benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate,
2-hydroxyethylsulfonate, methylsulfonate (mesylate), naphthalene- 1-sulfonate,
naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate,
tartrate, and the like.
It is well known that such compounds can form salts in various molar ratios with
the acid to provide, for example, the hemi-acid, mono-acid, di-acid salt, etc. Where in the
salt formation procedure, the acid is added in a specific stoichiometric ratio, unless
otherwise analyzed to confirm, the salt is presumed, but not known, to form in that molar
ratio. Terms such as "(acid)x" are understood to mean that the molar ratio of the salt
formed is not known and can not be presumed, as for example, but without limitation,
(HC1)X and (methanesulfonic acid)x.
Abbreviations used herein are defined as follows:
"2B-3 ethanol" means ethanol denatured with toluene.
"AIBN" means 2,2'-azobisisobutyronitrile.
"Anal. Calc'd" or "Anal. Calcd" means calculated elemental analysis.
"APCI" means atmospheric pressure chemical ionization.
"bp" means boiling point.
"BINAP" means rac-2,2'-bis(diphenylphosphino)-l,l'binaphthyl.
"Boc" or "f-Boc" means terr-butoxycarbonyl.
"Brine" means a saturated aqueous sodium chloride solution.
"CV" means calorific value of oxygen.
"DBU" means l,8-diazabicyclo[5.4.0]undec-7-ene.
"DCE" means 1,2-dichloroethane.
"DCM" means dichloromethane (i.e. methylene chloride, CH2CI2).
"DIBAL-H" means diisobutylaluminum hydride.
"DIEA" means .N,N-diisopropylethylamine.
"DMAP" means 4-(dimethylamino)pyridine.
"DME" means 1,2-dimethoxyethane.
"DMEA" means ivyV-dimethylethylamine.

"DMF" means Af./V-dimethylformamide.
"DMSO" means dimethylsulfoxide.
"DOI" means (±)-l-(2,5-dimethoxy-4-[125l]-iodophenyI)-2-aminopropane.
"EDC" means l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.
"EDTA" means ethylenediaminetetraacetic acid.
"EE" means energy expenditure.
"EtOAc" means ethyl acetate.
"GC-MS" means gas chromatography - mass spectrometry.
"GDP" means guanosine diphosphate.
"GTP" means guanosine triphosphate.
"GTPy[35S]" means guanosine triphosphate having the terminal phosphate
substituted with 35S in place of an oxygen.
"HATU" means O-(7-azabenzotriazoI-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
"HMPA" means hexamethylphosphoramide.
"HOBT" means 1-hydroxybenzotriazole hydrate.
"HPLC" means high-pressure liquid chromatography.
"HRMS" means high-resolution mass spectrometry.
"ISPA" means immunoadsorption scintillation proximity assay.
"TB-CPBA" means weta-chloroperoxybenzoic acid.
"mp" means melting point.
"Ms" in a chemical structure means the methanesulfonyl moiety (-SO2CH3).
"MS (ES+)" means mass spectroscopy using electrospray ionization.
"MTBE" means methyl r-butyl ether.
"NBS" means JV-bromosuccinimide.
"NMP" means l-methyl-2-pyrrolidinone.
"NMR" means nuclear magnetic resonance.
"Pd/C" means palladium on activated carbon.
"RQ" means respiratory quotient.
"SCX chromatography" means chromatography on an SCX column or cartridge.

"SCX column" or "SCX cartridge", as used herein, refers to a Varian Bond
Elute® silica based strong cation exchange resin column or disposable cartridge or
equivalent.
"Sudan III" means 1- [(4-phenylazo)phenylazo]-2-naphthalenol.
"Tf' in a chemical structure means the trifluoromethanesulfonyl moiety
(-SO2CF3).
"TFA" means trifluoroacetic acid.
"THF" means tetrahydrofiiran.
"TLC" means thin layer chromatography.
While all of the compounds of the present invention are useful as 5-HT2C agonists,
certain classes are preferred, as for example, compounds having any of the following
enumerated selections of substituents: Compounds wherein
1) R7 is halo;
2) R7 is chloro;
3) R7 is (C1-C6)alkyl optionally substituted with 1 to 6 fluoro substituents;
4) R7 is (C1-C3)alkyl optionally substituted with 1 to 6 fluoro substituents;
5) R7 is -CF3;
6) R7 is (C3-Ce)alkenyl optionally substituted with 1 to 6 fluoro substituents;
7) R7 is (C3-C6)alkenyl;
8) R7 is cyano;
9) R1"5 are each hydrogen;
10) R4 is methyl or ethyl;
11) R4 is methyl;
12) R3 is methyl;
13) R8 is hydrogen;
14) R9 is (C1-C3)alkoxy;
15) R9 is methoxy;
16) R9 is halo;
17) R9 is chloro;
18) R6 is -OC-R10;
19) R^isPh'-CCo-C^alkyl;
20) R^isPh'-CQ-C^alkyl;

21) R10 is Phenyl(Co-C3)alkyl;
22) R10 is (C3-C7)cycloalkyl(C0-C3)alkyl;
23) R!0is(C3-C7)cycloalkylmethyl;
24) R10 is (C4-C6)alkyl;
25) R10 is branched (Cr-QOalkyl;
26) R10 is (C|-C6)alkyl substituted with 2-6 fluoro substituents;
27) R10 is Ar'-CCH^alkyl;
28) R10 is Ar'-(C1-C2)alkyl;
29) R6 is -O-R12;
30) R12 is Ph2-(Co-C3)alkyl;
31) R12 is Ph2-(C1-C2)alkyl;
32) R12 is Ph2-(Ci-C2)alkyl and Ph2 is substituted with 1-3 halo substituents;
33) R12 is Ph2-(Ci-C2)alkyl and Ph2 is substituted with 1 -3 fluoro substituents;
34) R12 is Ph2-(Ci-C2)alkyl and Ph2 is substituted with cyano;
35) R12 is Ph2-(Ci-C2)alkyl and Ph2 is substituted with R30R31N-S(O)2-;
36) R12 is Ph2-(C1-C2)alkyl, Ph2 is substituted with R30R31N-S(O)2-, R30 is
(C1-C3)alkyl optionally further substituted with 1-3 fluoro substituents and
R31 is hydrogen;
37) R12 is Ai^-CCKyalkyl;
38) R12 is Ar^CK^alkyl;
39) R12 is Ar2-(C]-C2)alkyl and Ar2 is pyridyl, thiazolyl, oxazolyl, or pyrazolyl,
each optionally substituted with methyl;
40) R12 is benzazo)yl-(C1-C3)alkyl;
41) R12 is Ph2-C(O)-(C1-C3)alkyl,
42) R12 is Ph2-C(O)-(C1-C3)alkyl and Ph2 is substituted with 1 to 3 halo
substituents;
43) R12 is Ph2-C(O)-(C1-C3)alkyl and Ph2 is substituted with 1 to 3 halofluoro
substituents;
44) R12 is Ph'-S(O)2-;
45) R12 is (C1-C6)alkyl-O-C(O)-(C3-C6)alkyl;
46) R12 is (C1-C3jalkyl-O-C(O)-(C3-C6)alkyl;
47) R12 is R13-C(O)NH-(C2-C4)alkyl;

48) R12 is R13-C(O)NH-(C2-C4)alky] and R13 is Ph1;
49) R12 is Rl3-C(O)NH-(Cr-C4)alkyl, R13 is Ph1; substituted with 1 to 3 halo
substituents;
50) R12 is Rl3-C(O)NH-(C2-C4)alkyl and R!3 is (C3-C7)cycloalkyl;
51) R12 is R13-C(O)NH-(C2-C4)alkyl and R13 is pyridyl;
52) R12 is R13-C(O)NH-(C2-C4)alkyl and R13 is (C1-C3)alkoxy;
53) R12 is R13-C(O)NH-(Cr-C4)alkyl and R13 is (C3-C7)cycloalkyl;
54) R6 is -S-R14;
55) R6 is -S-R14 and R14 is Ph2;
56) R6 is -S-R14, R14 is Ph2 substituted with 1 to 3 halo substituents;

57) R6 is -S-R14, R14 is Ph2 substituted with cyano;
58) R6 is -S-R14, R14 is Ph2; substituted with cyano and 1 to 2 halo substituents;
59) R6 is -S-R14 and R14 is Ar2;
60) R6 is -S-R14, R14 is Ar2, and Ar2 is optionally substituted pyridyl or
pyridazinyl;
61) R6 is -S-R14, RM is Ar2, and Ar2 is optionally substituted thiophenyl,
thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, l,3>4-thiadiazolyl;
62) R6 is -S-R14 and R14 is tetrahydrofuranyl or tetrahydropyranyl;
63) R6 is -S-R14 and R14 is tetrahydrofuranyl or tetrahydropyranyl and the
tetrahydrofuranyl or tetrahydropyranyl is substituted with oxo on a carbon
adjacent to the ring oxygen;
64) R6is-S-R14andR14isRI5-L-;
65) L is (Ci-C2)alkylene;
66) L is branched (C2-C3)alkylene;
67) L is methyl-methylene;
68) L is di-methyl-methylene;
69) L is methyl-ethylene;
70) L is gem-di-methyl-ethylene;
71) L is gem-ethano-ethylene;
72) R15isPh2;
73) R15 is Ph2 substituted with 1 to 3 halo substituents;
74) R15 is Ph2 substituted with cyano;

75) R15 is Ph2 substituted with (C1-C6)alkoxy;
76) R15 is Ph2 substituted with (C1-C6)alkoxy optionally further substituted with
1 to 3 fluoro substituents;
77) R15 is Ph2 substituted with (C1-C6)alkoxy(Ci-Ci)alkyl;
78) R15 is Ph2 substituted with (C1-C6)alkoxy(Ci-Ci)alkyl further substituted
with 1 to 3 fluoro substituents;
79) R15 is Ph2 substituted with (C1-C6)alkylthio;
80) R15 is Ph2 substituted with (C1-C6)alkylthio optionally further substituted
with 1 to 3 fluoro substituents;
81) R15 is Ph2 substituted with (C1-C6)alkylthio(Ci-Ci)aIkyl;
82) R15 is Ph2 substituted with (C1-C6)alkylthio(Ct-Ci)alkyl further substituted
with 1 to 3 fluoro substituents;
83) R15 is Ph2 substituted with (C3-C7)cycloalkyl(Co-Ci)alkyl;
84) R15 is Ph2 substituted with (C1-C6)alkylsulfonyl(C(r-Ci)alkyl optionally
further substituted with 1 to 3 fluoro substituents;
85) R15 is Ph2 substituted with (C1-C6)alkylsulfinyl(Co-Ci)alkyl optionally
further substituted with 1 to 3 fluoro substituents;
86) R15 is Ph2 substituted with Ph'-CCo-COalkyl-sulfonyl;
87) R15 is Ph2 substituted with Ph'-CCo-COalkyl;
88) R15 is Ph2 substituted with R26R27N-;
89) R15 is Ph2 substituted with Het1;
90) R15 is Ph2 substituted with (C1-C6)alkyl-C(O)- optionally further substituted
with 1 to 3 fluoro substituents;
91) R15 is Ph2 substituted with (C1-C6)alkyl—O-C(O)- optionally further
substituted with 1 to 3 fluoro substituents;
92) R15 is Ph2 substituted with Ph1;
93) R15 is Ph2 substituted with Ph'(C0-C3)alkyl-O-;
94) R15 is Ph2 substituted with Ph'(C0-C3)alkyl-C(O)-;
95) R15 is Ph2 substituted with Ph1(C0-C3)alkyl-C(O)-;
96) R15 is Ph2 substituted with Ar2(C0-C3)alkyl-C(O)-;
97) R'5 is Ph2 substituted with Ar2(C0-C3)alkyl-C(O)- and Ar2 is pyrazolyl
optionally further substituted as provided for in Ar2;

98) R15 is Ph2 substituted with R28R29N-C(O)-;
99) R15 is Ph2 substituted with R28R29N-C(O)- and R28 is (C1-C6)alkyl;
100) R15 is Ph2 substituted with R28R29N-C(O)- and R28 is
(C3-C7)cycloatkyl(Co-C3)alkyl;
101) R15 is Ph2 substituted with R28R29N-C(O)- and R28 is Ph'-CCo-Cz^-alkyl
optionally substituted on the alkyl moiety when present with (C|-C3)alkyl,
dimethyl, or gem-ethano;
102) R15 is Ph2 substituted with R28R29N-C(O)- and R28 is Ar^Co-Cj^n-alkyl
optionally substituted on the alkyl moiety when present with (C1-C3)alkyl,
dimethyl, or gem-ethano;
103) R15 is Ph2 substituted with Het'-C(O)-;
104) R15 is Ph2 substituted with Het'-C(O)- further substituted with Ph1;
105) R^isAr2;
106) R15 is Ar2 further substituted with methyl;
107) R15 is Ar2 further substituted with (C3-C7)cycloalkyl(Co-C2)alkyl, Het1,
pyridyl, or phenyl optionally further substituted with methyl, -CF3, cyano,
-SCF3, or with 1 to 3 halo substituents;
108) R15 is pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl,
oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, or 1,3,4-
thiadiazolyl, any of which may optionally be substituted with 1 to 3
substituents selected from the group consisting of halo, cyano, -SCF3, (Ci-
C6)alkyl optionally further substituted with 1 to 6 fluoro, and (C1-C6)alkoxy
optionally further substituted with 1 to 6 fluoro.
109) R15 is pyridyl optionally further substituted as provided for in Ar2;
110) R15 is tetrahydrofuranyl or tetrahydropyranyl, either optionally being
substituted with an oxo substituent, or with one or two groups selected
independently from methyl and -CF3;
111) R15 is tetrahydrofuranyl or tetrahydropyranyl, being substituted with an oxo
substituent, and optionally being further substituted with one or two groups
selected independently from methyl and -CF3;
112) R15-L- is pyrid-2-yl-methyl;

113) R15-L-ispyrid-3-yl-methyl;
114) R15-L- is pyrid-2-yl-CH(CH3)-;
115) R15-L- is pyrid-3-yl-CH(CH3)-;
116) R15 is pyridazinyl optionally further substituted as provided for in Ar2;
117) R15-L- is pyridazin-2-yl-methyl;
118) R15-L- is pyridazin-3-yl-methyl;
119) Rl5-L- is pyridazin-2-yl-CH(CH3)-;
120) R15-L- is pyridazin-3-yl-CH(CH3)-;
121) R15 is pyridyl further substituted with (C3-C7)cycloalkyl(Co-C2)alkyl, Het1,
pyridyl, or phenyl optionally further substituted with methyl, -CF3, cyano,
-SCF3, or with 1 to 3 halo substituents;
122) R15is pyridazinyl further substituted with (C3-C7)cycloaIkyl(C Het1, pyridyl, or phenyl optionally further substituted with methyl, -CF3,
cyano, -SCF3, or with 1 to 3 halo substituents;
123) R15 is R22-C(O)-;
124) R15 is R22-C(O)- and R22 is (C1-C6)alkyl optionally substituted with 1 to 6
fluoro substituents;
125) R15 is R22-C(O)- and R22 is (C1-C6)alkoxy optionally substituted with 1 to 6
fluoro substituents;
126) R15 is R22-C(O)- and R22 is (C3-C7)cycloalkyl(Co-C3)alkyl;
127) R15 is R22-C(O)- and R22 is (C3-C7)cycloalkyl(Co-C3)alkyl-0-;
128) R15 is R22-C(O)- and R22 is Ph'-(Co-C3)alkyl;
129) R15 is R22-C(O)- and R22 is Ph'-(C0-C3)alkyl-O-;
130) R15 is R22-C(O)- and R22 is Ar2-(Co-C3)alkyl;
131) R15 is R22-C(O)- and R22 is Ar2-(C0-C3)alkyl-O-;
132) R15 is R22-C(O)- and R22 is R32R33N-;
133) R15 is phthalimido;
134) R15 is R17R18N-;
135) R15 is R17R18N- and R17 is (d-C3)alkoxy-C(O)-;
136) R15 is R17R18N- and R17 is (C3-C7)cycloalkyl(C0-C2)-C(O)-;
137) R15 is R17R18N- and R17 is Ph'-(C0-C2)-C(O)-;
138) R15 is R17R18N- and R17 is Ar^Co^)-^)-;

139) R15isR16O-;
140) R15 is R16O- and R16 is (C-C6)oalkyl-C(0)-;
141) R15 is R16O- and R16 is (C3-C7)cycloalkyl(Co-C2)-C(0)-;
142) R6 is R24R25N- and R24 is (C1-C6)alkoxy(C2-C5)alkyl optionally substituted
with 1 to 6 fluoro substituents;
143) R6 is R24R25N- and R24 is (C1-C6)alkylthio(C2-C5)alkyl optionally
substituted with 1 to 6 fluoro substituents;
144) R6 is R24R25N- and R24 is (C3-C7)cycloalkyl(Co-C,)alkyl-0-(C1-C5)alkyl;
145) R6 is R24R25N- and R24 is (C3-C7)cycloalkyl(Co-C,)alkyl-S-(Ci-C5)alkyl;
146) R6 is R24R25N- and R24 is phenyl(C1-C3) «-alkyl optionally substituted on
the «-alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano;
147) R6 is R24R25N- and R24 is Ph2-(C1-C3) «-alkyl optionally substituted on the
n-alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano;
148) R6 is R24R25N- and R24 is Ar^Co-Cs) w-alkyl optionally substituted on the n-
alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano;
149) R6 is R24R25N- and R24 is Ar2(C0-C3) w-alkyl optionally substituted on the n-
alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano,
wherein Ar2 contains a nitrogen atom, and Ar2 is substituted;
150) R6 is R24R25N- and R24 is Ar2(C0-C3) 77-alkyI optionally substituted on the n-
alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano,
wherein Ar2 contains a nitrogen atom, and Ar2 is substituted with
(Ci-Ce)alkoxy optionally further substituted with 1 to 6 fluoro,
(C1-C6)alkylamino optionally further substituted with 1 to 6 fluoro, or
(C3-C7)cycloalkyl(Co-C2)alkyl optionally further substituted with 1 to 6
fluoro;
151) R6 is R24R25N- and R24 is Ar^Co-Cs) /i-alkyl optionally substituted on the n-
alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano, and
wherein Ar2 is pyridyl or pyridazinyl and is substituted with (Ci-Ce)alkoxy
optionally further substituted with 1 to 6 fluoro, (C1-C6)alkylamino
optionally further substituted with 1 to 6 fluoro, or
(C3-C7)cycloalkyl(Co-C2)alkyl optionally further substituted with 1 to 6
fluoro;

152) R6 is R24R25N- and R24 is Ar2(C0-C3) «-alkyl optionally substituted on the n-
alkyl moiety when present with (C1-C3)alkyl, dimethyl, or gem-ethano, and
wherein Ar2 is pyridyl substituted with R28R29N-C(O)- and R28 is
(C3-C7)cycloalkyl(Co-C2)alkyl or Ph1 and R29 is hydrogen;
153) R6 is R24R25N- and R24 is Ar2(C0-C3) «-alkyl, wherein Ar2 is pyridyl
substituted with R28R29N-C(O)- and R28 is (C3-C7)cycloalkyl or phenyl
optionally substituted with 1 to 3 halo, preferably fluoro, and R29 is
hydrogen;
154) R6 is R24R25N- and R24 is Ph'-CCo-COalkyl-O^CrCsJalkyl;
155) R6 is R24R25N- and R24 is Ph1-(C0-Ci)alkyl-S-(C1-C5)alkyl;
156) R6 is R24R25N- and R24 is Ph1-(Co-C,)alkyl-C(0)NH-(C2-C4)alkyl;
157) R6 is R24R25N- and R24 isTV-(Co-Ci)alkyl-NH-C(0)NH-(C2-C4)aIkyl;
158) R6 is R24R25N- and R24 is pyridyl-(C0-C1)alkyl-C(O)NH-(C2-C4)alkyl
optionally substituted on the pyridyl moiety with methyl, -CF3, or 1 to 3 halo
substituents;
159) R6 is R24R25N- and R24 is pyridyl-(C0-Ci)alkyl-NH-C(O)NH-(C2-C4)alkyl
optionally substituted on the pyridyl moiety with methyl, -CF3, or 1 to 3 halo
substituents;
160) R6 is R24R25N- and R24 is A^-CCi-C^alkyl;
161) R6 is R24R25N- and R24 is Ar3-methyl;
It will be understood that the above classes may be combined to form additional
preferred classes. Exemplary combinations include, but are not limited to:
162) Any one of preferred embodiments 19) through 161) (the preferred
selections for R6), combined with any one of preferred embodiments 1)
through 9) (the preferred selections for R7);
163) Any one of preferred embodiments 19) through 161) (the preferred
selections for R6), wherein R7 is halogen;
164) Any one of preferred embodiments 19) through 161) (the preferred
selections for R6), wherein R7 is chloro;
165) A preferred combination according to 162), 163), or 164), wherein R1"5, and
R8 are each hydrogen;

166) A preferred combination according to 162), 163), or 164), wherein R1"5, R8
and R9, are each hydrogen.
167) Any one of preferred embodiments 37), 38), or 39), wherein R7 is other than
hydrogen;
168) Any one of preferred embodiments 37), 38), or 39), wherein R9 is hydrogen;
169) Any one of preferred embodiments 37), 38), or 39), wherein R7 is other than
hydrogen and R9 is hydrogen;
170) Any one of preferred embodiments 37), 38), or 39), wherein R7 is chloro and
R9 is hydrogen;
171) compounds of formula (I) wherein R6 is -C=C-R10 and wherein R10 is
selected from the values defined in any one of embodiments 19) to 28);
172) compounds of formula (I) wherein R6 is -O-R12 and wherein R12 is selected
from the values defined in any one of embodiments 30) to 53);
173) compounds of formula (I) wherein R5 is -S-R u and wherein R14 is selected
from the values defined in any one of embodiments 55) to 63) or 64)
wherein L is selected from the values of 65) to 71) and R15 is selected from
the values defined in any one of embodiments 72) to 141);
174) compounds of formula (I) wherein R6 is R24R25N- and wherein R24 is
selected from the values defined in any one of embodiments 142) to 161);
175) compounds according to embodiment 172) wherein R12 is selected from the
values defined in any one of embodiments 37), 38) or 39);
176) compounds of formula (I) wherein R7 is other than hydrogen;
177) compounds according to any one of embodiments 171) or 174) wherein R7
is other than hydrogen;
178) compounds according to any one of embodiments 171) or 174) wherein R7
is choro;
179) compounds according to any one of embodiments 171) or 174) wherein R9
is hydrogen;
180) compounds according to any one of embodiments 171) or 174) wherein R9
is (C1-C3)alkoxy;
181) compounds according to any one of embodiments 171) or 174) wherein R9
is methoxy;

182) compounds according to any one of embodiments 171) or 174) wherein R7
is choro and R9 is hydrogen;
183) compounds according to any one of embodiments 171) or 174) wherein R7
is choro and R9 is (C1-C3)alkoxy;
184) compounds according to any one of embodiments 171) or 174) wherein R7
is choro and R9 is methoxy;
185) compounds according to any one of embodiments 171) or 185) wherein R9
is hydrogen;
186) compounds according to any one of embodiments 171) or 185) wherein R9
is (C1-C3)alkoxy;
187) compounds according to any one of embodiments 171) or 185) wherein R9
is methoxy;
188) compounds according to any one of embodiments 171) or 187) wherein R1"5
are each hydrogen;
Generally, when R6 is -S-R14, then R15-L- is the more preferred R14. When R14 or
R15 is substituted Ar2, para-substitution is preferred. When L is present, particularly
preferred are methylene, and methyl-methylene. Particularly preferred R15-L- is when R15
is Ph2 and L is methylene. Also particularly preferred is when R15 is Ph2 and L is methyl-
methylene. Also particularly preferred is when R15 is Ar2 and L is methylene. Also
particularly preferred is when R15 is Ar2 and L is methyl-methylene.
Also generally, when R6 is -NR24R25, then Ph2-(C1-C3)-«-alkyl is particularly
preferred over phenyl(C1-C3)-«-alkyl.
Preferred compounds of formula (I) are those wherein
R6 is -C=C-R10 and wherein R10 is selected from the values defined in any
one of embodiments 19) to 28); or
R6 is -O-R12 and wherein R12 is selected from the values defined in any
one of embodiments 30) to 53); or
R6 is -S-R14 and wherein R14 is selected from the values defined in any one
of embodiments 55) to 63) or embodiment 64) wherein L is selected from

the values defined in any one of embodiments 65) to 71) and R15 is
selected from the values defined in any one of embodiments 72) to 111)
and 121 to 141), or Rl5-L- is selected from the values defined in any one of
embodiments 112) to 120); or
R6 is R24R25N- and wherein R24 is selected from the values defined in any
one of embodiments 143) to 161).
Particularly preferred compounds of formula (I) are those wherein R6 is -O-R12 and
wherein R12 is selected from the values defined in any one of embodiments 37), 38) or
39).
Further preferred compounds of formula (I) are those wherein R7 is other than
hydrogen. In particular, R7 is preferably selected from the values defined in any one of
embodiments 1) to 8). More preferably, R7 is selected from halo (especially chloro), (Ci-
C3)alkyl optionally substituted with 1 to 6 fluoro substituents (especially methyl, ethyl, n-
propyl or CF3), and cyano.
Particularly preferred compounds of formula (I) are those wherein R7 is halogen,
and in particular wherein R7 is chloro.
Preferred compounds of formula (I) are those wherein R9 is (C1-C3)alkoxy,
preferably methoxy, or halo, preferably chloro.
Also preferred are those compounds of formula (I) wherein R9 is hydrogen.
Particularly preferred compounds of formula (I) are those wherein R7 is other than
hydrogen and R9 is hydrogen, and most especially wherein R7 is chloro and R9 is
hydrogen.
Further preferred compounds of formula (I) are those wherein R1 is hydrogen.
Also preferred are those compounds of formula (I) wherein R2 is hydrogen.

Also preferred are those compounds of formula (I) wherein R3 is hydrogen or
methyl, and especially wherein R3 is hydrogen.
Another preferred class of compounds of formula (I) is that wherein R4 is hydrogen,
methyl or ethyl, particularly wherein R4 is hydrogen or methyl, and especially wherein R4
is hydrogen.
Further preferred are those compounds of formula wherein R5 is hydrogen.
Also preferred are those compounds of formula (I) wherein R8 is hydrogen.
One favored group of compounds of the present invention is that represented by
formula (la), and pharmaceutically acceptable salts thereof:

wherein
R7a is halogen, and especially chloro;
R9a is hydrogen, halogen or (C1-C3)alkoxy, particularly hydrogen, chloro or
methoxy, and especially hydrogen; and
R6 is as defined in relation to formula (I).
Specific preferred compounds of the present invention are those described in the
Examples herein, including the free bases and the pharmaceutically acceptable salts
thereof.
It will be appreciated that the preferred definitions of the various substituents
recited herein may be taken alone or in combination and, unless otherwise stated, apply to

the generic formula (I) for compounds of the present invention, as well as to the preferred
class of compounds represented by formula (la).
The compounds of the invention can be prepared according to the following
synthetic schemes by methods well known and appreciated in the art. Suitable reaction
conditions for the steps of these schemes are well known in the art and appropriate
substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will
be appreciated by those skilled in the art that synthetic intermediates may by isolated
and/or purified by various well known techniques as needed or desired, and that
frequently, it will be possible to use various intermediates directly in subsequent synthetic
steps with little or no purification. Furthermore, the skilled artisan will appreciate that in
some circumstances, the order in which moieties are introduced is not critical. The
particular order of steps required to produce the compounds of Formula I is dependent
upon the particular compound being synthesized, the starting compound, and the relative
liability of the substituted moieties as is well appreciated by those of ordinary skill in the
art. All substituents, unless otherwise indicated, are as previously defined, and all
reagents are well known and appreciated in the art.
Compounds of Formula I where R6 is an acetylene-linked substituent may be
prepared as illustrated in Scheme I where Pg is a suitable protecting group for a secondary
amine such as, but not limited to, 2,2,2-trifluoroacetyl or te/Y-butoxycarbonyl, and
variables R1, R2, R4, R5, R7, R8, R9 and R10 are as previously defined.

Mix the 6-triflate of the 2,3,4,5-tetrahydro-l//-benzo|W]azepines (a) with an
appropriately substituted acetylene, a suitable palladium/copper catalyst mixture in a
Scheme I

solvent, typically DMF, using triethylamine as base, and heat to afford the desired
compound (b). Deprotection reaction and the standard extractive and chromatographic
techniques afford the desired compound (la).
The appropriate 6-triflate of 2,3,4,5-tetrahydro-li7-benzo[*/]azepines (a) may be
prepared as described in Scheme II. Compound (a) may be prepared from 1-naphthol. 1-
Naphthol can be converted to 5-hydroxy-l,4-dihydronaphthalene (c) by Birch reduction
using ammonia and lithium metal at low temperature. Methylation of the 6-hydroxy
group affords the compound (d). Ozonolysis of (d) and subsequent reduction with
sodium borohydride provide the diol (e). After converting the two hydroxyl groups into
two good leaving groups, for example methanesulfonates, cyclize the compound (f) to the
6-methoxy-2,3,4,5-tetrahydro-l/f-benzo[cr]azepines (g) with aqueous ammonia under
pressure. Protect the ring nitrogen with a variety of alkyl halides, acid chlorides or
anhydrides such as trifluoroacetic anhydride to give compound (h). Subsequently convert
the methyl ether (h) to the phenol (i) with BBn in dichloromethane or other methods well
known in the literature [see for example, Greene and Wuts, Protective Groups in Organic
Synthesis, 3rd Ed., John Wiley and sons, Chapter III, New York (1999)].
Functionalization of the aromatic ring to introduce substituents R7, R8 and R9 are
well known in the art and very depending on the substitution desired. Subsequent
trifluoromethanesulfonylation of the 6-hydroxy (j) affords the desired 2,3,4,5-tetrahydro-
7#-benzo[d]azepines (a).


Alternately, compound (g) could be prepared from 1,2-bis(cyanomethyl)-3-
methoxybenzene (1), previously described in the literature (J. Med Chem. 1984,27, 918-
921), as shown in Scheme III below.

Compounds of Formula I where R6 is an oxygen-linked substituent may be
prepared as illustrated in Scheme IV where Pg is a suitable protecting group for secondary
amine, such as 2,2,2-trifluoroacetyl or tert-butoxycarbonyl, and variables R7, R9 and R12
are as previously defined.
Scheme IV


Compound (m) can be prepared by treating 6-hydroxy-2,3,4,5-tetrahydro-///-
benzo[d]azepines (j) with an appropriate alkylation reagent, such as an alkyl halide or
sulfonate, and a base in a suitable solvent, typically acetone, ethanol or acetonitrile,
followed by he standard extractive and chromatographic techniques. Deprotection of the
ring nitrogen gives the compound (Ib). Alternately, compound (m) can be obtained by
Mitsunobu reaction with an appropriate alcohol, a phosphine reagent such as
triphenylphosphine, and diethyl azodicarboxylate (DEAD) or l,l'-(azodicarbonyl)-
dipiperidine in an anhydrous solvent, for example THF.
Compounds of Formula Ic where R6 is a nitrogen-linked substituent may be
prepared as illustrated in the Scheme V. The 6-triflate protected 2,3,4,5-tetrahydro-7//-
benzo[d]azepines (a) can be converted to the compounds (n), under Buchwald conditions,
by treatment with an appropriate amine (q) in the presence of an effective palladium
catalyst, and a base in a suitable solvent, typically toluene or 1,4-dioxane under an inert
atmosphere. Introduction of a second substituent R25, if needed, may be performed.
Standard work-up and chromatographic techniques followed by deprotection, give the
compound (Ic).
Alternately 6-amino-2,3,4,5-tetrahydro-///-benzo[d]azepines (p) can be
transformed to the desired compounds (n) by reaction with an appropriate bromide (r),
and an appropriate base in a suitable solvent.
Bromides (r) are either commercially available or may be prepared by methods
well known to the skilled artisan. Amines (q) are either commercially available or may be
prepared by methods well known to the skilled artisan.


Compounds of Formula I where the R6 is a sulfur-linked substhuent may be
prepared as illustrated in the Scheme VI.


Heat the appropriately substituted 3-(tert-butoxycarbonyl-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[d]azepine (s) with an appropriate
base in a suitable solvent, such as methanol, to obtain the intermediate thiol (t). Isolate the
intermediate thiol (t), if required, and treat it with an appropriate electrophile (halide or
alkyl sulfonate). Isolate the compound (u) by standard extractive and chromatographic
techniques and deprotect to afford the desired compound (Id).
The requisite halides or alkyl sulfonates are either commercially available or may
be prepared by methods well known to the skilled artisan.
The skilled artisan will also appreciate that not all of the substituents in the
compounds of Formula I will tolerate certain reaction conditions employed to synthesize
the compounds. These moieties may be introduced at a convenient point in the synthesis,
or may be protected and then deprotected as necessary or desired, as is well known in the
art. The skilled artisan will appreciate that the protecting groups may be removed at any
convenient point in the synthesis of the compounds of the present invention. Methods for
introducing and removing protecting groups used in this invention are well known in the
art; see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed.,
John Wiley and sons, New York (1999).

The following Preparations and Examples are illustrative of methods useful for the
synthesis of the compounds of the present invention. Exemplified compounds are also
particularly preferred compounds of the present invention.
General Procedure 1-1
Dissolve the appropriately substituted 3-(2,2,2- trifluoroacetyl)-2,3,4,5-tetrahydro-
l#-benzo[c/]azepine in ammonia/methanol solution (1.0-7.0 M). Stir for 1-16 h at
ambient temperature unless otherwise specified. Remove the volatiles in vacuo. Purify
by chromatography on silica gel eluting with 1-20% 2M ammonia/methanol in DCM, or
by SCX chromatography eluting with 1.0-7.0 M ammonia in methanol.
General Procedure 1-2
Dissolve the appropriately substituted 3-(2,2,2- trifluoroacetyl)-2,3,4,5-tetrahydro-
l/Z-benzofrfJazepine (1.0 equiv.) in methanol. Add a 0.5 M aqueous solution of
potassium carbonate (4.0 equiv.) and stir at ambient temperature for 6 h. Concentrate in
vacuo and partition the residue between water and DCM. Extract the aqueous phase twice
with DCM. Dry the combined organic extracts over Na2SC>4, filter and concentrate in
vacuo. If needed, purify by chromatography on silica gel eluting with 1-20% 2M
ammonia/methanol in DCM, or by SCX chromatography eluting with 1.0-7.0 M ammonia
in methanol.
General Procedure 1-3
Dissolve the appropriately substituted 3-(2,2,2- trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[J]azepine (1.0 equiv.) in methanol or ethanol (0.1 to 2M solution) and add
from 10-50% by volume of a 1.0-5.0 N aqueous solution of sodium hydroxide or lithium
hydroxide. Stir the reaction mixture at ambient temperature for 0.25-16 h and concentrate
in vacuo. Partition the residue between EtOAc or DCM and water. Separate and dry the
organic fraction over Na2SC>4, filter, and concentrate in vacuo. Purify by SCX
chromatography, followed by chromatography on silica gel eluting with 1-20% 2M
ammonia/methanol in DCM or reverse phase HPLC.

General Procedure 1-4
Dissolve the appropriately substituted 3-ter/-butoxycarbonyl-2,3,4,5-tetrahydro-
l//-benzo[]azepine in 4M hydrogen chloride in dioxane or 1M hydrogen chloride in
ethyl ether and stir the mixture for 2-16 h at ambient temperature unless otherwise
specified. Remove the solvent in vacuo. If a solid is obtained, wash the solid with ether
and filter under vacuum to afford the desired hydrochloride salt. If an oil is obtained,
dissolve the oil in the minimal volume of DCM, methanol or EtOAc and add ether to
precipitate out the solid. Remove the solvent in vacuo, wash the solid with ether and
filter. Dry the solid in vacuo or under a stream of nitrogen.
General Procedure 1-5
Dissolve the appropriately substituted 3-rm-butoxycarbonyl-2,3,4,5-tetrahydro-
l//-benzo[|azepine in a mixture of trifluoroacetic acid/DCM (from 1:0 to 1:10 ratio) and
stir the reaction for 1-16 h at ambient temperature. Concentrate in vacuo and either
subject the residue to SCX chromatography or partition the residue between saturated
aqueous NaHCC>3 and DCM or EtOAc. Dry the organic layer over Na2SC>4 and
concentrate in vacuo. Purify by either chromatography on silica gel (eluting with 1-20%
2M ammonia/methanol in DCM) or reverse phase HPLC.
General Procedure 1-6
Add acetyl chloride (40 equiv.) to cold methanol (0 °C) and stir for 5 min. Then
add a solution of the appropriately substituted 7-chloro-3-(ter/-butoxycarbonyl)-2,3,4,5-
tetrahydro-l//-benzo[c/]azepine (1 equiv.) in methanol. Stir the reaction at ambient
temperature for 12 h. Remove the solvent in vacuo, basify with saturated aqueous
NaHCCh and extract three times with DCM. Dry the combined organic extracts over
Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel, eluting
with 1-20% 2M ammonia/methanol in DCM.
General Procedure 2-1
Dissolve the purified free base (1 equiv.) in acetone, ether or methanol and add a
solution of succinic acid (1 equiv.) in a minimal volume of acetone or methanol. Stir for
1 h at ambient temperature. Concentrate to an oil, add a minimal volume of DCM and

ethyl ether to precipitate out the salt. Alternatively, to precipitate out the salt, allow the
reaction mixture to stand 1-16 h at ambient temperature, 4 °C or -10 °C and add ether or
hexane. Filter and wash the solid with ether or hexane to obtain the succinate salt.
Alternatively, evaporate the solvent in vacuo, wash the solid with ether and filter or
decant the solvent to obtain the succinate as a solid. Dry the solid in vacuo or under a
stream of nitrogen.
General Procedure 2-2
Dissolve the purified free base (1 equiv.) in a minimal volume of acetone,
dioxane, methanol or DCM and add an excess of 4M hydrogen chloride in dioxane or a
1M solution of hydrogen chloride in ethyl ether. Stir for 1 h and evaporate the solvent to
obtain the salt as a solid. Alternatively, allow the reaction mixture to stand 1 to 16 h at
ambient temperature and add ether or hexane to precipitate out the salt. Filter and wash
the solid with ether or hexane to obtain the salt as a solid. Alternatively, evaporate the
solvent in vacuo, wash the solid with ether, filter or decant the solvent to obtain the
hydrochloride salt as a solid. Dry the solid in vacuo or under a stream of nitrogen.
General Procedure 2-3
Dissolve the purified free base in methanol, add a solution of ammonium chloride
(1 equiv.) in methanol and stir for 1 h. Slowly remove the volatiles in vacuo. Dissolve
the residue in methanol and remove most of the solvent in vacuo. Add anhydrous ethyl
ether or EtOAc to precipitate out the hydrochloride salt. Collect the solid, wash the solid
with ether and then dry the solid in vacuo or under a stream of nitrogen.
General Procedure 2-4
Dissolve the purified free base (1.0 equiv.) in methanol. Add a 0.5 M solution of
methanesulfonic acid in methanol (2.0 equiv). Mix well, stir for 1 h, then remove the
solvent in vacuo. Dissolve the residue into a minimal volume of DCM. Add ethyl ether
to precipitate out the solid. Remove the solvent in vacuo to form a foam. Dry in vacuo or
under a stream of nitrogen to obtain the methanosulfonic acid salt.
General Procedure 2-5

Dissolve the purified free base (1 equiv.) in a minimal volume of acetone and add
a solution of oxalic acid (1 equiv.) in a minimal volume of acetone. Allow the mixture to
stand 10 min to 16 h at ambient temperature to -10°C, and/or add ether or hexane to
precipitate out the solid. Filter and wash the solid with ether or hexane to obtain the
oxalic acid salt as a solid. Dry the solid in vacuo or under a stream of nitrogen.
General Procedure 2-6
Dissolve the purified free base (1 equiv.) in a minimal volume of cyclohexane,
isohexane, chloroform, dichloromethane, methanol or a mixture thereof and add a
solution of (I)-tartaric acid in isopropanol or methanol. If a solid precipitate out, filter
and wash the solid with ether, cyclohexane, isohexane or EtOAc. If no solid formation is
observed, remove all the volatiles in vacuo to form a foam. Dry in vacuo or under a
stream of nitrogen to obtain the tartaric acid salt.
General Procedure 3
Dissolve the appropriately substituted 3-ter/-butoxycarbonyl-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro- l//-benzo[ trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//Lbenzo[rf]azepine(l
equiv.), PdCl2(PPh3)2 (0.1 equiv.), tetrabutyl ammonium iodide (3 equiv.), and copper(I)
iodide (0.3 equiv.) in triethylamine/DMF (1:5). Stir the mixture for 5 min at ambient
temperature, add the appropriately substituted acetylene (2 equiv.) and heat at 70 °C for 2-
16 h in a sealed tube. Cool the reaction mixture to ambient temperature, dilute with
EtOAc/hexane (1:1) and wash with water. Dry the organic fraction over Na2SC>4, filter
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc mixtures.
Preparation 1
7-Chloro-3-(2,2;2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine


5-Methoxv-l,4-dihvdronaphthalene: Add powdered potassium carbonate (193.1 g,
1.397 mol) to a solution of 5-hydroxy-l,4-dihydronaphthalene [68.08 g, 90% potency
based on 'H-NMR, 0.4657 mol, from Societa Italiana Medicinala Scandicci, s.r.l.,
Reggello (Firenze), Italy] in ethanol (700 mL). Cool the solution to 0°C with ice/water
and add dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the
temperature between 5°C and 10°C. Then heat the reaction mixture to 40°C until the
TLC (10:1 hexane/EtOAc) shows the absence of starting material (about 2 h). Filter off
the solids by vacuum filtration and remove the solvent in vacuo. Dilute the residual
brown oil with diethyl ether (500 mL), wash with 10% aqueous NH4OH (500 mL), water
(500 mL), brine (500 mL), dry the organic layer over Na2SQt, filter and concentrate in
vacuo to give the crude product as a brown oil (73 g). Purify the crude product by short
path distillation under vacuum (bp 120-130°C/ 5 Torr) to give the desired intermediate as
a clear oil (69.0 g, 92.5% potency corrected) (contains some l,2,3,4-tetrahydro-5-
methoxynaphthalene as an impurity). 'H NMR (300 MHz, CDC13), 87.15 (t, 1H, J= 7.9),
6.72 (dd, 2H, 7= 15.7, 7.9), 5.93-5.88 (m, 2H), 3.83 (s, 3H), 3.42-3.39 (m, 2H), 3.30-3.28
(m, 2 H); Rf = 0.58 eluting with 10:1 hexane/EtOAc.
2,3-Bis-(2-hvdroxvethyl)-l-methoxvbenzene: Charge a four-neck 5 L flask equipped
with an over-head mechanical stirrer, reflux condenser, thermocouple, and gas dispersion
apparatus with 5-methoxy-l,4-dihydronaphthalene (264.54 g, 89.5% potency based on
'H-NMR, 1.478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Add sudan III (10 mg) to
give a faint red color. Cool the solution to -65 °C or lower, then pass O3 through the

solution until the solution turns a light yellow color and the TLC (10:1 hexane/EtOAc,
KMnC>4 stain) shows the absence of the starting material (about 30 h). Transfer the
solution via cannula into a slurry of NaBH4 (97.8 g, 2.59 mol) in 2B-3 ethanol (500 mL)
cooled in ice/water. It is important that the temperature be maintained at or above 0°C, as
for example between 0°C and 10°C, throughout the transfer to ensure the ozonide is
completely reduced to the diol. After the transfer is complete, warm the solution to
ambient temperature and stir for about 30 min. Cool the slurry to 0°C with ice/water then
slowly add acetone (540 mL, 7.4 mol) to remove excess NaBRj. After all the solids
dissolve, remove the solvent in vacuo. Dissolve the yellow solid in DCM (1 L) and water
(1 L), separate the layers and extract the aqueous layer with DCM (750 mL). Wash the
combined organic layers with brine (1.5 L), add toluene (750 mL) and remove the solvent
in vacuo. Dissolve the solid in DCM (500 mL) with heating, then add toluene (750 mL)
and concentrate the solution in vacuo to give the desired intermediate as a light yellow
solid (283.7 g, 89% potency corrected, mp 82-83°C) (contains l,2,3,4-tetrahydro-5-
methoxynaphthalene as an impurity (8.6%)). Further purify the product by vacuum drying
overnight at 75°C, 5 Torr, to remove all but trace amount of the l,2,3,4-tetrahydro-5-
methoxynaphthalene impurity. 'H NMR (300 MHz, CDC13), 5 7.16 (dd, 1H, J= 8.2,
7.6), 6.83 (s, 1H, J= 7.0), 6.76 (s, 1H, J= 8.2), 3.85-3.77 (m, 7H), 3.01-2.91 (m, 4H),
2.35 (s, 2H); 13CNMR (300 MHz, DMSO-rf6), 5 157.5, 138.9, 126.5, 125.2, 122.0, 108.4,
62.1, 60.5, 55.3, 36.1, 29.6; IR(KBr): 3006, 2960, 2886, 2829, 1583, 1461, 1440, 1264,
1091, 1041 cm"1; MS (ES+) m/z 178 (M+H)+; Anal. Calc'd for C, iH,6O3: C, 67.32; H,
8.22; N, 0. Found: C, 67.26, H, 8.10, N, 0.21; Rf = 0.23 eluting with 95:5
DCM/methanol.
2,3-Bis-(2-methanesulfonyloxvethvr)-l-methoxybenzene: To a slurry of 2,3-bis-(2-
hydroxyethyl)-l-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g,
0.774 mol, 3 equiv.) in DCM (500 mL) at 0°C, add dropwise a solution of
methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min.
The addition is exothermic and the methanesulfonyl chloride is added at a rate to keep the
temperature below 10°C. After the addition is complete, warm the reaction to ambient
temperature. Wash the solution with water (2 x 500 mL), and then brine (750 mL). Dry

the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired
intermediate as a dark yellow oil (87.4 g, 96.2%), which is used in the next reaction
without further purification. An analytical sample is obtained by flash column
chromatography eluting with 100% diethyl ether. 'H NMR (300 MHz, CDC13), 8 7.20 (t,
1H, J= 7.9), 6.82 (s, 1H, J= 7.2), 6.80 (s, 1H, J= 8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H),
3.16-3.09 (m, 4H), 2.91 (s, 3H), 2.87 (s, 3H); 13C NMR (300 MHz, CDC13), 5 158.07,
136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47;
I3C NMR (300 MHz, DMSO-cfc), 5 157.58, 136.79, 127.81, 122.91, 122.00, 109.33,
70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8, 1469.4, 1358.51,
1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm'1; MS (ES+) m/z 257 (M+H)+; Anal.
Calc'd. for C,3H2o07S2: C, 44.31; H, 5.72; N, 0. Found: C, 44.22, H, 5.68, N, 0.13; Rf=
0.72 eluting with 95:5 DCM/methanol.
6-Methoxv-23,4,5-tetrahydro-l//-benzo[(/lazepine: Dissolve 2,3-bis-(2-
methanesulfonyloxyethyl)-l-methoxybenzene (474.4 g, 1.346 mol) in acetonitrile (7 L)
and split the mixture into two equal lots. In two separate runs, add concentrated aqueous
NH4OH (3.5 L) and charge the solution to a pressure vessel (PARR apparatus). Heat the
solution in a closed reactor to 100°C over 20 min (internal pressure reaches about 100
psi), and maintain at 100°C until the reaction is complete (about 1 h, HPLC monitored).
Cool the reaction mixture to ambient temperature. Combine the two lots and remove the
solvent in vacuo. Dissolve the residue in MTBE (3.5 L) and water (3.5 L). Adjust the pH
to 6.5 using 2M aqueous NaOH or 1M aqueous HC1 as appropriate (typically the pH is
about pH=5.1 and the adjustment requires about 50 mL 2M aqueous NaOH). Discard the
organic layer, adjust the aqueous layer to pH=13 using 50% NaOH (about 150 mL).
Extract with MTBE (2 x 3.5 L), wash the combined organic layers with brine (3.5 L), dry
over Na2SO4, filter and concentrate in vacuo to give the title compound as a crude yellow
oil that solidifies upon standing (179.3 g). Use the material for the next step without
further purification. Prepare an analytical sample by purification by two Kugelrohr
distillations to give a clear oil that solidifies upon standing, mp 44.3-45.0°C. I3C NMR
(300 MHz, DMSO-de) D 156.1, 144.4, 130.3, 126.2, 121.5, 108.9, 55.5, 48.2, 47.9, 39.9,

29.1; MS (ES+) m/z 163 (M+H)+; Anal. Calc'd for C,iH15NO: C, 74.54; H, 8.53; N, 7.90.
Found: C, 74.28, H, 8.62, N, 7.86.
6-Methoxv-2,3,4,5-tetrahvdro-l/^benzo[ methoxy-2,3,4,5-tetrahydro-l//-benzo[rf)azepine (35.1 g, 0.198 mol) in 2B-3 ethanol (250
mL), heat the solution to reflux and add 2M HC1 in ethanol (108.9 mL, 0.218 mol, 1.1
equiv.). Slowly add heptane (700 mL) over 10 min, then remove the heating mantle and
cool the solution to ambient temperature, and finally continue the cooling with an
ice/water mixture. Collect the resulting solid by vacuum filtration and wash with cold
ethanol:heptane (1:2) (3 x 100 mL), air-dry for 15 min under vacuum, then further dry the
product in a vacuum oven at 60°C for 1 h to give the desired intermediate as a white
granular solid (35.53 g, 63%): mp 246.6-246.9°C; 'H NMR (300 MHz, DMSO-40, 5
9.82 (broad s, 1H), 7.12 (dd, 1H, J= 7.6, 7.9), 6.88 (d, 1H J= 8.2), 6.78 (d, 1H, 7= 7.3),
3.75 (s, 3H), 3.20-3.00 (m, 8H); 13C NMR (300 MHz, DMSO-4$), 8 156.2, 141.3, 127.4,
127.2, 121.6, 109.7, 55.7, 44.9, 44.7, 31.6, 21.7; MS (ES+) m/z 178 (M+H)+; Anal. Calc'd
for C, ,H15C1NO: C, 62.12; H, 7.11; N, 6.59. Found: C, 61.95, H, 7.64, N, 6.58.
6-McthQxy-3-(2,2,2-trifluoroacetvl>-23,4,5-tetrahvdro-li/-benzol(/1azepine: Toa
slurry of 6-methoxy-2,3,4,5-tetrahydro-l//-benzo[e0azepine hydrochloride (35.3 g, 0.165
mol, 1 equiv.) and triethylamine (69.1 mL, 0.496 mol, 3 equiv.) in DCM (300 mL) cooled
at 0°C with ice/water, add dropwise a solution of trifluoroacetic anhydride (25.7 mL,
0.182 mol, 1.1 equiv.) in DCM (40 mL) over 30 min, but at a rate that maintains the
temperature below 10°C. After the addition is complete, warm the reaction mixture to
ambient temperature and stir until the reaction is complete (verify by TLC using 9:1
CH2Cl2:methanol, about 2 h.). Wash the solution with water (2 x 350 mL), and then brine
(350 mL), dry the organic layer over Na2SO4, filter and concentrate in vacua to give
desired intermediate as a yellow oil that solidifies upon standing (44.9 g, 96%). Use the
material without further purification in the next step. Prepare an analytical sample by
chromatography on silica gel eluting with 40% diethyl ether in hexane, mp 74-76°C. *H
NMR (300 MHz, CDC13), 8 7.16-7.11 (m, 1H), 6.81-6.74 (m, 2H), 3.81 (s, 3H), 3.79-3.64
(m, 4H), 3.11-3.07 (m, 2H), 2.99-2.95 (m, 2H); 'H NMR (300 MHz, DMSO-cfc), 8 7.13

(dd, 1H,/= 1.5, 7.0), 7.08 (d, \H,J= 1.5), 6.88-6.74 (m, 1H), 3.75 (s, 3H), 3.67-3.61 (m,
4H), 3.04-2.92 (m, 4H); 13C NMR (300 MHz, DMSO-d6), 8 156.43. 156.38, 155.06,
155.00, 154.60, 154.54, 154.14, 154.08, 141.31, 141.04, 127.44, 127.18, 127.05, 127.01,
122.27, 121.94, 121.90, 118.46, 114.64, 110.80, 109.52, 109.41,55.63,55.61,47.11,
47.07, 46.67, 46.63, 45.61, 45.16, 35.90, 34.65, 26.18, 24.91; Anal. Calc'd for
Q3H14F3NQ2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.17, H, 5.27, N, 5.08.
6-Hydroxy-3-(2>2Jl-trifluoroacetvl)-23,4,5-tetrahvdro-l/r-benzo[tflazepine: To a 1M
solution of BBr3 (1.1 L, 1.6 equiv.), cooled at 0°C with an ice-water bath, add 6-methoxy-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li7-benzo[rf]azepine (187 g, 0.684 mol) in
DCM (200 mL) over 1 h., while maintaining the temperature between 0°C and 10°C.
Warm the reaction mixture to ambient temperature and stir until HPLC indicates
completion of the reaction (about 2 h.). Cool the solution to 0°C and transfer it via
cannula into an ice/water solution (1.2 L), thereby precipitating the product as a white
"selid. Add EtOAc (2 L) to dissolve most of the precipitate, separate the layers and
concentrate the organic layer in vacua. Extract the aqueous layer three times with EtOAc
(2 x 2 L, 1 x 1 L). Wash the combined organic layers with water (2 L), and then brine (2
L), dry over Na2SO4, filter and concentrate in vacuo to give the desired intermediate as a
light yellow solid (166.3 g, 94%). Use the product for the next step without further
purification. Prepare an analytical sample by chromatography on silica gel eluting with
40% diethyl ether in hexane: mp 183.0-185.2°C. ]H NMR (300 MHz, DMSO-d6), 5 9.39
(s, 1H), 6.94-6.88 (m, 1H), 6.72-6.68 (m, 1H), 6.61-6.57 (m, 1H), 3.67-3.32 (m, 4H),
2.99-2.86 (m, 4H); 13C NMR (300 MHz, DMSO-efc), 8 154.50, 141.47, 141.18, 126.77,
126.64, 125.77, 125.33, 120.38, 120.32, 118.49, 114.67, 113.64, 113.47,47.31,47.27,
47.00, 46.96, 45.83, 45.49, 36.17, 34.93, 26.46, 25.18, 20.66, 14.00; MS (ES+) m/z 260
(M+H)+; Anal. Calc'd. for Ci2Hi2F3NO2: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.51, H,
4.71, N, 5.29.
7-Chloro-6-hydroxv-3-(2.2.2-trifluoroaeetvn-2J,4,5-tetrahvdro-lg-benzoftflazepine:
Heat a mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lJH'-
benzo[J]azepine (120 g, 0.4629 mol) and toluene (14.4 L) to 70°C for 45 min until most

of the starting material is dissolved. Add diisobutylamine (1.197 g, 1.62 mL, 9.26 mmol)
followed by addition of sulfuryl chloride (62.48 g, 37.19 mL, 0.463 mol) in toluene (360
mL) over 20 min. Stir the reaction mixture for 50 min and then add additional sulfuryl
chloride (4.536 g, 2.70 mL, 0.0336 mol) neat and stir the reaction mixture for 15 min at
70°C. Cool the reaction mixture to 24°C over 30 min and then add IN hydrochloric acid
(2.00 L). Separate, wash the organic layer with saturated aqueous NaHCCb (2.00 L),
brine (2.00 L) and then dry over Na2SO4. Filter and remove the solvent with a rotary
evaporator at 70°C until about 672.5 g remains using the minimum effective vacuum in
order to maintain a vapor phase sufficient to prevent drying above the solvent line and
self-seeding, thus preventing crystallization under these conditions. Using toluene heated
to 70°C, transfer the light-yellow solution to a preheated (70°C) 3-neck flask equipped
with a mechanical stirrer. Lower the temperature to 58°C over 1 h. If available, seed the
solution with crystals of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l/f-benzo[ reduce the temperature further to 55°C and observe the initiation of the crystallization
process. Hold the temperature at 55°C for 2 h. followed by 4 h. at 45°C, then turn off the
heat allowing the mixture to slowly reach 24°C (ambient temperature). After stirring for 8
h. with the heat off, cool the mixture to 0°C for 2 h. followed by 2 h. at -10°C. Collect the
resulting dense, white, granular crystals by vacuum filtration at -10°C. Rinse the crystals
twice with cold (-10°C) toluene and vacuum dry at 50°C, 5 Torr, for 12 h., to obtain the
desired intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp 133-134°C. MS
(ES+) m/z 294 (M+H)+. Anal. Calc'd for CnHnClFsNOz: C, 49.08; H, 3.78; N, 4.77; Cl,
12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32.
7-Chloro-3-f2.2,2-trifluoroacetvn-6-trifluoromethanesulfonyloxv-2J.4,5-tetrahYdro-
l/7-benzo[tf]azepine: Cool a solution of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine (60 g, 0.204 mol), triethylamine (62.6 mL, 0.448
mol, 2.2 equiv.), and DCM (590 mL) in an ice bath and add dropwise
trifluoromethanesulfonic anhydride (43.5 mL, 0.258 mol, 1.26 equiv.) over 70 min.
Remove the ice bath and stir the reaction mixture for 2 h. Wash the reaction mixture
sequentially with water (500 mL), IN aqueous HC1 (500 mL), water (500 mL), and brine
(500 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo to give the crude

product as a brown solid (90 g). Dissolve the solid in warm toluene (200 mL). Further
purify by plug filtration chromatography over silica gel (500 g) eluting sequentially with
hexane (1 L), hexane/EtOAc (9:1, 1L), hexane/EtOAc (4:1, 1L), and hexane/EtOAc (7:3,
9L). Pool the eluents and evaporate the solvent to obtain the product as a yellow tan solid
(86.3 g). Dissolve the solid in warm EtOAc (86 mL) and then add hexane (700 mL). If
available, seed the solution with crystals of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanelsulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cf)azepine from a prior
synthesis to enhance crystallization. Allow the mixture to stand at ambient temperature
for 30 min. Cool the mixture at about -10°C for 2 h., filter, rinse the crystals with cold (-
10°C) hexane/EtOAc, and air-dry on the filter under vacuum to obtain the title compound
as a first crop of crystals (73.54 g). Concentrate the mother liquor to obtain a solid (12.7
g). Recrystallize the solid in a mixture of EtOAc/hexane (15 mL:121 mL) to obtain
additional title compound (7.65 g, total yield: 81.19 g, 93%).
Preparation 2
3-(2r2,2-Trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2r3,4,5-tetrahydro-li/-
benzo[
Cool a solution of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-ltf-
benzo[ in a cryogenic bath set at -30 °C and add dropwise trifluoromethanesulfonic anhydride
(1.7 mL, 10.1 mmol) over 20 min. Stir at -30°C for 2 h and then warm to ambient
temperature overnight. Wash the reaction mixture sequentially with water (100 mL), IN
aqueous HC1 (100 mL), water (200 mL), and brine (200 mL). Dry the organic layer over
Na2SC>4 and concentrate in vacuo to give the title compound as a colorless to light yellow
oil (2.7 g, 89%) that was used without purification. Obtain an analytical sample by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound
as an off-white waxy solid. GC-MS m/z: 391 (Nf1).


Preparation 3
3-tert-Butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
Dissolve 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzofaQazepine (5 g, 19.3 mmol) in 7N ammonia in methanol (50 mL) and stir at
ambient temperature for 16 h. Concentrate the reaction mixture to an oil and use without
further purification. Dissolve the residue in a solvent mixture consisting of methanol (20
mL), DCM (10 mL) and water (100 mL), and add potassium carbonate (5 g) and d\-tert-
butyl-dicarbonate (5.05 g, 23.2 mmol). Stir the reaction mixture at ambient temperature
for 16 h and concentrate in vacuo. Extract the aqueous phase with DCM, dry over
Na2SO4, filter and concentrate. Use the residue without further purification. Dissolve the
material in a mixture of DCM (300 mL) and pyridine (30 mL) and cool in an ice bath.
Add dropwise to the stirred solution trifluoromethanesulfonic anhydride (5.84 mL, 34.7
mmol) and stir the reaction mixture for 2 h at ambient temperature. Dilute the reaction
mixture with DCM (400 mL) and wash with 2.5N aqueous HC1. Dry the organic fraction
over Na2SO4, filter and concentrate to give the title compound as a yellow solid (6.1 g,
80%). MS (ES+) m/z: 396 (M+H)+.
Preparation 4
7-Fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[c/lazepine

Add A7-fluoro-4,6-bis(trifluoromethyl)-pyridinium 2-sulfonate (3.02 g, 9.6 mmol)
to a stirred mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[J]azepine (2.5 g, 9.6 mmol) and hexafluoro-2-propanol (10 mL) in DCM (150

mL). Stir at ambient temperature for 16 h. Concentrate the reaction mixture and partition
the residue between EtOAc and IN aqueous HC1. Wash the organic fraction with
saturated aqueous NaHCCh, brine, dry over Na2SO4, filter and concentrate. Purity by
chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 6:1, 5:1 and 3:1) to
give7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[c/Jazepine
as a white solid (1.8 g, 68%). Dissolve 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[]azepine (1.5 g, 5.41 mmol) in a mixture of DCM (20 mL)
and pyridine (2 mL) and cool in an ice bath. Add dropwise to the stirred solution a
mixture of trifluoromethanesulfonic anhydride (1.64 mL, 9.74 mmol) in DCM and stir the
reaction for 1.5 h at ambient temperature. Dilute the reaction with DCM (300 mL) and
wash with 2.5N aqueous HC1. Dry the organic fraction over Na2SC>4, filter and
concentrate to give the title product as a white solid (2.2 g, 99%). MS (ES+) m/z: 410
(M+H)+.
Preparation 5
3-fer/-Butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-l//-benzo[d]azepine

Dissolve 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4>5-tetrahydro-l//-
benzo[c/]azepine (3 g, 10.2 mmol) in 7 N ammonia in methanol (50 mL) and stir at
ambient temperature for 16 h. Concentrate the reaction mixture to an oil and use without
further purification. Dissolve the residue in a solvent mixture consisting of DCM (25
mL) and saturated aqueous potassium carbonate solution (25 mL) and add di-terr-butyl-
dicarbonate (2.2 g, 10.2 mmol). Stir the reaction mixture at ambient temperature for 4 h,
concentrate in vacuo and extract the aqueous residue with DCM. Dry the organic fraction
over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with EtOAc/hexane (1:5) to give the title compound as a white solid (2.3 g, 76%).
MS (ES-) m/z: 296 (M-Hy.


Example 1
6-(3-Phenyl-prop-l-ynyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepineHydrochloride
Use a method similar to the General Procedure 3 to couple 3-tert-butoxycarbonyl-
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cflazepine (0.6 g, 1.5 mmol)
with 3-phenyl-l-propyne (0.38 mL, 3 mmol). Purify by chromatography on silica gel
eluting with hexane/EtOAc (1:0,40:1 and 20:1) to give 3-ter/-butoxycarbonyl-6-(3-
phenyl-prop-l-ynyl)-2,3,4,5-tetrahydro-li/-benzo[ Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-6-(3-phenyl-prop-l-ynyl)-2,3,4,5-tetrahydro-l//-benzo[c/)azepine (68 mg,
0.19 mmol). Purify by chromatography on silica gel eluting with DCM/2M ammonia in
methanol (1:0, 20:1 and 10:1) to obtain the free base of the title compound. Use a method
similar to the General Procedure 2-2 to give the title compound as a tan solid (48 mg,
85%). MS (ES+) m/z: 262 (M+H)+.
Examples 2-4 may be prepared essentially as described in Example 1 by using 3-
terr-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[ in the Table below.




Example 5
6-(3,3-Dimethyl-but-l-ynyI)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Succinate

Use a method similar to the General Procedure 3 to couple 3-/err-butoxycarbonyl-
6-trifluoromethanesulfonyIoxy-2,3,4,5-tetrahydro-l//-benzo[£/)azepine (0.5 g, 1.3 mmol)
with 3,3-dimethyl-l-butyne (0.311 mL, 2.5 mmol). Purify by chromatography on silica gel
eluting with hexane/EtOAc (10:1) to give 3-tert-butoxycarbonyl-6-(3,3-dimethyl-but-l-
ynyI)-2,3,4,5-tetrahydro-l//-benzo[d]azepine as a yellow oil (304 mg, 74%).
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-6-(3,3-dimethyl-but-l-ynyl)-2,3,4,5-tetrahydro-l//-benzo[ Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (1:0,
50:1,20:1, 15:1 and 10:1) to obtain the free base of the title compound. Use a method
similar to the General Procedure 2-1 to give the title compound as a tan solid (171 mg,
53%). MS (ES+) m/z: 228 (M+H)+.

Example 6
6-(3,3-Dimethyl-but-l-ynyl)-7-fluoro-2,3,4,5-tetrahydro-l//-benzo[c?]azepine Succinate

Use a method similar to the General Procedure 3 to couple 7-fluoro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromemanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf)azepine (1
g, 2.4 mmol) with 3,3-dimethyl-l-butyne (0.599 mL, 4.9 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 6-(3,3-dimethyl-
but-1 -ynyl)-7-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a
yellow oil (700 mg, 84%).
Use a method similar to the General Procedure 1-3 to deprotect 6-(3,3-dimethyl-
but-l-ynyl)-7-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine.
Purify by SCX chromatography followed by chromatography on silica gel eluting with
DCM/2M ammonia in methanol (1:0, 50:1,20:1, 15:1 and 10:1) to obtain the free base of
the title compound. Use a method similar to the General Procedure 2-1 to give the title
compound as a white solid (589 mg, 83%). MS (ES+) m/z: 246 (M+H)+.
General Procedure 4-1
Add7-chloro-6-hydroxy-3-(2,2,2-trifiuoroacetyl)-2,3,4,5-tetrahydro-lfl-
benzo[]azepine (1 equiv.), the appropriate alkylating agent (1.2 equiv.), ground K2CO3
(3 equiv.) and Kl (0.1 equiv.) to a proper solvent (acetone, ethanol or acetonitrile) and
heat to reflux for 6 to 16 h unless otherwise specified. Cool the reaction mixture to
ambient temperature, quench with IN aqueous HC1 and extract the aqueous layer three
times with EtOAc. Combine the organic fractions, wash with saturated aqueous
NaHCC>3, brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc mixtures.

General Procedure 4-2
Add7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[]azepine (1 equiv.), the appropriate alcohol (1.1 equiv.), triphenylphosphine (1.2
equiv.) and diethyl azodicarboxylate(l.l equiv.) sequentially to anhydrous THF. Stir the
mixture at ambient temperature under nitrogen. Re-add triphenylphosphine (1.2 equiv.)
and diethyl azodicarboxylate (1.1 equiv.) if the reaction is not completed (monitored by
TLC). Dilute the mixture with EtOAc, wash with saturated aqueous NaHCC>3, brine, dry
over Na2SC>4 and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc mixtures.
General Procedure 4-3
Add7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-
benzo[*/]azepine (1 equiv.), the appropriate alcohol (1.2-1.5 equiv.) and
triphenylphosphine (1.5 equiv.) sequentially to anhydrous THF. Stir the mixture at 0°C
under nitrogen for 10 min. Add l,r-(azodicarbonyl)dipiperidine (1.5 equiv.) and let the
mixture warm to ambient temperature over 16 h. Dilute with ether, filter and concentrate
in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc mixtures.
Preparation 6
7-Chloro-9-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro- l//-benzo[rf]azepine


l-Fluoro-4-methoxy-2-(2-nitro-vinY0-benzene: Heat 2-fluoro-5-methoxybenzaldehyde
(15 g, 97.4 mmol) with nitromethane (32 mL, 584 mmol) and ammonium acetate (30 g,
390 mmol) in acetic acid (136 mL) under reflux for 30 min. Evaporate the solvent and
dissolve the residue in ether. Wash the organic fraction with water, saturated aqueous
NaHCO3 and evaporate to give the desired intermediate (18.7 g, 97%). GC-MS m/z: 197
(M)+.
2-(2-Fluoro-5-methoxvDhenvIV-ethvlamine: Cautiously add sulfuric acid (14.7 mL, 265
mmol) dropwise at 0°C to lithium aluminum hydride (1M solution in THF, 565 mL) with
efficient stirring. Warm the mixture to ambient temperature for 20 min and then cool
back to 0°C. Add a solution of l-fluoro-4-methoxy-2-(2-nitro-vinyl)-benzene (18.7 g, 95
mmol) in THF (150 mL) by cannula and stir 2.5 h at ambient temperature. Cool the
mixture to 0°C, cautiously add water (4.6 mL) followed by 2N aqueous NaOH (4.6 mL)
and water (6.5 mL). Remove the precipitate by filtration and evaporate the filtrate to give
the desired intermediate (16 g, 100 %). MS (ES+) m/z: 170 (M+H)+.
Ar-(2,2-Dimethoxv-ethyl)-2^vZ-trifluoro-A^-[2-(2-fluoro-5-methoxv-phenvl)-ethvn-
acetamide: Dissolve 2-(2-fluoro-5-methoxyphenyl)-ethylamine (16 g, 95 mmol) and
dimethoxy acetaldehyde (60 % aqueous, 21.5 mL, 142 mmol) in methanol (500 mL).
After 1.5 h, cautiously add sodium borohydride (5.39 g, 142 mmol) at 0°C and then stir at
ambient temperature for 3 h. Add acetone and evaporate the mixture. Dissolve the
residue in DCM (250 mL), cool to 0°C and add triethylamine (26.5 mL, 190 mmol) and
trifluoroacetic anhydride (20.1 mL, 142 mmol). After 30 min, wash the mixture with IN
aqueous HC1 (4 x 100 mL), brine and saturated aqueous NaHCCh. Dry the organic layer
over Na2SC>4 and concentrate in vacuo. Purify by chromatography on silica gel to give the
desired intermediate (19.7 g, 59%). MS (ES+) m/z: 322 (M-OMe)+.
9-Fluoro-6-methoxv-3-(2,2,2-trifluoroacetvI)-2.,3-dihvdro-lg-benzorrflazepine:
Dissolve A^-(2,2-dimethoxy-ethyl)-2,2,2-trifluoro-JV-[2-(2-fluoro-5-methoxy-phenyl)-
ethyl]-acetamide (5 g, 14.2 mmol) in chlorobenzene (100 mL). Add polyphosphoric acid
(5 g) and P2O5 (2.5 g) and heat at 80°C for 2 h. Add water to the hot mixture, cool to

room temperature and extract with DCM. Dry the organic extracts over Na2SO4 and
concentrate in vacuo to obtain the desired intermediate (3.0 g, 73%). MS (ES+) m/z: 290
(M+H)+.
9-Fluoro-6-methoxy-3-(2,2^-trifluoroacervl)-2,3,4,5-tetrahydro-l//-benzof Dissolve 9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-l//-benzo[rf]azepine
(9.4 g, 32.4 mmol) with 10 % Pd/C (dry basis, Degussa type, 1.4 g, 0.65 mmol) in
EtOAc/ethanol (1:1, 200 mL) and stir at ambient temperature under a balloon of hydrogen
for 4.5 h. Filter the mixture through a pad of silica gel and evaporate the filtrate to obtain
the desired intermediate (8.6 g, 91%). MS (ES+) m/z: 292 (M+H)+.
9-Fluoro-6-hydroxv-3-(2,2,2-trifluoroacervI)-2,3,4,5-tetrahvdn>-l.ff-benzof Dissolve 9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyI)-2,3,4,5-tetrahydro-1/7-
benzo[rf]azepine (8.1 g, 27.7 mmol) in DCM (250 mL), cool to 0°C and add boron
tribromide (5.24 mL, 55.5 mmol). Stir at ambient temperature for 1.5 h, wash the mixture
with brine, dry the organic layer over Na2SC>4 and concentrate in vacuo to obtain the
desired intermediate (7.6 g, 99%). MS (ES+) m/z: 278 (M+H)+.
7-Chloro-9-fluoro-6-hydroxv-3-(2^v2-trifluoroacetyl)-2J,4,5-tetrahvdro-lff-
benzoUflazepine: Dissolve 9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[ diisopropylamine (41 \iL, 0.29 mmol). Warm to 60°C and add dropwise a solution of
sulfuryl chloride (0.32 mL, 3.97 mmol) in toluene (10 mL). After 2 h, wash the mixture
with brine, dry the organic layer over Na2SC>4 and evaporate onto silica gel. Purify by
chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0) to obtain the desired
intermediate (1.0 g, 92%). MS (ES+) m/z: 312 (M+H)+.
7-Chloro-9-fluoro-3-(2,2v2-trifluoroacetyO-6-trifluoromethanesulfonyloxv-2,3,4,5-
tetrahvdro-l/?-benzo[ (2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[(5(]azepine (2.5 g, 8.0 mmol), pyridine
(3.25 mL, 40.2 mmol) and DCM (80 mL) at 0 °C and add dropwise

trifluoromethanesulfonic anhydride (2.43 mL, 14.5 mmol) over 20 min. Stir at room
temperature for 1 h. Wash the reaction mixture sequentially with IN aqueous HC1,
saturated NaHCC>3 solution and brine. Dry the organic fraction over Na2SC>4 and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
(gradient from 19:1 to 1:1) to obtain the title compound (3.1 g, 87%).
Preparation 7
4-Bromomethyl-./V-methyl-benzenesulfonamide

Mix 4-(bromomethyl)benzenesulfonyl chloride (2.7 g, 10 mmol), anhydrous
potassium carbonate (1.4 g, 10 mmol) and anhydrous THF (60 mL) under nitrogen. Cool
the mixture in an ice bath, add dropwise a 2M solution of methylamine in THF, and stir at
this temperature for 30 min. Remove the ice bath and stir at ambient temperature for 16
h. Dilute with EtOAc then wash with IN aqueous HC1. Separate the organic layer, dry
over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc (1:0, 4:1, 7:3 and 13:7) to obtain the title compound (1.5 g, 71%).
MS (ES+) m/z: 266 (M+H)+.
The compounds of Preparations 8-9 may be prepared essentially as described in
Preparation 7 by using 4-(bromomethyl)benzenesulfonyl chloride and the appropriate
amine. Yields and MS (ES+) data are shown in the Table below.


Preparation 10
Thiazol-2-yl-methanol

Mix under nitrogen 2-thiazolecarboxaldehyde (1.1 g, 10 mmol) and ethanol (30
mL). Add sodium borohydride (416 mg, 11 mmol) at 0°C. Stir and warm the mixture
slowly to ambient temperature for 12 h. Quench with saturated aqueous ammonium
chloride and concentrate in vacua. Dilute the residue with EtOAc and wash with brine.
Dry the organic fraction over Na2SC>4 and concentrate in vacuo to obtain the title
compound as an oil (1.0 g, 87%). MS (ES+) m/z: 116 (M+H)+.
Preparation 11
(1 -Methyl-1 //-pyrazol-3-yl)-methanol

Dissolve 3-dimethoxymethyl-l-methylpyrazole (1.562 g, 10 mmol) in acetone
(100 mL), add p-toluenesulfonic acid (190 mg, 1.0 mmol) and stir at ambient temperature
for 12 h. Remove volatiles in vacuo, dissolve the residue in EtOAc, wash with saturated
aqueous NaHCC>3, dry over Na2SO4, filter and concentrate in vacuo to afford an oil.
Dissolve the oil in methanol (15 mL), add sodium borohydride (567 mg, 15 mmol) and
stir the reaction mixture at ambient temperature for 12 h. Remove volatiles in vacuo,
dissolve the residue in EtOAc, wash with saturated aqueous NaHCCb, dry over Na2SC>4,
filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with
EtOAc/hexane (6:1) to give the title compound as an oil (530 mg, 47%).
Preparation 12
6-(2-Am ino-ethoxy)-7-chloro-3 -(2,2,2-trifluoroacetyl)-2,3,4,5 -tetrahydro- \H-
benzo[e?]azepine


6-(2-terf-Butoxvcarbonvlamino-ethoxvV7-chloro-3-(2,2t2-trifluoroacetYl)-23,4,5-
tetrahydro-17/-benzo[|azepine: Use a method similar to the General Procedure 4-3,
using 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine
(277 mg, 0.94 mmol) and N-(tert-butoxycarbonyl)ethanolamine (244 mg, 1.51 mmol) to
give, after chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1), the
desired intermediate (392 mg, 95%). MS (ES+) m/z: 337 (M+H-Boc)+.
6-(2-Amino-ethoxvV7-chloro-3-(2JU-trifluoroacetvl)-2J.4t5-tetrahvdro-lir-
benzo| trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[£f]azepine (997 mg, 2.28 mmol) in 4M
hydrogen chloride in dioxane (15 mL) and stir at ambient temperature for 30 min.
Concentrate to obtain the hydrochloride salt. Dissolve the salt in DCM and wash with
saturated aqueous NaHCO3. Extract the basic aqueous layer with DCM. Dry the
combined organic extracts over MgSC>4, and concentrate in vacuo to afford the title
compound (731 mg, 95%). MS (ES+) m/z: 337 (M+H)+.
The compounds of Preparations 13-14 may be prepared essentially as described in
Preparation 12 by using 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[f/]azepine and the appropriate alcohol. Overall yields and MS (ES+) data are
shown in the Table below.



Example 7
7-Chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-l//-benzo[rf]azepineSuccinate

Prepare a slurry of sodium hydride (60% in mineral oil; 99 nag, 2.5 mmol) in DMF
(4 mL) and heat to 65° C. Add a solution of 3-terf-butoxycarbonyl-7-chloro-6-hydroxy-
2,3,4,5-tetrahydro-l/f-benzo[rf]azepine (250 mg, 0.84 mmol) in DMF (5 mL) dropwise
and stir for 1 h. Add a solution of 4-fluorobenzyl bromide (191 mg, 1.0 mmol) in DMF
(1 mL), stir at 65°C for 1.5 h and cool to ambient temperature. Add water (1 mL) and
concentrate the mixture to an oily residue. Partition the residue between EtOAc/hexane
(1:1) and water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo.
Dissolve the residue in DCM, wash with 2N aqueous NaOH, dry the organic layer over
Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc (20:1, 10:1 and 7:1) to give 3-ter/-butoxycarbonyl-7-chloro-6-(4-
fluorobenzyloxy)-2,3,4,5-tetrahydro-l//-benzo[]azepine as an oil.
Use a method similar to General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-l//-benzo[«/|azepine.
Purify by SCX chromatography followed by chromatography on silica gel eluting with
DCM/2M ammonia in methanol (1:0, 50:1, 20:1, 15:1 and 10:1) to give the free base of

the title compound. Use a method similar to the General Procedure 2-1 to give the title
compound as a white solid (178 mg, 50%). MS (ES+) m/r. 306 (M+H)+.
Example 8
7-Chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-l//-benzo[c(|azepineHydrochloride

Combine 3-/ert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-lW-
benzo[J]azepine (200 mg, 0.67 mmol), potassium carbonate (111 mg, 0.8 mmol), and 4-
cyanobenzyl bromide (263 mg, 1.34 mmol) in DMSO (5 mL) and heat the stirred mixture
to 100° C for 24 h. Cool to ambient temperature and partition the mixture between water
and EtOAc/hexane (1:1). Wash the organic layer with brine and dry over Na2SC>4, filter
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (5:1) to give 3-ter/-butoxycarbonyl-7-chloro-6-(4-cyanobenzyloxy)-
2,3,4,5-tetrahydro-l/f-benzo[J]azepine as an oil.
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine.
Purify by SCX chromatography to give the free base of the title compound. Use a method
similar to the General Procedure 2-2 to give the title compound as an off-white solid (66
mg, 27%). MS (ES+) m/r. 313 (M+H)+.
Example 9
7-Chloro-6-[2-(4-fluorophenyl)-2-oxo-ethoxy)]-2,3,4,5-tetrahydro-li/-benzo[rf]azepine
Hydrochloride


Use a method similar to the General Procedure 4-1, using 7-chloro-6-hydroxy-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ bromo-4'-fluoroacetophenone (260 mg, 1.2 mmol) to give, after purification by
chromatography on silica gel eluting with hexane/EtOAc (7:1), 7-chloro-6-[2-(4-
fluorophenyl)-2-oxo-ethoxy)]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//L
benzo[>/]azepine as a solid (402 mg, 93%). MS (ES+) m/z: 430 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[2-(4-
fluorophenyl)-2-oxo-ethoxy)]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[cf]azepine (402 mg, 0.93 mmol). Purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (96:4) to give the free base of the title compound
(278 mg, 89%). MS (ES+) m/z: 334 (M+H)+. Use a method similar to the General
Procedure 2-3 to give the title compound.
Example 10
7-Chloro-6-(4-methylsulfamoyl-benzyloxy)-2,3,4,5-tetrahydro-ltf-
benzo[]azepine Hydrochloride

Dissolve under nitrogen 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l/f-benzo[cOazepine (200 mg, 0.68 mmol) in acetone (30 mL). Add powdered
anhydrous potassium carbonate (276 mg, 2.0 mmol) and powdered potassium iodide (11.3
mg, 0.068 mmol) followed by 4-bromomethyl-./V-methyl-benzenesulfonamide (528 mg,

2.0 mmol). Stir the reaction mixture at ambient temperature for 12 h. Concentrate in
vacuo, dilute with EtOAc and wash twice with IN aqueous HC1. Separate the organic
layer, dry over Na2SO4 and concentrate in vacuo. Purity by chromatography on silica gel
eluting with hexane/EtOAc (1:0 and 4:1) to obtain 7-chloro-6-(4-methylsulfamoyl-
benzyloxy)-3-(2,2,2-trifluoroacetyI)-2,3,4,5-tetrahydro-li/-benzo[c/Jazepine (201 mg,
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(4-
methylsulfamoyl-benzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lJr7-
benzo[cQazepine (196 mg, 0.41 mmol). Purity by SCX column to give the free base of the
title compound (110 mg, 70%). MS (ES+) m/z: 381 (M+H)+. Use a method similar to the
General Procedure 2-2 to obtain the title compound.
Examples 11-12 may be prepared essentially as described in Example 10 by using
7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[f/]azepineand
the appropriate bromide. MS (ES+) data are shown in the Table below.

Example 13 Allen 1
7-Chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[J]azepine Hydrochloride

r
Dissolve 7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rfjazepine (0.25 g, 0.8 mmol) in DMF (8 mL), add potassium carbonate (0.56 g,
4.0 mmol) and 4-fluorobenzyl bromide (0.46 mL, 2.4 mmol). After 14 h at 90 °C, dilute
with ether and wash with brine. Dry the organic layer over Na2SO4 and evaporate onto
silica gel. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0)
to obtain 7-chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-1 H-betuo[d] azepine.
Use a method similar to the General Procedure 1-1, using 7-chloro-9-fluoro-6-(4-
fluorobeiizyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rfJazepine, to give
the free base of the title compound. Use a method similar to the General Procedure 2-2 to
obtain the title compound (275 mg, 95%). HRMS calc'd for Ci7Hi7NOF2Cl 324.0902,
found 324.0957.
Example 14
7-Chloro-6-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-l//-benzo[JlazepineSuccinate

Prepare a slurry of sodium hydride (60% in mineral oil, 168 mg, 4.2 mmol) in
DMF (4 mL) and heat to 65° C. Add dropwise a solution of 3-/er/-butoxycarbonyl-7-
chloro-6-hydroxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (250 mg, 0.84 mmol) in DMF
(5 mL) and stir for 1 h. Add a solution of 2-(bromomethyl)-pyridine hydrobromide (256

mg, 1 mmol) in DMF (1 mL), stir at 65° C for 0.5 h and cool to ambient temperature.
Add water (1 mL) and concentrate the reaction mixture to an oily residue. Partition the
residue between EtOAc/hexane (1:1) and water. Dry the organic layer over Na2SC>4, filter
and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc
(10:1, 5:1 and 3:1) to give 3-ter/-butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethoxy)-
2,3,4,5-tetrahydro-lfl-benzo[rf]azepine as an oil.
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-lH-
benzofcfjazepine. Purify by SCX chromatography to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
as a white solid (228 mg, 67%). MS (ES+) mJr. 289 (M+H)+.
Example 15
7-Chloro-6-(pyridin-3-y1methoxy)-2,3,4,5-tetrahydro-l/J-benzo[rf]azepineDisuccinate

Use a method similar to the Example 14, using 3-ter/-butoxycarbonyl-7-chloro-6-
hydroxy-2,3,4,5-tetrahydro-l/f-benzo[]azepine (250 mg, 0.84 mmol) and 3-
(bromomethyl)-pyridine hydrobromide (256 mg, 1 mmol) to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 with two equivalents of
succinic acid to give the title compound as a white solid (354 mg, 80%). MS (ES+) m/r.
289 (M+H)+.
Example 16
7-Chloro-6-(thiazol-2-ylmethoxy)-2,3,4,5-tetrahydro-l//-benzo[c/]azepineHydrochloride


Use a method similar to the General Procedure 4-2, using 7-chloro-6-hydroxy-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lff-benzo[rf]azepineand thiazol-2-yl-methanol
(86.2 mg, 0.75 mmol) to give, after chromatography on silica gel eluting with
hexane/EtOAc (9:1 and 7:3), 7-chloro-6-(thiazol-2-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-lfl-benzo[]azepine (163 mg, 61%). MS (ES+) m/z 391 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-
(thiazol-2-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-2)3,4,5-tetrahydro-l//-benzo[ Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol
(94:6) to obtain the free base of the title compound (99 mg, 81%). MS (ES+) m/z: 295
(M+H)+. Use a method similar to the General Procedure 2-2 to give the title compound.
Example 17
7-Chloro-6-(thiazol-5-ylmethoxy)-2,3,4,5-tetrahydro-l//-benzo[c/lazepineHydrochloride

Use a method similar to the General Procedure 4-2, using 7-chloro-6-hydroxy-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[cf]azepine (294 mg, 1.0 mmol) and 5-
hydroxymethylthiazole (127 mg, 1.1 mmol) to give, after chromatography on silica gel
eluting with EtOAc/hexane (1:3), 7-chloro-6-(thiazol-5-ylmethoxy)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[c/lazepine as an oil (350 mg, 89%). MS
(ES+)m/z:391 (M+H)+.

Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-
(thiazol-5-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(350 mg, 0.90 mmol). Purify by chromatography on silica gel eluting with DCM/2M
ammonia in methanol (95:5) to give the free base of the title compound (203 mg, 76%).
MS (ES+) m/z: 295 (M+H)+. Use a method similar to the General Procedure 2-2 to give
the title compound.
Examples 18-19 may be prepared essentially as described in Example 17 by using
7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lJr7-benzo[rf]azepineand
the appropriate alcohol. Overall yields and MS (ES+) data are shown in the Table below.

Use a method similar to the General Procedure 4-2, using 7-chloro-6-hydroxy-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[t/]azepineand3-(methylthio)-l-
propanol (191 mg, 1.8 mmol) to give, after chromatography on silica gel eluting with
EtOAc/hexane (1:8), 7-chloro-6-(3-methylthio-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l#-benzo[d]azepine as an oil (65 mg, 14%).

Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(3-
methyithio-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/7-benzo[ mg, 0.17 mmol). Purify by chromatography on silica get eluting with DCM/2M ammonia
in methanol (94:6) to give the free base of the title compound (25 mg, 51%). MS (ES+)
m/z: 286 (M+l)+. Use a method similar to the General Procedure 2-1 to give the title
compound.
Example 21
7-ChIoro-6-(4-methylthio-butoxy)-2,3,4,5-tetrahydro-l//-benzo[]azepine Succinate

Use a method similar to the Example 20, using 7-chloro-6-hydroxy-3-(2,2,2-
trifluoroacetyI)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine and 4-(methylthio)-l-butanol to
give the title compound. MS (ES+) m/z: 300 (M+l)+.
Example 22
7-Chloro-6-(3-pyridin-2-yl-propoxy)-2,3,4,5-tetrahydro-l//-benzo[ Hydrochloride

Use a method similar to the General Procedure 4-3, using 7-chloro-6-hydroxy-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[£/|azepine (50 mg, 0.17 mmol) and 3-
(2-pyridyl)-l-propanol (35 mg, 0.255 mmol) to give, after reverse phase HPLC (10-95%
of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent
B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5Dm, 12 nm, 100 x

20 mm), 7-chloro-6-(3-pyridin-2-yl-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[]azepine.
Use a method similar to the General Procedure 1-1, using 7-chloro-6-(3-pyridin-2-
yl-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine to give the
free base of the title compound. Use a method similar to the General Procedure 2-2 to
give the title compound as a solid (26 mg, 39%). MS (ES+) m/z: 317 (M+H)+.
Examples 23-26 may be prepared essentially as described in Example 22 by using
7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li]r-benzo[c/]azepineand
the appropriate alcohol. Overall yields and MS (ES+) data are shown in the Table below.



6-(2-Benzoylamino-ethoxy)-7-chloro-2,3,4,5-tetrahydro-l/f-benzo[Gf|azepine
Hydrochloride
Combine benzoyl chloride (193 mg, 0.137 mmol), PS-morpholine (109 mg, 0.272
mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzofrfjazepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature
for 16 h. Filter the resin, wash with DCM and concentrate in vacua. Purify by reverse
phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1%
trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-
341-5, S-5um, 12 nm, 100 x 20 mm) to give 6-(2-benzoylamino-ethoxy)-7-chIoro-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine.
Use a method similar to the General Procedure 1-1, using 6-(2-benzoylamino-
ethoxy)-7-chloro-3-(2,2,2-trifluoroaceryl)-2,3,4,5-tetrahydro-l//-benzo[d]azepinetogive
the free base of the title compound. Use a method similar to the General Procedure 2-2 to
give the title compound as a solid (51 mg, 98%). MS (ES+) mJz: 345 (M+H)+.
Examples 28-40 may be prepared essentially as described in Example 27, using 6-
(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-
benzo[d]azepine or 6-(3-amino-propoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro- l#-benzo[cf]azepine or 6-(4-amino-butoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[ and MS (ES+) data are shown in the Table below.




Dissolve 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (100 mg, 0.297 mmol) in DCM (5 mL). Add 2-fluorobenzoyl
chloride (39 uL, 0.326 mmol), triethylamine (62 uL, 0.445 mmol) and stir at ambient
temperature for 72 h under nitrogen atmosphere. Dilute with DCM, add 1M aqueous HC1
and extract the aqueous phase with DCM. Dry the combined organic extracts over MgSO4
and concentrate in vacuo. Purify by chromatography on silica gel eluting with

hexane/EtOAc (7:3 and 2:1) to give 7-chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (111 mg, 82%).
Use a method similar to the General Procedure 1-1, using 7-chloro-6-[2-(2-
fluorobenzoylamino)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine to give the free base of the title compound. Use a method similar to the
General Procedure 2-2 to give the title compound as a solid (112 mg, 95%). MS (ES+)
m/z: 363 (M+H)+.
Example 42
7-Chloro-6-{2-[(pyridine-2-carbonyl)-amino]-ethoxy}-2,3,4,5-tetrahydro-l//-
benzo[t/|azepine Hydrochloride

Combine picolinic acid (40 mg, 0.327 mmol), EDC (57 mg, 0.297 mmol) and
HOBT (40 mg, 0.297 mmol) in DCM (3 mL). Stir for 10 min at ambient temperature.
Add6-(2-amino-ethoxy)-7-chloro-3-(2^,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/Jazepine (100 mg, 0.297 mmol). Stir for 16 h at ambient temperature. Dilute
with DCM, add water and extract the aqueous layer with DCM. Wash the combined
organic extracts with 1M aqueous NaOH and brine. Dry the organic layer over MgSCv
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (3:2) to give 7-chloro-6-{2-[(pyridine-2-carbonyl)-amino]-ethoxy}-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lJ7-benzo[rf]azepine (94 mg, 74%).
Use a method similar to the General Procedure 1-1, using 7-chloro-6-{2-
[(pyridine-2-carbonyl)-amino]-ethoxy}-3-(2,2,2-trifluoroaceryl)-2,3,4,5-tetrahydro-l//-
benzo[cT]azepine to give the free base of the title compound. Use a method similar to the

General Procedure 2-2 to give the title compound as a solid (81 mg, 72%). MS (ES+)
m/z: 346 (M+H)+.
Example 43
7-Chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethoxy}-2,3,4,5-tetrahydro-l//-
benzo[c/)azepine Hydrochloride

Use a method similar to Example 42, using nicotinic acid (40 mg, 0.327 mmol)
and6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lfl-
benzo[rf)azepine (100 mg, 0.297 mmol) to give the title compound as a solid (105 mg,
93%). MS (ES+) m/z: 346 (M+H)+.
Example 44
7-Chloro-6-[2-(3-phenyl-ureido)-ethoxy]-2>3,4>5-tetrahydro-lW-benzo[J]azepine
Hydrochloride

Combine phenyl isocyanate (16.3 mg, 0.137 mmol), 6-(2-amino-ethoxy)-7-chloro-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l#-benzo[rf]azepine (46 mg, 0.137 mmol) in
DCM (1.5 mL) and stir at ambient temperature for 16 h. Concentrate in vacuo. Purify by
reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water,
0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC
SH-341-5, S-5um, 12 nm, 100 x 20 mm) to give 7-chloro-6-[2-(3-phenyl-ureido)-ethoxy]-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine.

Use a method similar to the General Procedure 1-1, using 7-chloro-6-[2-(3-phenyl-
ureido)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[cf]azepinetogive
the free base of the title compound. Use a method similar to the General Procedure 2-2 to
give the title compound as a solid (8 mg, 15%). MS (ES+) m/r. 360 (M+H)+.
Examples 45-46 may be prepared essentially as described in Example 44 by using
phenyl isocyanate and the appropriate 6-(3-amino-propoxy)-7-chloro-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l/?-benzo[rflazepineor6-(4-amino-butoxy)-7-chloro-3-
(2,2,2-trifluoroacety1)-2,3,4,5-tetrahydro-l#-benzo[flQazepine. Overall yields and MS
(ES+) data are shown in the Table below.



Add methyl 4-bromobutyrate (1.9 mL, 10.4 mmol) to a mixture of 3-tert-
butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-benzo[tjT]azepine (310 mg, 1.0
mmol), DBU (0.23 mL, 1.6 mmol) and DMF (10 mL) at ambient temperature under
nitrogen. Stir the reaction mixture for 16 h. Dilute with hexane/EtOAc (1:1, 60 mL),
wash the mixture with 10% aqueous NaCl (4 x 25 mL), dry the organic layer over Na2SO4
and concentrate in vacua. Purify by chromatography on silica gel eluting with
hexane/EtOAc (19:1 to 2:3) to obtain 3-ter/-butoxycarbonyl-7-chloro-6-(3-
methoxycarbonyI-propyloxy)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (303 mg, 73%). MS
(ES+) m/z: 398 (M+H)+.
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propyloxy)-2,3,4,5-tetrahydro-li/-
benzo[rf]azepine (295 mg, 0.74 mmol). Purify by SCX chromatography followed by
chromatography on silica gel eluting with DCM/2M ammonia in methanol (99:1 to 90:10)
to give the free base of the title compound. Use a method similar to the General Procedure
2-1 to give the title compound (160 mg, 52%). MS (ES+) m/z: 298 (M+H)+.
General Procedure 5-1
Dissolve the appropriately substituted 3-(2,2,2-trifluoroacetyl)-6-trifluoromethane-
sulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rflazepine (1 equiv.), palladium(II) acetate (0.1-
0.4 equiv.), BINAP (0.2-0.8 equiv.; BINAP/catalyst ratio 2:1) and cesium carbonate (1.4-
3.0 equiv.) in toluene (0.2-0.05 M solution). Add the amine (1-3 equiv.), degas the
mixture with vacuum/nitrogen or argon purge and heat at 80-110°C for 4-16 h. Cool the
mixture to ambient temperature, dilute with EtOAc, filter through a pad of silica gel or
through Celite® washing with EtOAc or ether, and evaporate the solvent to obtain the
crude mixture. Alternatively, partition the reaction mixture between brine or saturated
aqueous NaHCO3 and EtOAc, ether or DCM, dry the organic layer over Na2SO4, and
concentrate to obtain the crude mixture. Purify the crude mixture by chromatography on
silica gel eluting with hexane/EtOAc mixtures and further SCX chromatography if
needed.

General Procedure 5-2
Dissolve the appropriately substituted 3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[t/|azepine(l equiv.),
tris(dibenzylideneacetone)dipalladium(0) (0.1-0.5 equiv.), BINAP (0.2-1.0 equiv.;
BINAP/catalyst ratio 2:1) and cesium carbonate (1.4 equiv.) in toluene (0.05-0.5 M
solution). Degas under vacuum and fill three times with nitrogen. Add the appropriately
substituted amine (1.0-5.0 equiv.) and heat the mixture to 80-100°C for 2-16 h in a sealed
flask under a nitrogen atmosphere. Cool the reaction flask to ambient temperature, dilute
the mixture with EtOAc or DCM, filter through Celite® and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/EtOAc mixtures and further SCX
chromatography if needed.
General Procedure 5-3
Add the appropriately substituted 3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine (1 equiv.), the
appropriate amine (1.2-3.0 equiv.), palladium(II) acetate (0.2-0.4 equiv.),
tris(dibenzylideneacetone)dipalladium(0) (0.1-0.2 equiv.), BINAP (0.6-1.2 equiv.;
BINAP/catalysts ratio 2:1), cesium carbonate (2-2.5 equiv.) and toluene or 1,4-dioxane
(0.05-0.2 M solution) to a flask, degas and fill three times with nitrogen. Heat the mixture
at 80-100°C for 10-16 h. Dilute the mixture with EtOAc, wash with saturated aqueous
NaHCC>3 and brine, dry over Na2SC>4, filter and concentrate in vacuo to give the crude
mixture. Alternatively remove the volatiles from the reaction mixture to give directly the
crude mixture, or filter the reaction mixture through Celite® and concentrate in vacuo.
Purify by chromatography on silica gel eluting with hexane/EtOAc mixtures and further
SCX chromatography if needed.
General Procedure 5-4
Combine 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/] azepine, the appropriate bromide (1.0-2.0 equiv.), potassium or cesium
carbonate (1.0-2.0 equiv.) and toluene, DMF or acetonitrile in a sealed tube and heat at

50-150°C for 3-72 h. Cool to ambient temperature and evaporate the solvent in vacuo to
obtain the crude mixture. Alternatively, partition the reaction mixture between diethyl
ether/brine (1:1), dry the organic layer over anhydrous Na2SO4 and concentrate to obtain
the crude mixture. Purify by chromatography on silica gel eluting with hexane/EtOAc
(1:0, 9:1, 4:1, 7:3 and 3:2).
General Procedure 6-1
Dissolve 4-(te/"f-butoxycarbonylamino-methyl)-benzoic acid (1 equiv.), HATU (1
equiv.), DIEA (2 equiv.) and the appropriately substituted amine (1 equiv.) in DCM or
DCM/DMF and stir at ambient temperature for 4-16 h. Concentrate in vacuo, dissolve the
residue in DCM and wash successively with saturated aqueous NaHCCb, IN aqueous
HC1, water, brine, and dry over Na2SC>4. Filter and concentrate the solution and use the
material without further purification. Deprotect the residue using the General Procedure
1-5 and purify by SCX chromatography.
General Procedure 6-2
Dissolve 4-(/ert-butoxycarbonylamino-methyl)-benzoic acid or 5-(tert-
butoxycarbonylamino-methyl)-pyridine-2-carboxylic acid lithium salt (1 equiv.), HATU
(1 equiv.), DIEA (2 equiv.) and the appropriately substituted amine (1 equiv.) in DCM or
DCM/DMF and stir at ambient temperature for 4-16 h. Concentrate in vacuo, dissolve the
residue in DCM and wash successively with saturated aqueous NaHCCh, water, brine, and
dry over Na2SO4. Filter and concentrate the solution and use the material without further
purification. Deprotect the residue using the General Procedure 1-5 and purify by SCX
chromatography.
General Procedure 6-3
Dissolve the appropriately substituted acetophenone (1.0-1.2 equiv.) in THF, add
titanium(IV) ethoxide (33-35% TiO2, 2.0 equiv.) and the corresponding (/?)-2-methyl-2-
propanesulfinamide or (S)-2-methyl-2-propanesulfmamide (1.0 equiv.). Heat the mixture
to 40-60 °C for 2-16 h under a nitrogen atmosphere. Cool the reaction to -78°C, then add
the cold mixture over 3-10 min to a slurry of THF/NaBILt (2-4 M) at -78 CC. Allow the

mixture to warm up to ambient temperature over 2-16 h. Pour the mixture into brine,
filter the resulting slurry through Celite® and wash thoroughly with EtOAc. Concentrate
in vacuo. Dilute the oil with EtOAc, wash with brine and extract the aqueous phase with
EtOAc. Dry the combined organic extracts over Na2SC>4 and concentrate in vacuo. Purify
the crude sulfinamide on silica gel eluting with hexane/EtOAc mixtures to obtain the
major diastereomer. Dissolve the major diastereomer in excess of 4M hydrogen chloride
in dioxane, stir the mixture for 1 h and concentrate in vacuo to a solid. Slurry the solid in
diethyl ether, then filter in vacuo to obtain the hydrochloride salt of the desired amine.
The free base of the amine is prepared either via SCX chromatography or by basic
extraction.
General Procedure 6-4
Add the appropriately substituted benzonitrile portion wise to a flask containing a
slurry of lithium aluminum hydride (3.0-6.0 equiv.) in diethyl ether (0.1-0.3 M solution)
under a nitrogen atmosphere. Stir the mixture for 1 h and quench slowly with water (0.5-
2.0 mL), followed by 5N aqueous NaOH (0.5-2.0 mL). Filter the slurry through Celite®
and wash the cake with diethyl ether. Concentrate in vacuo to obtain the desired amine.
If additional purification is needed, dissolve the amine in ether and add an excess of 2M
hydrogen chloride in ether. Filter to obtain the desired amine as the hydrochloride salt.
Prepare the free base by using SCX chromatography or by dissolving the hydrochloride
salt in an aqueous solution of cesium carbonate (1.0-5.0 equiv.) or saturated aqueous
NaHCO3 (1.0-5.0 equiv.). Extract the mixture with DCM or toluene, dry over Na2SO4
and concentrate in vacuo to obtain the amine.
General Procedure 6-5
Add BH3-THF complex (1-3 equiv., 1M solution in THF) dropwise to a solution
of appropriately substituted benzonitrile in anhydrous THF at room temperature then stir
overnight. Alternatively the reaction can be heated at reflux overnight. Add either
methanol or aqueous HC1 (3 equiv.) cautiously at room temperature and stir vigorously
until gaseous evolution stops. Concentrate in vacuo, basify and then extract into EtOAc.
Wash the organic phase with brine, dry over MgSO4 and concentrate in vacuo. Purify by

SCX chromatography eluting with methanol followed by a solution of ammonia in
methanol (3-7 M) to give the desired benzylamine.
Preparation 15
7-Cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine

7-Bromo-6-hvdroxv-(2>2^-trifluoroacetvl>-2J,4^-tetrahvdro-lJ/-benzo[ Dissolve 6-hydroxy-3-(2^,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[£/lazepine (18
g, 69.4 mmol) and DffiA (0.98 mL) in DCM (1.4 L). Add dropwise a solution of NBS
(12.4 g, 69.4 mmol) in DCM (500 mL) over 75 min. Stir the reaction mixture at ambient
temperature for 1 h, pour into water (500 mL) and extract the mixture with DCM. Wash
the organic fraction with brine, dry over Na2SC>4, filter and concentrate. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to give the desired
intermediate as a white solid (20.9 g, 89%). MS (ES-) m/z: 337 (M-H)7-CYano-6-hYdroxy-3-f2J^2-trifluoroacetvl)-23,4^-tetrahvdro-l.ff-benzo[ Add copper nitrile (2.6 g, 28 mmol) to a solution of 7-bromo-6-hydroxy-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-li/-benzo[d]azepine (2.4 g, 7.0 mmol) in anhydrous
NMP (45 mL), degas and purge with nitrogen and heat to 150°C for 18 h. Allow the
reaction mixture to cool to ambient temperature and then dilute with EtOAc/heptane (2:1)
and filter through a silica pad. Dilute the filtrate with water, and extract the aqueous
phase twice with EtOAc. Dry the combined organic extracts over MgSC>4, filter and
concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/heptane
(1:4 to 1:1) to obtain the desired intermediate as an orange oil (1.7 g, 86%). MS (ES-)
m/z: 283 (M-H)
7-CYano-3-(2,2,2-trifluoroacetvl)-6-trifluoromethanesulfonvloxy-2,3,4,5-tetrahvdro-
lg-benzofrflazepine: Add dry pyridine (3 mL) to 7-cyano-6-hydroxy-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[d]azepine (1.1 g, 3.9 mmol) in anhydrous
DCM (45 mL) and cool to 0 °C. Add slowly trifluoromethanesulfonic anhydride (1.3 mL,
7.7 mmol), allow the reaction mixture to warm to ambient temperature and stir for 3 h.
Dilute with DCM and wash with 2N aqueous HC1. Dry the organic layer over MgSC>4,
filter and concentrate in vacua to obtain the title compound as an orange/brown oil (1.6 g,
100%) that was used without purification. MS (ES-) m/z: 415 (M-H)".
Preparation 16
3-(2,2,2-Trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-
tetrahydro-177-benzo[i/lazepine

6-Hydrory-7-iodo-3-(2^^-trifluoroacetvl>-2^,4^-tetrahvdro-lfl-benzof Add 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l^-benzo[f/lazepine (1.037 g,
4.0 mmol) and diisopropylamine (60.7 mg, 0.6 mmol) to anhydrous DCM (350 mL) and
stir at 10-20 °C. Add slowly a solution of A^-iodosuccinimide (1.035 g, 4.6 mmol) in
DCM (100 mL) over a period of 3 h. Stir the reaction mixture overnight and gradually
warm to ambient temperature. Quench the reaction with saturated aqueous NaHCCh,
separate the organic layer, wash the organic layer with 0. IN aqueous HC1, brine, dry over
Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting
with EtOAc/hexane (1:20 to 1:10) to give the desired intermediate as a white solid (1.0 g,
65%). MS (ES+) m/z: 386 (M+H)+.

7-Iodo-3-(2,2v2-trifluoroacetvn-6-trifluoromethanesulfonvloxv-2,3,4,5-tetrahydro-
Lff-benzoFtflazepine: Add triethylamine (496 mg, 4.90 mmol) to a solution of 6-hydroxy-
7-iodo-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-177-benzo[|azepine (945 mg, 2.45
mmol) in DCM (30 mL) at 0 °C. Add dropwise trifluoromethanesulfonic anhydride
(1.244 g, 4.41 mmol) and stir at 0°C for 1 h. Warm to ambient temperature overnight.
Dilute the mixture with DCM, wash with water, saturated aqueous NaHCC>3 and brine.
Dry over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with EtOAc/hexane (1:6) to give the desired intermediate as a white solid (1.246
g, 98%). MS (ES+) m/r. 518 (M+H)+.
3-(2,2,2-Trifluoroacctyl>-6-trifluoromethanesulfonvloxv-7-trifluoromethvl-23,4,5-
tetrahydro-l/7-henzoUf]azenine: Add Cul (367 mg, 1.93 mmol), methyl 2,2-difluoro-2-
(fluorosulfonyl)acetate (1.852 g, 9.64 mmol) and HMPA (1.728 g, 9.64 mmol) to a
solution of 7-iodo-3-(2^,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[]azepine (1.246 g, 2.41 mmol) in DMF (8 mL) and heat the
mixture at 70 °C for 1.5 h. Add same amount of Cul, methyl 2,2-difluoro-2-
(fluorosulfonyl)acetate, and HMPA and stir further for 4 h. Cool the mixture to ambient
temperature, quench with saturated aqueous ammonium chloride, separate the organic
layer, and extract the aqueous layer with EtOAc three times. Combine the organic layers,
wash with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate in
vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:20 to 1:10)
to give the title compound as a white solid (321 mg, 29%) and to recover the starting
material (741 mg, 59%). MS (ES+) m/z: 460 (M+H)+.
Preparation 17
7-Ethyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li7-
benzo[]azepine


9-Bromo-6-hvdroxv-3-(2,2J-trifluoroacetvlV23,4,5-tetrahvdrQ-lff-benzo[ Add dropwise bromine (10.8 mL, 0.21 mol) in acetonitrile (260 mL) to a slurry of 6-
hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[^|azepine (51.8 g, 0.2 mol)
in acetonitrile (400 mL) at 0 °C cooling with ice-water to keep the temperature between
2-5°C. Warm the reaction to ambient temperature and stir for 30 min. Pour the mixture
into ice-cold water (2 L) to obtain a white precipitate. Collect the solid by vacuum
filtration, wash with water and dry under vacuum at 105 °C. Recrystallize the crude
material in toluene/heptane and cool the mixture in an ice bath. Collect the solid by
vacuum filtration, wash with heptane and dry under vacuum at 105 °C to obtain the
desired intermediate as a white solid (54.63 g, 81%). MS (ES+) m/z: 338 (M+H)+.
6-Acetoxv-9-bromo-3-(2JJ-trifluoroacetvl)-2^3,4,5-tetrahvdro-l-H-benzo[ Under nitrogen atmosphere, mix 9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[fi(]azepine (6 g, 17.8 mmol), anhydrous pyridine (0.06 mL, 0.72
mmol), DMAP (222 mg, 1.8 mmol) and acetic anhydride (30 mL). Heat the mixture at
reflux for 8 h and then stir at ambient temperature for another 8 h. Concentrate in vacua,
dilute the residue in EtOAc, wash with IN aqueous HC1, and then with saturated aqueous
NaHCO3. Dry the organic layer over Na2SC>4, filter, and concentrate in vacuo to obtain
the desired intermediate (5.64 g, 84%) that was used without further purification. MS
(ES+) m/z: 380 (M+H)+.

7-Acetvl-9-bromo-6-hvdroxv-3-(2,2^-trifluoroacetvl)-2,3,4,5-tetrahvdro-lg-
benzoftflazepine: Under nitrogen atmosphere, mix 6-acetoxy-9-bromo-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[£/]azepine (2.8 g, 7.4 mmol) and
nitrobenzene (5 mL). Add anhydrous aluminum chloride (980 mg, 7.4 mmol). Heat at
180°C for 2 h. Cool the mixture to ambient temperature. Add concentrated HC1 (10 mL)
dropwise. Stir the mixture for 30 min. Add IN aqueous HC1 then extract with EtOAc.
Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:4) to afford the desired
intermediate (833 mg, 30%). MS (ES-) m/z: 378 (M-H)~.
7-Acetvl-6-hvdroxv-3-(2^^-trifluoroacetvn-23.4.5-tetrahydro-lg-benzo[rflazepine:
Mix7-acetyl-9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[*/]azepine (833 mg, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg,
0.13 mmol) and sodium formate (224 mg, 3.3 mmol) in anhydrous DMF (15 mL). Degas
twice then flush with argon. Keep the flask under argon and heat the reaction at 95°C for
16 h. Dilute with EtOAc then wash with IN aqueous HC1. Separate the organic layer,
dry over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with EtOAc/hexane (0:1, 1:9 and 1:4) to give the desired intermediate (448 mg,
68%). MS (ES+) m/z: 302 (M+H)+.
7-Ethvl-6-hvdroxv-3-(2J^-trifluoroacetvl)-23.4^-tetrahvdro-l//-benzo[(/lazepine:
Under nitrogen dissolve 7-acetyl-6-hydroxy-3-(2^,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
lfl-benzo[rf]azepine (1.0 g, 3.32 mmol) in anhydrous THF (100 mL). Cool the solution
to 0°C, add boron trifluoride diethyl etherate (3.4 mL, 26.6 mmol) and sodium
cyanoborohydride (836 mg, 13.3 mmol). Remove the ice bath and stir for 5 h at ambient
temperature. Dilute with EtOAc and wash with 0.1N aqueous HC1. Separate the organic
layer, dry over Na2SO4, filter and concentrate in vacuo. MS (ES-) m/z: 302 (M-H)\ Mix
the residue with trifluoroacetic acid (40 mL) and anhydrous DCM (50 mL) under
nitrogen. Cool to 0 °C in an ice bath and add triethyl silane (3.5 mL, 21.9 mmol). After
15 min, remove the ice bath and stir at ambient temperature for 16 h. Concentrate in

7-Ethvl-3-(2.2.2-trifluoroacetvn-6-trifluoromethanesulfonyloxv-23,4,5-tetrahvdro-
1/y-benzofrflazepine: Under nitrogen mix 7^ethyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-lJ!7-benzo[ mmol) and anhydrous DCM (25 mL). Cool the mixture in an ice bath, add dropwise
trifluoromethanesulfonic anhydride (0.81 mL, 4.8 mmol) and stir at ambient temperature
for 3 h. Quench with water and extract three times with DCM. Wash the organic extracts
with 0.1N aqueous HC1 and brine. Dry over Na2SC«4, filter and concentrate to obtain the
title compound (1.0 g, 100%). MS (ES+) m/z: 420 (M+H)+.
Preparation 18
7-Propyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[
6-Allvloxv-3-(2JvZ-trifluoroacetvl)-2r3.,4,5-tetrahvdro-lff-benzol 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (1 g, 3.9
mmol) in acetone (5 mL) ami add powdered potassium carbonate (2.8 g, 20 mmol). Add
dropwise a solution of allyl bromide (1.04 mL, 12 mmol) in acetone (3 mL) over 10 min
and stir at ambient temperature overnight. Filter solids, wash with acetone and
concentrate in vacuo to give the desired intermediate as an off-white solid (1.15 g, 98%).
GC-MS m/z: 299 (M+).
7-Allvl-6-hvdroxv-3-(2JJ-trifluoroacetvn-2«3.4.5-tetrahvdro-l/f-benzof Dissolve 6-allyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[t/]azepine (1.1
g, 3.7 mmol) in DCM (15 mL) and cool to -15 °C. Add 1M boron trichloride in DCM

(15 mL, 15 mmol) and warm to ambient temperature. Stir for 30 min at ambient
temperature. Add water (50 mL) and extract the aqueous layer three times with DCM.
Wash the combined organic extracts with water (100 mL), brine (100 mL), dry over
MgSC>4, filter, and concentrate in vacuo to give the desired intermediate (980 mg, 89%) as
a light yellow oil which solidified to an ofF-white solid upon standing at ambient
temperature. MS (ES+) m/z: 300 (M+H)+.
6-Hvdrorv-7-Dropvl-3-C2.2^-trifluoroacetvl)-23.4.5-tetrahvdro-lg-benzofrflazepine:
Dissolve 7-allyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[cT|azepine (1.5 g, 5 mmol) in EtOAc (50 mL) containing 10% Pd/C (1.3 g). Stir at
ambient temperature at 1 atm with H2 (balloon) for 30 min. Filter the catalyst and wash
with water (100 mL). Extract the resulting filtrate three times with EtOAc, wash the
combined organic extracts with brine, dry over MgSC>4, filter and concentrate in vacuo to
give the desired intermediate as a white solid (1.45 g, 97%). MS (ES+) m/z: 302 (M+H)+
7-Propyl-3-(2J^-trifluoroacctvl)-6-trifluoromethanesulfonvloxv-23 lg-benzof|azepine: Cool a solution of 6-hydroxy-7-propyl-3-(2,2,2-trifiuoroacetyl)-
2,3,4,5-tetrahydro-lff-benzo[)azepine (500 mg, 1.9 mmol), triethylamine (390 ^L, 2.3
mmol) and DCM (20 mL) in a cryogenic bath set at -35°C and add dropwise over 20 min
trifluoromethanesulfonic anhydride (325 fiL, 2.3 mmol). Stir at this temperature
overnight. Wash the reaction mixture sequentially with water, IN aqueous HC1, water,
and brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the title
compound as an off-white waxy solid (550 mg, 75%). MS (ES+) m/z: 434 (M+H)+
Preparation 19
6-Amino-7-chloro-3-(2,2,2-trifluoroacetyI)-2,3,4,5-tetrahydro-li/-benzo[c/]azepine


7-Chloro-6-f4-methoxvbenzYlaniino)-3-f2^J-trifluoroacetvl)-23 benzo[rf|azepine: Couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine (15 g, 35.3 mmol),
with 4-methoxybenzylamine (13.7 mL, 106 mmol) using tris(dibenzylideneacetone)-
dipalladium(O) (1.62 g, 1.76 mmol), BINAP (4.40 g, 3.5 mmol) and cesium carbonate
(16.1 g, 49.4 mmol) at 80°C for 17 h. Filter the mixture through a pad of Celite® and
evaporate the filtrate. Dissolve the residue in DCM and filter through a pad of silica gel.
Evaporate the filtrate and purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0 to 2:3) to give the desired intermediate as a white solid (12.4 g, 86%).
MS (ES+) m/r. 412 (M+H)+.
6-Amino-7-chloro-3-(2^J-trifluoroacetviy-23,4.5-tetrahvdro-l/f-benzol Treat 7-chloro-6-(4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
17/-benzo[t/]azepine(5.41 g, 13.1 mmol) with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (3.59 g, 15.8 mmol) in toluene (66 mL) at ambient temperature for 2 h.
Dilute the mixture with EtOAc and wash with saturated aqueous NaHCO3 (5 x 100 mL).
Extract the aqueous layer with ether, combine the organic extracts and evaporate to a
volume of 300 mL. Extract the organic phase with IN aqueous HC1 (5 x 100 mL), and
then wash the combined aqueous layers with ether (4 x 75 mL). Cool the aqueous phase
to 0°C, neutralize with 5N aqueous NaOH (100 mL), and extract with DCM (5 x 200
mL). Wash the combined organic extracts with brine, dry over Na2SC>4 and evaporate to
obtain the title compound as a white solid (3.6 g, 94%). MS (ES+) mJr. 293 (M+H)+.


6-(2-te/i/-Butoxvcarbonvlamino-ethYlamino)-7-chloro-3-(2,2^-trifluoroacetYl)-
2,3,4,5-tetrahvdro-l/7-benzo[ 5-1, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[]azepine (150 mg, 0.352 mtnol), palladium(II) acetate (8 mg,
0.0352 mmol), BINAP (22 mg, 0.0352 mmol), cesium carbonate (163 mg, 0.5 mmol), t-
butyl JV-(2-aminoethyl)-carbamate (254 mg, 1.59 mmol) and toluene (6 mL) to give, after
chromatography on silica gel eluting with hexane/EtOAc (4:1), the desired intermediate
(136 mg, 89%).
6-(2-Amino-ethvlamino)-7-chloro-3-(2^^-trifluoroacetYlV-2 benzof (2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine (136 mg, 0.31 mmol) in 4M
hydrogen chloride in dioxane (20 mL) and stir at ambient temperature for 25 min.
Concentrate to afford the hydrochloride salt. Dissolve the salt in DCM and wash with
saturated aqueous NaHC(>}. Extract the basic aqueous layer with DCM, dry the organic
layer over MgSCu, filter, and concentrate in vacuo to give the title compound (64 mg,
62%). MS (ES+) m/z: 336 (M+H)+.
Preparation 21
6-(3-Amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzor-"""—:—


Use a method similar to the Preparation 20, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
(600 mg, 1.41 mmol) and ter/-butyl iV-(3-aminopropyl)-carbamate (1.11 g, 6.34 mmol) to
give the title compound (34% overall).
Preparation 22
7-Chloro-6-(4-hydroxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[
Dissolve 7-chloro-6-(4-methoxybenzylamino)-3-(2,2^-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[]azepine (1.667 g) in DCM (40 mL). Add a 1M solution of boron tribromide
in DCM (10 mL) at 0°C. Stir the reaction for 12 h and gradually raise to room
temperature. Quench the reaction with saturated aqueous NaHCCb and extract with DCM
three times. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and
concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3) to
give the title compound as an oil (888 mg). MS (ES+) m/z: 399 (M+l)+.
Preparation 23
7-Chloro-6-(3-chloro-4-hydroxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
li/-benzo[rf]azepine


7-Chloro-6-(3-chloro-4-inethoxYbenzvlaniinoV3-(2,2,2-trifluoroacetvn-23,4,5-
tetrahvdro-l/7-bcnzo[tflazepine: Use a method similar to General Procedure 5-3, using
7-chloro-3 -(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5 -tetrahydro-1H-
benzo[ mmol) to give the desired intermediate as a slightly yellow oil (1.554 g, 100%).
7-Chloro-6-(3-chIoro-4-hvdroxvbenzylaminoV3-(2^,2-trifluoroacetvn-23 tetrahydro-l/f-benzoU/|azepine: Use a method similar to Preparation 22, using 7-
chloro-6-(3-chloro-4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[c/]azepine (1.36 g, 3.0 mmol) to give the title compound as an off-white solid
(876 mg, 67% yield). MS (ES+) m/z: 433 (M+H)+. MS (ES-) m/z: 431 (M-H)Preparation 24
3-(rert-Butoxycarbonyl)-6-(4-carboxy-benzylamino)-7-chloro-23,4,5-tetrahydro-l/T-

Combine 7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine (0.4 g, 0.82 mmol), potassium carbonate (4 g,
28.9 mmol), methanol (3 mL), water (3 mL) and heat at 50°C for 2 h. Cool the reaction
mixture to ambient temperature, add saturated aqueous Na2CO3 and dilute with DCM (10
mL). Add di-terf-butyl-dicarbonate (2.4 g, 10.9 mmol) by portions. Separate the organic
layer and extract the aqueous layer with DCM (3x10 mL). Combine the organic extracts,
dry over anhydrous Na2SC>4, evaporate the solvent and purify by chromatography on silica
gel eluting with DCM and DCM/methanol (9:1) to give the title compound as a white
solid (0.3 g, 80%). MS (ES+) m/z: 331 (M+H-Boc)+.


("2-BenzyloxyethvD-carbamic acid tert-bntyl ester: Dissolve tert-butyl-N-(2-
hydroxyethyl)-carbamate (10 mL, 64.5 mmol) in anhydrous THF (500 mL) at 0 °C. Add
sodium hydride (60% in mineral oil, 3.1 g, 77.4 mmol) and stir for 30 min at 0 °C. Add
benzyl bromide (9.2 mL, 77 mmol) followed by tetrabutylammonium iodide (3.7 g, 10
mmol) and stir at ambient temperature overnight. Quench with water (500 mL), extract
with diethyl ether (3 x 100 mL), wash the combined organic extracts with brine, dry over
MgSO4, filter, and evaporate to give the desired intermediate (15 g), that was used
without further purification.
2-BenzyIoxyethYlamine: Dissolve (2-benzyloxyethyl)-carbamic acid /erf-butyl ester (15
g) in DCM (50 mL), add trifluoroacetic acid (20 mL) and stir at 0°C for 3 h. Concentrate
and dissolve the residue in a minimal amount of DCM. Purify by chromatography on
silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc and 2M ammonia
in methanol to give the title compound (8.3 g, 85%).
Preparation 26
(/f)-2-Benzyloxy-1 -methyl-ethylamine

(/?)-3-Benzyloxv-2-(ferr-biitoxvcarbonYlamino)-propane: Dissolve (R)-(+)-2-(tert-
butoxycarbonylamino)-l-propanol (875 mg, 5 mmol) in anhydrous THF (50 mL). Add
sodium hydride (60% in mineral oil, 210 mg, 5.2 mmol) and stir at 0°C for 30 min. Add
benzyl bromide (620 \iL, 5.2 mmol) followed by tetrabutylammonium iodide (20 mg, 0.05
mmol) and stir for 3 h at ambient temperature. Pour the mixture into water (200 mL),
extract with DCM (3 x 50 mL), wash with brine, dry over MgSC>4, filter and concentrate.

Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give the
desired intermediate as a colorless oil (800 mg, 60%).
(/fV2-Benzyloxv-l-methvl-cthvlamine: Dissolve (/?)-3-benzyloxy-2-(ferf-
butoxycarbonylamino)-propane (800 mg, 3 mmol) in DCM (10 mL), add trifluoroacetic
acid (5 mL), and stir at 0 °C for 20 min. Evaporate and purify by SCX chromatography to
give the title compound as a colorless oil (440 mg, 89%). MS (ES+) m/z: 166 (M+H)+
Preparation 27
(R)-2-(4-Fluorobenzyloxy)-l-methyl-ethylamine

(Jt)-2-(/cr/-ButoxycarbonvlaniiDo)-3-(4-fluorobenzvloxvVproDane: Dissolve (R)-(+)-2-
(ter/-butoxycarbonylamino)-l-propanol (1.75 mg, 10.5 mmol) in anhydrous THF (50
mL). Add sodium hydride (60% in mineral oil, 480 mg, 12 mmol) and stir at 0°C for 30
min. Add 4-fluorobenzyl bromide (1.5 mL, 12 mmol) followed by tetrabutylammonium
iodide (370 mg, 0.1 mmol) and stir for 72 h at ambient temperature. Pour the mixture
into water (500 mL), extract with DCM (3 x 150 mL), wash with brine, dry over MgSC>4,
filter'and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1) to give the desired intermediate as a yellow oil (2.18 g, 77%).
(/?)-2-(4-FluorobenzvloxvH-methvl-ethylamine: Dissolve (R)-2-{tert-
butoxycarbonylamino)-3-(4-fluorobenzyloxy)-propane (2.18 g, 7.7 mmol) in DCM (50
mL), add trifluoroacetic acid (25 mL), and stir at 0°C for 20 min. Evaporate and purify by
SCX chromatography to give the title compound as a colorless oil (1.2 g, 85%). MS
(ES+) m/z: 184(M+H)+
Preparation 28
(R)-1 -Methyl-2-phenoxy-ethylamine


(in-2-(fert-ButoxvcarbonylaminoV3-phenoxv-propane: Dissolve (R)-(+)-2-(tert-
butoxycarbonylamino)-l-propanol (1.75 g, 10 mmol) and phenol (0.95 g, 10 mmol) in
anhydrous THF (75 mL). Cool to 0°C, add triphenylphosphine (4.0 g, 15 mmol) and
diisopropylazodicarboxylate dropwise and stir at ambient temperature for 18 h. Pour the
mixture into water (300 mL), basify to pH 10 with 5N aqueous NaOH, and extract with
ethyl ether (3 x 100 mL). Wash the organic phase with brine, dry over MgSO^, filter and
concentrate. Purity by chromatography on silica gel eluting with hexane/EtOAc (9:1) to
give the desired intermediate as an off-white solid (340 mg, 14%).
(JtV-l-Methvl-2-phenoxv-ethvlamine: Dissolve (i?)-2-(ter/-butoxycarbonylamino)-3-
phenoxy-propane (340 mg, 1.35 mmol) in DCM (80 mL), add trifluoroacetic acid (35
mL), and stir at 0 °C for 2 h. Evaporate and purify by SCX chromatography to give the
title compound as a colorless oil (186 mg, 91%). MS (ES+) m/z: 151 (M+H)+
Preparation 29
4-(Aminomethyl)-2-methyl-thiazole

4-(Azidomethvl)-2-methyl-thiazole: Dissolve 4-(chloromethyl)-2-methyl-thiazole (350
mg, 2.37 mmol) and azidotrimethylsilane (315 \JL, 2.37 mmol) in anhydrous THF (1 mL)
under nitrogen. Add a 1M solution of tetrabutylammonium fluoride (3.6 mL, 3.56 mmol)
in THF and stir at ambient temperature overnight. Pour the reaction mixture into water
(10 mL), extract with ethyl ether (3x2 mL), wash the organic extracts with brine, dry
over MgSC>4, filter, and evaporate. Purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (165 mg, 45%).

4-(Aminomethvl)-2-methyl-thiazole: Add 4-(azidomethyl)-2-methyl-thiazole (165 mg,
1.07 mmol) to a slurry of methanol containing 10% Pd/C (75 mg) and stir vigorously
under 1 atm H2 for 1 h. Filter, evaporate the solvent, and purify by SCX chromatography
to give the title compound (55 mg, 40%).

(4-Bromo-2-fIuorobenzvD-carbamie acid tert-butyl ester: Mix under nitrogen 4-
bromo-2-fluorobenzylamine hydrochloride (7.2 g, 30 mmol), di-ferr-butyl-dicarbonate
(9.8 g, 45 mmol), and potassium carbonate (12.4 g, 90 mmol) in anhydrous THF (200
mL). Stir at ambient temperature for 16 h. Filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired
intermediate (6.4 g, 70%). GC-MS m/z: 247 [(M-C^)*].
(2-Fluoro-4-phenoxv-ben2yl)-carbamic acid tert-batyl ester: Mix under argon
atmosphere (4-bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester (2.12 g, 7.0 mmol),
phenol (1.32 g, 14 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (129 mg, 0.7 mmol), and
cesium carbonate (4.56 g, 14 mmol) in anhydrous NMP (15 mL). Degas the flask, fill
with argon and add copper(I) chloride (346 mg, 3.5 mmol) quickly. Degas the flask then
fill with argon and heat at 120°C for 5 h. Cool to ambient temperature, dilute with EtOAc
and filter. Wash the mixture sequentially with 0.5N aqueous HC1, 0.5N aqueous NaOH
and brine. Separate the organic layer, dry over Na2SC>4 and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 3:1) to obtain
the desired intermediate (1.28 g, 58%). GC-MS m/z: 260 [(M-C4H9)+].

2-Fluoro-4-phenoxv-benzylamine; Dissolve (2-fluoro-4-phenoxy-benzyl)-carbamic acid
ferf-butyl ester (2.44 g, 7.72 mmol) in DCM (200 mL). Add trifluoroacetic acid (50 mL)
then stir at ambient temperature for 16 h. Evaporate the solvent, dissolve the residue in
DCM and wash with IN aqueous NaOH. Dry over Na2SC»4 and concentrate in vacuo.
Purify by SCX chromatography to obtain the title compound (557 mg, 33%). MS (ES+)
m/z: 201 (M+H-NH3)+.
Preparation 31
2-Fluoro-4-(3'-fluorophenoxy)-benzylamine

Use a method similar to Preparation 30, using (4-bromo-2-fluorobenzyl)-carbamic
acid terf-butyl ester (2.12 g, 7.0 mmol) and jw-fluorophenol (1.57 g, 14 mmol) to give the
title compound (468 mg, 47% overall).
Preparation 32
4-(2' -Fluorophenoxy)-benzylam ine

^(I'-FluorophenoxvVbenzonitrile: Mix under argon atmosphere 4-bromobenzonitrile
(2.0 g, 11.3 mmol), 2-fluorophenol (2.5 g, 22.6 mmol), 2,2,6,6-tetramethylheptane-3,5-
dione (203 mg, 1.1 mmol), and cesium carbonate (7.4 g, 22.6 mmol) in anhydrous NMP
(19 mL). Degas the flask, fill with argon and add copper(I) chloride (554 mg, 5.6 mmol)
quickly. Degas the flask then fill with argon and heat at 120°C for 3 h. Cool to ambient
temperature, dilute with EtOAc, filter and wash the filtrate sequentially with 2M aqueous
HC1, 0.3M aqueous HC1, 2M aqueous NaOH and brine. Separate the organic layer, dry
over Na2SC>4 and concentrate in vacuo. Purify by chromatography on silica gel eluting

with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate (1.6 g, 66%). MS
(ES+) m/z: 231 (M+NH4)+.
4-(2'-FIiiorophenoxy)-benzylamine: Add 4-(2'-fluorophenoxy)-benzonitrile (1.5 g, 7.0
mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel.
Immediately add a 7N solution of ammonia in methanol (170 mL) and seal the vessel.
Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen
(3400 KPa), seal the vessel, agitate the reaction and heat to 60°C. Continue the reaction
for 18 h, turn off the heat and allow the reaction mixture to cool to ambient temperature.
Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the
reaction mixture to remove the Raney® nickel. Concentrate in vacuo and purify by
chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain
the title compound (1.2 g, 79%). MS (ES+) m/z: 201 (M+H-NH3)+.
The compound of Preparation 33 may be prepared essentially as described in
Preparation 32 using 4-bromobenzonitriie and 3-fluorophenol. Overall yield and MS
(ES+) data are shown in the Table below.

Use a method similar to Preparation 32 (Step 1), using 4-bromobenzonitrile (2.0 g,
11.3 mmol) and 3-isopropylphenol (3.08 g, 22.6 mmol) to give 4-(3'-isopropylphenoxy)-
benzonitrile (885 mg, 33%). MS (ES+) m/z: 255 (M+NH4)+.

Use a method similar to the reduction procedure described in Preparation 45 (Step
2), using 4-(3'-isopropylphenoxy)-benzonitrile (875 mg, 3.7 mmol) to give the title
compound (703 mg, 79%). MS (ES+) m/z: 225 (M+H-NH3)+.
The compounds of Preparations 35-39 may be prepared essentially as described in
Preparation 34 by using 4-bromobenzonitrile and the appropriate phenol. Overall yields
and MS (ES+) data are shown in the Table below.

(4-Hvdroxvbenzvfl-carbamic acid tert-butvl ester: Mix 2,2,2-trifluoro-JV-(4-
hydroxybenzyl)-acetamide (8.8 g, 40 mmol), and 5N aqueous NaOH (20 mL) in methanol
(100 mL). Stir at ambient temperature for 4 h. Adjust pH to about 8 with aqueous HC1.
Add solid sodium bicarbonate (4.4 g, 52 mmol), di-ter/-butyl-dicarbonate (9.3 g, 40
mmol) and DCM. Stir at ambient temperature for 16 h. Dilute with DCM, wash with IN
aqueous HC1 and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1
to 5:5) to obtain the desired intermediate (7.8 g, 87%). MS (ES-) m/z: 222 (M-H)
2-(4-Aminomethyl-phenoxy)-benzonitrile: Mix under argon (4-hydroxybenzyl)-
carbamic acid fert-butyl ester (1.5 g, 6.7 mmol), 2-bromobenzonitrile (813 mg, 4.5
mmol), 2,2,6,6-tetramethylheptane-3,5-dione (83 mg, 0.45 mmol), and cesium carbonate
(2.2 g, 6.7 mmol) in anhydrous NMP (8.5 mL). Degas the flask and fill with argon. Add
copper(I) chloride (223 mg, 2.25 mmol) quickly. Degas the flask, fill with argon and heat
at 120°C for 3 h. Cool to ambient temperature, dilute with EtOAc, filter and concentrate
in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and
3:1). Evaporate the solvent and dissolve the residue in DCM( 100 mL). Add
trifluoroacetic acid (20 mL) and stir at ambient temperature for 16 h. Concentrate in
vacuo, dissolve the residue in EtOAc and wash with IN aqueous NaOH. Dry over
Na2SC>4 and concentrate in vacuo. Purify by SCX chromatography to obtain the title
compound (385 mg, 38%). MS (ES+) m/z: 225 (M+H)+.
The compounds of Preparation 41-43 may be prepared essentially as described in
Preparation 40 by using (4-hydroxybenzyI)-carbamic acid ferf-butyl ester (1.5 g, 6.7
mmol) and the appropriate bromide. Overall yields and MS (ES+) data are shown in the
Table below.

Use a method similar to Preparation 40 (Step 2), using 2,2,2-trifluoro-iV-(4-
hydroxybenzyl)-acetamide (1.0 g, 5.5 mmol) and 3-bromobenzonitrile (673 mg, 3.7

mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3;1).
Concentrate in vacuo. Dissolve the residue (287 mg, 0.89 mmol) in methanol (25 mL) and
add 5N NaOH (7 mL). Stir at room temperature for 4 h. Dilute with DCM and add solid
sodium chloride to the mixture. Extract the aqueous layer three times with DCM.
Combine organic extracts, dry over Na2SC>4 and concentrate in vacuo. Purify by
chromatography on silica gel eluting with DCM/2M ammonia in methanol (94:6) to
obtain the title compound (124 mg, 62%). MS (ES+) m/z: 500 (M+H)+.
Preparation 45
4-(3,3-Dimethylbutoxy)-benzylamine

4-(33-Dimethylbiitoxv)-benzonitrile: Mix 4-cyanophenol (1.2 g, 10 mmol), 1-bromo-
3,3-dimethylbutane (5.3 g, 32 mmol), powdered potassium carbonate (4.14 g, 30 mmol),
and powdered potassium iodide (166 mg, 1 mmol) in acetone (60 mL). Stir under inert
atmosphere and heat at reflux for 48 h. Cool the reaction mixture to ambient temperature.
Dilute with acetone, filter and evaporate. Purify by chromatography on silica gel eluting
with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate (1.8 g, 89%). MS
(ES+) m/z: 221 (M+NRO*.
4-(3,3-Dimethylbutoxy)-benzYiamine: Mix lithium aluminum hydride (1.0 g, 26.6
mmol) and anhydrous ethyl ether (70 mL) under nitrogen atmosphere. Stir and cool to 0
°C in an ice bath. Add dropwise a solution of 4-(3,3-dimethylbutoxy)-benzonitrile (1.8 g,
8.87 mmol) in anhydrous ethyl ether (20 mL). Stir for 2 h at 0 °C, remove the ice bath
and stir at ambient temperature for 18 h. Cool the reaction flask in an ice bath and add
carefully dropwise and sequentially water (1 mL), 2N aqueous NaOH (1 mL), and water
(2 mL). Stir for 30 min, filter, separate the organic layer, dry over Na2SC>4 and
concentrate in vacuo to obtain the title compound (1.62 g, 88%). MS (ES+) m/z: 191
(M+H-NH3)+.

The compounds of Preparations 46-48 may be prepared essentially as described in
Preparation 45 by using 4-cyanophenol and the appropriate bromide. Overall yields and
MS (ES+) data are shown in the Table below.

4-Benzyloxv-benzonitrile: Add 4-cyanophenol (1.191 g, 10 mmol), benzyl bromide
(1.881 g, 11 mmol), potassium carbonate (3.455 g, 25 mmol) and potassium iodide (166
mg, 1 mmol) to acetonitrile (80 mL) and heat at reflux for 12 h. Cool, partition between
EtOAc and water, separate the organic layer, and extract the aqueous layer with EtOAc.
Combine the organic extracts, wash with brine, dry over Na2SC>4, filter and concentrate.
Purify by chromatography on silica gel eluting with EtOAc/hexane (1:6) to give the
desired intermediate as a white solid (2.098 g, 100%). MS (ES+) m/z: 227 (M+NH4)+.
4-Benzvloxv-benzvIamine: Use a method similar to Preparation 58, using 4-benzyloxy-
benzonitrile (2.098 g, 10 mmol), to give the title compound as a white solid (2.021 g,
94%). MS (ES+) m/z: 197 (M+H-NH3)+.
Preparation 50


(±>4-(l-Phenylethoxy)-benzonitrile: Add triphenylphosphine (7.869 g, 30 mtnol) to a
solution of sec-phenylethyl alcohol (1.467 g, 12 mmol), 4-cyanophenol (1.191 g, 10
mmol) and diethyl azodicarboxylate (4.528 g, 26 mmol) in anhydrous THF (50 mL) at
0 °C. Stir the reaction at ambient temperature for 12 h. Dilute with EtOAc, wash with
brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel
eluting with EtOAc/hexane (1:8) to give (±)-4-(l-phenylethoxy)-benzonitrile with a small
amount of triphenylphosphine (2.49 g total).
(±)-4-(l-Phenvlethoxv>-benzvlamine: Use a method similar to Preparation 58, using
crude (±)-4-(l-phenylethoxy)-benzonitrile, to give the title compound as a colorless oil
(1.6 g, 70% two steps). MS (ES+) m/r. 211 (M+H-NH3)+, 455.3 (2M+H)+.

2,2,2-Trifluoro-7V-(4-methoxybcnzvl)-acetamide: Mix under nitrogen atmosphere 4-
methoxybenzylamine (13.7 g, 100 mmol) and iV-methylmorpholine in anhydrous THF
(300 mL). Cool to 0°C in an ice bath. Add dropwise a solution of trifluoroacetic
anhydride (15.6 mL, 110 mmol) in anhydrous THF (25 mL). Warm up to ambient
temperature slowly and stir for 16 h. Concentrate in vacuo. Dissolve in EtOAc and wash
successively with IN aqueous NaOH, IN aqueous HC1, and brine. Separate the organic
layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel

eluting with hexane/EtOAc (9:1 and 4; 1) to obtain the desired intermediate (19 g, 81%).
MS (ES-) m/z: 232 (M-H)2J^-Trifluoro-AL(4-hYdroxv-benrvl>-acetamide: Dissolve under nitrogen atmosphere
2,2,2-trifluoro-A^-(4-methoxybenzyl)-acetamide (11.6 g, 50 mmol) in DCM (250 mL).
Cool to 0°C in an ice bath. Add dropwise 1M boron tribromide in DCM (100 mL, 100
mmol) and stir for 20 min after addition. Warm to ambient temperature and stir for 16 h.
Cool the reaction mixture in an ice bath and quench very carefully with saturated aqueous
NaHCCh. Separate the organic layer. Extract the aqueous layer twice with chloroform.
Dry the combined organic extracts over Na2SO4 and concentrate in vacuo to obtain the
desired intermediate (8.8 g, 40 mmol). MS (ES-) m/z: 218 (M-H)/V-|4-(33-Dimethyl-2-oxo-butoxy)-beiizvll-2v2,2-trifluoroacetainide:
Mix 2,2^-trifluoro-A^-(4-hydroxy-benzyl)-acetamide (438 mg, 2.0 mmol), 1-
bromopinacolone (430 mg, 2.4 mmol), anhydrous potassium carbonate (829 mg, 6.0
mmol) and potassium iodide (33 mg, 0.1 mmol) with acetone. Heat under reflux for 12 h.
Acidify with IN aqueous HC1 and extract with EtOAc three times. Combine the organic
extracts, wash with brine, dry over N^SCu, filter and concentrate. Purify by
chromatography on silica gel eluting with EtOAc/hexane (1:3) to give the desired
intermediate as a colorless oil. MS (ES+) m/z: 335 (M+NH4)+. MS (ES-) m/z: 316
(M-H)".
4-(3,3-Dimethvl-2-oxo-butoxy)-benzYlainine: Add 5N aqueous NaOH (15 mL) to a
solution of//-[4-(3,3-dimethyl-2-oxo-butoxy)-benzyl]-2,2,2-trifluoro-acetamide (552 mg,
1.74 mmol) in methanol (10 mL) and stir for 2 h at ambient temperature. Extract the
mixture with DCM three times. Dry the combined organic extracts over Na2SC>4, filter
and concentrate. Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (92:8) to give the title compound as a colorless oil (337 mg, 87%). MS
(ES+) m/z: 205 (M+H-NH3)+.
Preparation 52
Ar-(2-Chloro-acetyl)-piperidine


Add chloroacetyl chloride (1.242 g, 11.0 mmol) to a mixture of potassium
carbonate (2.073 g, 15 mmol) and piperidine (852 mg, 10 mmol) in THF (50 mL) at 0 °C.
Stir the reaction for 12 h and gradually raise to room temperature. Dilute with water,
extract with EtOAc three times. Combine the organic extracts and wash sequentially with
saturated aqueous NaHCO3, 0.1N aqueous HC1 and brine. Dry over Na2SO4, filter and
concentrate to give the title compound (1.65 g, 100%).
Preparation S3
4-Benzylthio-benzylamine

4-Beiizvlthio-benzonitrile: Mix under argon atmosphere 4-fluorobenzonitrile (1.21 g, 10
mmol), benzyl mercaptan (1.86 g, 15 mmol), and cesium carbonate (6.5 g, 20 mmol) in
anhydrous NMP (20 mL). Degas the flask and fill with argon. Heat at 120°C for 3 h.
Cool to ambient temperature, dilute with EtOAc, filter and wash with IN aqueous HC1.
Separate the organic layer, dry over Na2SC>4 and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the
desired intermediate (689 mg, 31%). GC-MS mJz: 225 (M*).
4-BenryIthio-benzylamine: Use the reduction procedure described in Preparation 45
(Step 2), using 4-benzylthio-benzonitrile (689 mg, 3.1 mmol) to give, after SCX
chromatography, the title compound (464 mg, 64%). MS (ES+) m/z: 213 (M+H-NH3)+.


4-(2,23*33-Pentafluoropropoxv)-benzonitrile: Heat a mixture of 4-hydroxy-
benzonitrile potassium fluoride complex (3.0 g, 16.9 mmol) and l,l,l,2,2-pentafluoro-3-
iodo-propane (10.8 g, 37.2 mmol) in DMSO (80 mL) to 130°C for 20 h. Cool the mixture
to ambient temperature, dilute with hexane/EtOAc (1:1,200 mL) and wash with aqueous
10% NaCl (3 x 50 mL). Dry the organic layer, concentrate in vacuo and purify by
chromatography on silica gel eluting with hexane/EtOAc (10:1, 10:2 and 10:3) to obtain
the desired intermediate (1.1 g, 26%). GC-MS m/r. 251 (M+).
4-(2,2,3.33-Pentafluoropropoxv)-benzylamine: Use a method similar to the General
Procedure 6-4, using 4-(2,2,3,3,3-pentafluoropropoxy)-benzonitrile (1.1 g, 4.1 mmol), to
obtain the title compound (1.1 g, 99%). GC-MS m/r. 254 (NT-H).
Preparation 55
4-(2,2,3,3-Tetrafluoropropoxy)-benzylamine

Use a method similar to Preparation 54, using 4-hydroxy-benzonitrile potassium
fluoride complex (4.2 g, 23.7 mmol) and l,l,2,2-tetrafluoro-3-iodo-propane (10 g, 41.3
mmol), to give the title compound (38% overall). GC-MS m/z: 236 (M^H).


4-(2,2 propanol (3.4 g, 27 mmol) slowly to a slurry of sodium hydride (0.6 g, 60% in mineral oil,
washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add
a solution of 4-nitrobenzonitrile (2.0 g, 13.5 mmol) in HMPA (10 mL). Stir the resulting
purple slurry at ambient temperature for 16 h, dilute with diethyl ether (100 mL) and wash
with 5% aqueous HC1 (30 mL). Separate the layers and extract the aqueous layer with
diethyl ether (2 x 50 mL). Combine the organic extracts and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the
desired intermediate (780 mg, 25%). GC-MS m/r. 229 (M1).
4-(2.2.2-Trifluoro-l.l-dimethvl-ethorv>-benzvlaniine: Use a method similar to the
General Procedure 6-4 to reduce 4-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-benzonitrile (780
mg, 3.4 mmol). Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (40:1,20:1 and 10:1) to obtain the title compound (780 mg, 98%). GC-MS
m/r. iyi (M^-H).
Preparation 57
(±)-4-(2,2,2-Trifluoro-1 -methyl-ethoxy)-benzylamine

(±)-4-(2,2^-Trifluoro-l-methvl-etlioxv>-benzonitriIe: Add l,l,l-trifluoro-2-propanol
(3.8 g, 66 mmol) slowly to a slurry of sodium hydride (730 mg, 60% in mineral oil,
washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add

4-fluorobenzonitrile (2 g, 16,5 mmol). Heat the slurry in a sealed flask to 90°C for 16 h.
Cool the mixture to ambient temperature and pour the mixture into a flask containing 5%
aqueous HC1 (20 mL). Extract the mixture with diethyl ether (3 x 50 mL), and wash with
5% aqueous HC1 (25 mL). Dry the organic layer over Na2SC>4 and concentrate in vacuo.
Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the
desired intermediate (2.5 g, 70%). GC-MS m/z: 215 (NT).
(±)-4-(2,2,2-Trifluoro-l-methyl-ethoxy)-benzvlamine: Use a method similar to the
General Procedure 6-4, using (±)-4-(2,2,2-trifluoro-l-methyl-ethoxy)-benzonitrile (1.0 g,
4.6 mmol), to obtain the title compound (1.1 g, 95%). GC-MS m/z: 218 (Nf-H).
Preparation 58
3-Methoxybenzylamine

Add lithium aluminum hydride (3.795 g, 100 mmol) portion wise to a solution of
3-methoxybenzonitrile (5.326 g, 40 mmol) in anhydrous ethyl ether (200 mL) at 0°C. Stir
for 1 h, warm to ambient temperature and continue to stir for 12 h. Quench the reaction
with 0.1N aqueous NaOH, filter the solid, dry the filtrate over Na2SO4 and concentrate to
give the title compound as a colorless oil (5.107 g, 93%). MS (ES+) m/z: 138 (M+H)+.
Preparation 59
3-(tert-Butyl)benzylamine


Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL).
Add NBS (530 mg, 3 mmol) and irradiate the reaction mixture with a 250 watt sun-lamp
with simultaneous heating to reflux for 1 h. Cool to ambient temperature, filter, and
concentrate filtrate to dryness to give crude l-bromomethyl-3-tert-butylbenzene. Dissolve
crude l-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portion wise
sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h. Pour the mixture
into water (250 mL), extract with EtOAc (3x50 mL), wash combined organic extracts
with brine, dry over MgSC>4, filter and evaporate solvent to give crude l-azidomethyl-3-
/ert-butylbenzene, that was used without further purification. Dissolve crude 1-
azidomethyl-3-ter/-butylbenzene in methanol containing 10% Pd/C (75 mg) at 5°C, and
stir the resulting slurry under 1 atm Ft for 1 h. Filtrate, concentrate in vacuo and purify by
chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1),
EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53%
overall). MS (ES+) m/z: 164 (M+H)+.
Preparation 60
(3 -Pyrrolidin-1 -yl)benzylamine

Slurry a mixture of (3-bromobenzyl)-carbamic acid /ert-butyl ester (600 mg, 2.1
mmol, U.S. Pat. Appl. Publ. US 2003134885), pyrrolidine (450 mL, 5.2 mmol),
tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.21 mmol), BINAP (400 mg, 0.63
mmol) and cesium carbonate (960 mg, 2.94 mmol) in anhydrous toluene (10 mL). Degas
under vacuum, fill the system with nitrogen and heat in a sealed flask at 90 °C for 18 h.
Cool to room temperature, dilute with diethyl ether, filter, and concentrate in vacuo.
Dissolve the resulting residue in DCM (10 mL) and add trifluoroacetic acid (5 mL). Stir at
ambient temperature for 1 h and concentrate in vacuo. Purify by chromatography on silica
gel eluting sequentially with hexane/EtOAc (1:1), EtOAc and 2M ammonia in methanol.
Purify again by SCX chromatography to give the title compound as a brown oil (300 mg,
85% overall). MS (ES+) m/z: 178 (M+H)+.


4-AIlvloxv-3-bromo-benzonitrile: Mix 3-bromo-4-hydroxy-benzonitrile (1.520 g, 8.0
mmol), allyl bromide (1.161 g, 9.6 mmol), potassium carbonate (3.317 g, 24 mmol) and
potassium iodide (133 mg, 0.1 mmol) in acetone (80 mL). Heat the mixture to reflux for
12 h. Cool to ambient temperature, add EtOAc, wash the organic layer with water, and
extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over
Na2SC>4, filter and concentrate. Purify by chromatography on silica gel eluting with
EtOAc/hexane (1:8) to obtain the desired intermediate.
(±y3-Methvl-23-dihvdro-benzofuran-5-carbonitrile: Add tri-n-butyltin hydride (5.821
g, 20 mmol) and AIBN (411 mg, 2.5 mmol) to a solution of 4-allyloxy-3-bromo-
benzonitrile (595 mg, 2.5 mmol). Heat the reaction at reflux for 20 h. Dilute with EtOAc
and wash with water. Extract the aqueous layer with EtOAc three times. Combine the
organic extracts, wash with brine, dry over Na2SO4, filter and concentrate in vacuo.
Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give the
desired intermediate as a white solid (474 mg, 100% with a trace amount of tributyltin
derivative).
(±VC-(3-Methvl-2^-dihvdro-benzofuran-5-vl)-inethvlamine: Use a method similar to
Preparation 58, using (±)-3-methyl-2,3-dihydro-benzofiiran-5-carbonitrile (474 mg, 2.98
mmol) to give the title compound as a colorless oil (410 mg, 84%).
The compounds of Preparations 62-64 may be prepared essentially as described in
Preparation 61 by using 3-bromo-4-hydroxy-benzonitrile or 4-bromo-3-hydroxy-
benzonitrile and the appropriately substituted allyl bromide. MS (ES+) data are shown in
the Table below.


JV-f2.2-Dimethvl-3-oxo-23-dihvdro-benzofuran-S-vlmethvl)-2J2-trifluoro-
acetamidc: Add 2-bromoisobutyryl bromide (1.724 g, 7.5 mmol) to a solution of 2,2,2-
trifluoro-A'-(4-methoxy-benzyl)-acetamide (1.166 g, 5.0 mmol) in 1,2-dichloroethane (8
mL) at 15°C, then add powdered anhydrous iron(III) chloride (973 mg, 6.0 mmol). Stir
the reaction at 15°C for 3 h and at ambient temperature for 8 days. Add dropwise
saturated aqueous potassium sodium tartrate, then water and EtOAc, and stir for 1 h.
Filter off the solid, separate the organic layer, and extract the aqueous layer three times

with EtOAc. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and
concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane
(1:3) to give the desired intermediate (253 mg, 17%).
C-(2,2-dimethvl-3-oxo-23-dihvdro-benzofuran-5-yl)-methvlamine: Dissolve i^-(2,2-
dimethyl-3-oxo-2,3-dihydro-benzoruran-5-ylmethyl)-2,2>2-trifluoro-acetamide(253 mg,
0.88 mmol) in 7M ammonia in methanol and stir at ambient temperature for 5 days.
Remove volatiles in vacuo, purify by chromatography on silica gel eluting with DCM/2M
ammonia in methanol (92:8) to give the title compound (44 mg, 26%). MS (ES+) m/z:
175 (M+H-NH3)+.
Preparation 66
C-(2,2-Dimethyl-3-oxo-2,3-dihydro-benzofiiran-6-yl)-methylamine

2J3-Trifluoro-N-(3-method-beiizvlVacetamide: Add trifluoroacetic anhydride (6.3 g,
30 mmol) to a solution of 3-methoxybenzylamine (3.43 g, 25 mmol) and A'-methyl-
morpholine (3.793 g, 37.5 mmol) in THF (80 mL) at 0°C and stir at this temperature for 4
h. Warm to ambient temperature and stir for 12 h. Dilute with EtOAc, wash sequentially
with water, IN aqueous HC1, saturated aqueous NaHCCh and brine. Dry the organic layer
over Na2SC>4, filter and concentrate. Purify by chromatography on silica gel eluting with
EtOAc/hexane (1:3) to give the desired intermediate (5.344 g, 91%).
C-(2..2-Dimethyl-3^xo-23-dihvdro-benzofuran^vn-methvlamine: Use a method
similar to Preparation 65, using 2,2,2-trifluoro-#-(3-methoxy-benzyl)-acetamide (1.166 g,
5 mmol), to give the title compound (220 mg, 23% two steps). MS (ES+) m/z: 192
(M+H)+.

Preparation 67
6-Arninomethyl-2,2-dimethyl-2//-chromene

Add 2,2-dimethyl-2//-chromene-6-carbonitrile (1.5 g, 8.1 mmol) and ethanol wet
Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add 7N ammonia
in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen,
pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the
reaction and heat to 60°C for 20 h. Turn off the heat and allow the reaction mixture to
cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the
vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Purify by
chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain
the title compound (1.5 g, 97%). MS (ES+) m/z: 175 (M+H-NH3)+.
Preparation 68
4-(2-Methylthiazol-4-yl)-benzylamine

4-(2-Methylthiazol-4-yl)-benzonitrile: Suspend 4-cyanophenacyl bromide (515 mg, 2.23
mmol) in ethanol (15 mL). Add thioacetamide (171 mg, 2.23 mmol) and sodium
bicarbonate (187 mg, 2.23 mmol) and heat the mixture under reflux for 2 h. Concentrate
in vacuo and dissolve the residue in DCM. Wash the organic fraction with water, dry
over Na2SC>4, filter and concentrate to give a solid. Suspend the solid in ether/hexane and
filter under vacuum washing with hexane to obtain the desired intermediate as a white
solid (415 mg, 93%). GC-MS m/z: 200 (M*).

4-(2-Methvlthiazol-4-vO-benzvlamine: Dissolve 4-(2-methylthiazol-4-yl)-benzonitrile
(305 mg, 1.52 mmol) in anhydrous THF (50 mL). Add a 1M solution of lithium
aluminum hydride in THF (3.05 mL, 3.05 mmol). Heat the mixture overnight under
reflux. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc
and water. Filter the mixture over Celite®. Separate the organic phase, and extract the
aqueous phase with chloroform. Dry the combined organic extracts over Na2SO4, filter
and concentrate to obtain the title compound as an oil (120 mg) that was used without
further purification. GC-MS nt/z: 204 (M4).
Preparation 69
4-(Pyridin-4-yl)-benzylamine

JV-fte/f-ButoxvcarbonvlV-4-bromo-benzylamiue: Add di-terf-butyl-dicarbonate (1.173
g, 5.375 mmol) and triethylamine (1.087 g, 1.0 mL, 10.75 mmol) to a stirred solution of
4-bromobenzylamine (1.0 g, 5.375 mmol) in anhydrous DCM (15 mL). Stir overnight at
ambient temperature, dilute with DCM and wash with water. Separate the organic phase,
dry over NajSCU, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (1:0, 19:1 and 9:1) to obtain the desired intermediate as a
solid (1.24 g, 81%).
JV-(tert-Butoxvcarbonvn-4-(Dvridin-4-vl>-benzvlamine: Dissolve NAtert-
butoxycarbonyl)-4-bromo-benzylamine (0.8 g, 2.807 mmol) in anhydrous DME (12 mL)
under nitrogen. Add tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol),
pyridine-4-boronic acid (0.513 g, 4211 mmol), and a 2M aqueous Na2CO3 solution (2.8
mL, 5.614 mmol). Heat the reaction overnight at 70°C. Cool the mixture to ambient
temperature, dilute with EtOAc, and filter over Celite®. Wash the organic fraction with
water, dry over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on

silica gel eluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give the title compound as an
oil (0.295 g, 37%). GC-MS m/z: 284 (M+).
4-(Pvridin-4-yI)-benzvlamine: Dissolve 7V-(ter/-butoxycarbonyl)-4-(4-pyridyl)-
benzylamine (363 mg, 1.276 mmol) in anhydrous DCM (10 mL). Add 4N hydrogen
chloride in dioxane (10 mL) and stir overnight at ambient temperature. Concentrate in
vacuo to obtain the hydrochloride salt in pure form as a solid. Dissolve the solid in
saturated aqueous NaHCC>3 and extract three times with DCM and three more times with
EtOAc. Combine the organic extracts, dry over NajSCv, filter and concentrate to obtain
the title compound as a solid (166 mg, 71 %). GC-MS m/z: 184 (M^).

4-(2-Pyridvl)-benzaldeliyde oxime: Add hydroxylamine hydrochloride (0.379 g, 5.458
mmol) and a solution of NaOH (0.327 g, 8.187 mmol) in water (2 mL) to a solution of 4-
(2-pyridyl)-benzaldehyde (0.5 g, 2.729 mmol) in ethanol (10 mL). Heat the mixture at 80
°C for 2 h. Cool to ambient temperature and remove the solvent in vacuo. Partition the
residue between EtOAc and water. Separate and dry the organic phase over Na2SO4, filter
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0 and 4:1) to obtain the desired intermediate (311 mg, 58%). GC-MS
m/z: 198 (M"1").
4-(Pvridin-2-vn-benzvlamine: Add Pd/C (10%, 50 mg) and concentrated HC1 (2 mL) to
a solution of 4-(2-pyridyl)-benzaldehyde oxime (0.29 g, 1.46 mmol) in absolute ethanol
(20 mL). Hydrogenate the mixture at 50 psi for 2 h. Filter over Celite®, wash with
ethanol and concentrate in vacuo to obtain the hydrochloride salt in pure form as a solid.
Dissolve the solid in saturated aqueous NaHCCh, extract the aqueous solution three times

with DCM and three more times with EtOAc. Combine the organic extracts, dry over
Na2SC>4, filter and concentrate in vacuo to obtain the title compound as a solid (130 mg,
48 %). GC-MS m/z: 184 (M+).
Preparation 71
4-(l-Methyl-l//-imidazol-2-yl)-benzylamine

f4-(l-Methvl-l/f-imidazol-2-vlVbcnzyIl-carbamic acid tert-butyl ester: Add 4-(N-tert-
Butoxycarbonyl-aminomethyl)phenylboronic acid (1.9 g, 7.4 mmol), 2-bromo-l-methyl-
1/7-imidazole (800 mg, 5.0 mmol), tetrakis(triphenyIphosphine)-palladium(0) (287 mg,
0.25 mmol) and potassium carbonate (860 mg, 6.2 mmol) to a flask containing toluene
(10 mL). Heat the mixture in a sealed flask at 90°C for 16 h. Cool the mixture, dilute
with EtOAc (50 mL), filter through Celite®, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc/methanol (49:50:1) to obtain the
desired intermediate (1.2 g, 83%). GC-MS m/z: 287(M+).
4-(l-Methvl-l//-imidazol-2-yl)-benzvlaroine: Dissolve [4-(l -methyl- li/-imidazol-2-yl)-
benzyl]-carbamic acid ter/-butyl ester (500 mg, 1.7 mmol) in DCM (20 mL) and
trifluoroacetic acid (5 mL). Stir the mixture for 1 h at ambient temperature. Concentrate
in vacuo and purify by SCX chromatography to obtain the title compound (240 mg, 74%).
MS (ES+) m/z: 188 (M+H)+.
Preparation 72
4-Ethanesulfonyl-benzylamine


4-Ethylthio-benzonitrile: Combine 4-mercapto-benzonitrile (0.4 g, 2.96 mmol),
bromoethane (1.4 mL, 8.88 mmol) and potassium carbonate (3.3 g, 23.7 mmol) in
anhydrous DMF (7 mL) and heat at 60°C for 17 h. Cool the reaction mixture to ambient
temperature and partition between brine (20 mL) and EtOAc (20 mL). Separate the
organic layer, dry over anhydrous Na2SC>4 and concentrate. Purify by chromatography on
silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate
as a colorless oil (0.4 g, 83%).
4-Ethanesulfonyl-benzonitrile: Dissolve 4-ethylthio-benzonitrile (0.4 g, 2.4 mmol) in
TFA (10 mL) and add slowly hydrogen peroxide (30 w%, 10 mL) at 5 °C. Stir the
reaction mixture at ambient temperature for 2 h and partition between brine (20 mL) and
DCM (20 mL). Separate the organic layer, dry over anhydrous Na2SO4 and concentrate to
obtain the desired intermediate as a white solid (0.5 g, 100%). GC-MS m/r. 195 (M*).
4-EthanesuIfonyI-benzylamine: Combine 4-ethanesuIfonyl-benzonitrile (0.7 g, 3.5
mmol), Raney® 3201 nickel (slurry in water, 0.1 g), 2N ammonia in methanol (20 mL)
and hydrogenate at 50 psi for 17 h. Filter the reaction mixture through a pad of Celite®
and concentrate in vacuo. Purify by SCX chromatography to obtain the title compound as
a yellow oil (0.3 g, 43%).
Preparation 73
4-(2-Propanesulfonyl)-benzylamine


Use a method similar to Preparation 72, using 4-mercapto-benzonitrile (0.5 g, 3.7
mmol) and 2- bromopropane (1.4 g, 11.38 mmol), to obtain the title compound as a
yellow oil (0.3 g, 39% overall).
Preparation 74
4-Aminometyl-iV-/er/-butyl-benzamide

TV-fert-butyl-^cvano-benzamide: Combine 4-cyanobenzoic acid (30 mg, 2.07 mmol),
terf-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89 mmol), and HATU (1.1
g, 2.89 mmol) in anhydrous DMF (7 mL). Stir at ambient temperature for 17 h. Partition
the reaction mixture between brine (15 mL) and diethyl ether (15 mL), separate the
organic layer, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by
chromatography on silica gel eluting with DCM to obtain the desired intermediate as a
white solid (0.4 g, 89%). MS (ES+) m/z: 203 (M+H)+.
4-Aminometvl-7V-terf-butyl-benzamide: Combine A^-/err-butyl-4-cyano-benzamide (0.4
g, 1.78 mmol), Raney® 3201 nickel (slurry in water, 0.03 g), 2N ammonia in methanol
(20 mL) and hydrogenate at 50 psi for 1 h. Filter the reaction mixture through a pad of
Celite®, remove the solvent and purify by SCX chromatography to obtain the title
compound as a colorless oil (0.4 g, 95%). MS (ES+) m/z: 207 (M+H)+.
Preparation 75
4-Aminometyl-2-fluoro-./V-tert-butyl-benzamide


4-Bromo-Af-/grt-butyl-2-fluoro-benzamide: Combine 4-bromo-2-fluoro-benzoic acid
(5.0 g, 22.83 mmol), thionyl chloride (10 rnL, 0.137 mol) in toluene (10 mL) and reflux
for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0
g, 93%) and use for the next step without further purification. Dissolve terr-butylamine
(0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL),
cool to 0°C and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol)
in anhydrous DCM (10 mL). Stir the reaction mixture at 0°C for 10 min, warm to
ambient temperature and continue to stir for 30 min. Wash the reaction mixture with
brine (2x10 mL), dry the organic extracts over anhydrous Na2SC>4, evaporate the solvent
and purify by chromatography on silica gel eluting with DCM to obtain the desired
intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
ALter/-Butvl-4-cyano-2-f1uoro-benzamide: Combine 4-bromo-A'-ferf-butyl-2-fluoro-
benzamide (1.0 g, 3.65 mmol) and copper(I) cyanide (0.7 g, 7.29 mmol) in anhydrous
DMF (10 mL) and reflux for 17 h. Cool the reaction mixture to ambient temperature and
treat with 50% (v/v) aqueous ethylenediamine (20 mL). Extract the reaction mixture with
diethyl ether (3x10 mL), combine the organic extracts, wash with brine (2x10 mL) and
dry the organic layer over Na2SC»4. Evaporate the solvent and purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0, 9:1,4:1, 7:3 and 3:2) to obtain the desired
intermediate as a white solid (0.6 g, 77%). MS (ES+) m/z: 221 (M+H)+.
4-Aminomethvl-2-fluoro-,/V-fcr/-butvl-benzarnide: Combine JV-terf-butyl-4-cyano-2-
fluoro-benzamide (0.6 g, 1.78 mmol), Raney® 3201 nickel (slurry in water, 30 mg), 2N
ammonia in methanol (30 mL) and hydrogenate at 50 psi for 1 h. Filter the reaction
mixture through a pad of Celite®, concentrate in vacuo and purify by SCX
chromatography to obtain the title compound as a colorless oil (0.6 g, 96%).
Preparation 76
4-Aminometyl-2-fluoro-./V-methyl-Ar-propyl-benzarnide


Use a method similar to Preparation 75, using 4-bromo-2-fluoro-benzoic acid (1.0
g, 4.56 mmol) and AT-methyl-propylamine (0.5 mL, 5.05 mmol), to give the title
compound as a colorless oil (0.5 g, 49%). GC-MS m/z: 224 (M*).
Preparation 77
4-Aminomethyl-iV-(2,2,2-trifluoro-ethyl)-benzamide

Use the General Procedure 6-1, using 2,2,2-trifluoroethylamine (197 mg, 2 mmol)
and 4-(ter/-butoxycabonylamino-methyl)-benzoic acid, to give the title compound as a
clear oil (440 mg, 94%). MS (ES+) m/z: 233 (M+H)+.
The compounds of Preparations 78-93 may be prepared essentially as described in
Preparation 77 by using 4-(ter/-butoxycabonylamino-methyl)-benzoic acid and the
appropriate amine. Overall yields and MS (ES) data are shown in the Table below.





Use the General Procedure 6-1, using piperidine (373 mg, 4.4 mmol) and 4-(tert-
butoxycabonylamino-methyl)-benzoic acid to give the title compound as a white solid
(1.03 g, 100%). MS (ES+) m/r. 219 (M+H)+.
Preparation 95
4-Aminomethyl-JV-cyclohexyl-2-fluoro-benzaraide

4-Bromo-iV-cyclohexvl-2-fluoro-benzainide: Dissolve 4-bromo-2-fluoro-benzoyl
chloride (1 g, 4.21 mmol) in DCM and cool the solution in an ice bath. Add triethylamine
(0.87 mL, 6.32 mmol) and cyclohexylamine (502 mg, 5.1 mmol) and stir the mixture at
ambient temperature for 2 h. Partition the reaction mixture between brine and DCM. Dry
the organic layer over Na2SO4, filter and concentrate in vacuo to give the desired
intermediate as a white solid (1.24 g, 98%).
4-Cvano-JV-cvclohexyl-2-fluoro-benzamide: Heat a mixture of 4-bromo-Ar-cyclohexyl-
2-fluoro-benzamide (1.24 g, 4.13 mmol) and copper cyanide (740 mg, 8.26 mmol) in

DMF (20 mL) to reflux for 16 h. Cool the mixture to ambient temperature, add aqueous
ethylenediamine and stir for 30 min. Extract the mixture with hexane/EtOAc (1:1), dry the
organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by
chromatography on silica gel eluting with hexane/EtOAc (5:1) to give the desired
intermediate as a white solid (620 nig, 61%). MS (ES-) m/z: 245 (M-H)".
4-Aminomethvl-/V-cvclohexvl-2-fluoro-benzamide: Dissolve 4-cyano-./v"-cyclohexyl-2-
fluoro-benzamide (620 mg, 2.5 mmol) in 7N ammonia in methanol (150 mL) and
hydrogenate at 500 psi pressure in the presence of Raney® nickel (500 mg) for 16 h at
60°C. Filter the mixture and concentrate in vacuo. Purify by SCX chromatography to give
the title compound as a white solid (600 mg, 94%). MS (ES-) m/z: 251 (M-H)'.
Preparation 96
5-(Aminomethyl)-pyridine-2-carboxylic acid cyclohexylamide

Lithium 5-(/grt-butoxvcarbonvlamino-methvO-pvridiiie-2-carboxvlate: Dissolve 5-
aminomethyl-2-chloro-pyridine (2 g, 14 mmol) and di-tert-butyl-dicarbonate (3.37 g, 15.4
mmol) in DCM (30 mL) and stir at room temperature for 2 h. Concentrate the reaction
mixture and purify by chromatography on silica gel eluting with hexane/EtOAc (10:1 and
5:1) to give 5-(ter/-butoxycarbonylamino-methyl)-2-chloro-pyridine as a yellow solid
(3.6 g, 100%). MS (ES+) m/z: 243 (M+H)+. Dissolve 5-(terf-butoxycarbonylamino-
methyl)-2-chloro-pyridine (1 g, 4.12 mmol) in a mixture of ethanol (15 mL) and DMF
(5 mL), and add potassium carbonate (427 mg, 3.09 mmol), palladium(II) acetate (92 mg,
0.4 mmol) and diphenylphosphinoferrocene (240 mg, 0.44 mmol). Pressurize the mixture
to 15 psi with carbon monoxide gas and heat the reaction mixture to 90°C for 16 h. Filter
the reaction mixture, concentrate the filtrate, and partition the residue between water and
hexane/EtOAc (1:1). Dry the organic layer over Na2SC>4, filter, and concentrate in vacuo.
Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (3:2) to

give 5-(ter/-butoxycarbonylamino-methyl)-pyridine-2-carboxylic acid ethyl ester as a
brown oil (920 mg, 80%). MS (ES+) m/z: 281 (M+H)+. Dissolve 5-(tert-
butoxycarbonylamino-methyl)-pyridine-2-carboxyIic acid ethyl ester (920 mg,
3.28 mmol) in a mixture of waterHUF (1:2, 15 mL) and add lithium hydroxide (87 mg,
3.61 mmol). Stir the mixture at ambient temperature for 4 h and concentrate to a solid.
Dry the material by azeotrope distillation with toluene to give the desired intermediate as
a brown solid (1 g, 100%). MS (ES+) m/z: 253 (M+H)+
5-(Aminomethyl)-pvridine-2-carboxYlic acid cyclohexylamide: Use the General
Procedure 6-2, using cyclohexylamine (1 mL), lithium 5-(ter/-butoxycarbonylamino-
methyl)-pyridine-2-carboxylate (1 g, 3.96 mmol) and DIEA (5 mL) as cosolvent, to give
the title compound as a white solid (200 mg, 22%). MS (ES+) m/z: 234 (M+H)+.
Preparation 97
5-(Aminomethyl)-pyridine-2-carboxylic acid 4-fluoro-benzylamide

Use the General Procedure 6-2, using 4-fluoro-benzylamine (551 mg, 4.4 mmol),
lithium 5-(ter/-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (740 mg, 2.93
mmol) and DIEA (2.6 mL) as cosolvent, to give the title compound as a white solid (200
mg, 26%). MS (ES+) m/z: 260 (M+H)+.

Preparation 98
2-Aminomethyl-5-(2,2,2-trifluoroethoxy)-pyridine

2-Methyl-5-(2.2.2-trifluoroethoxY)-PYridine; Add 5-hydroxy-2-methyl-pyridine (3.3 g,
30.6 mmol), potassium carbonate (17 g, 122.4 mmol) and 2-bromo-l,l,l-trifluoroethane
(10 g, 61.2 mmol) to a flask containing DMF (60 mL) and heat to 95°C for 20 h. Cool the
mixture, dilute with aqueous 10% NaCI (20 mL) and extract with hexane/EtOAc (1:1, 100
mL). Filter the bi-phasic mixture through Celite®, separate and wash the organic layer
with aqueous 10% NaCI (3 x 50 mL) and concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate
(4.1 g, 70%).
2-Bromomethyl-5-(2.2.2-trifluoroethoiv)-pyridine: Add 2-methyl-5-(2,2,2-
trifluoroethoxy)-pyridine (2.5 g, 13.1 mmoI),NBS (2.3 g, 13.1 mmol) and benzoyl
peroxide (50 mg) to a flask containing carbon tetrachloride (30 mL). Heat the mixture at
80°C in a sealed flask for 16 h. Cool the flask, add NBS (1.1 g, 6.5 mmol) and benzoyl
peroxide (100 mg), then continue heating at 80°C for an additional 5 h. Cool the mixture,
dilute with DCM, then wash with saturated sodium bisulfite (10 mL). Collect the organic
layer and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1) to obtain the desired intermediate (460 mg, 13%).
2-Aminomethyl-5-(2,2.2-trifluoroethoxv)-pvridine: Dissolve sodium azide (270 mg,
4.0 mmol) in DMF (30 mL). Cool the solution to 0°C, then add 2-bromomethyl-5-(2,2,2-
trifluoroethoxy)-pyridine (440 mg, 1.6 mmol) at 0°C. Slowly heat the mixture from 0cC
to 80°C over 30 min. Cool the reaction, dilute with EtOAc (100 mL) and wash with 10%
aqueous NaCI (3 x 25 mL). Collect the organic layer and concentrate in vacuo to a
volume of 50 mL. Transfer the solution to a pressure vessel. Add 10 % Pd/C (Degussa

type El01, 50% water by wt, 500 mg) and pressurize the vessel under hydrogen (10 psi)
for 1 h with stirring. Filter the mixture through Celite® and wash filter cake with warm
methanol followed by DCM. Concentrate in vacuo, then purify by chromatography on
silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound
(180 mg, 54%). MS (ES+) m/z: 207 (M+H)+.
Preparation 99
2-Aminomethyl-5-(2)2,2-trifluoro-l,l-dimethyl-ethoxy)-pyridine

5-Chloro-pyridine-2-carbonitrile: Add 2,5-dichloropyridine (6.0 g, 40.5 mmol), zinc
cyanide (2.9 g, 24.7 mmol), zinc dust (116 mg, 1.8 mmol) and 1,1'-
[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.98 mmol) to a flask
containing DMF (40 mL). Heat the mixture to reflux for 5 h, then cool to ambient
temperature. Dilute the mixture with EtOAc (300 mL) and wash with 10% aqueous NaCl
(3x75 mL). Collect the organic layer, concentrate in vacuo and purify by chromatography
on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate
(2.6 g, 46%).
5-Fluoro-pyridine-2-carbonitrile: Add 5-chloro-pyridine-2-carbonitrile (3.0 g, 21.7
mmol) and potassium fluoride (3.9 g, 67.1 mmol) to a flask containing NMP (75 mL).
Heat the mixture to reflux for 16 h. Add additional potassium fluoride (1.0 g, 17.2 mmol)
and NMP (10 mL), then continue heating at reflux for 3 h. Cool the mixture, dilute with
EtOAc, then wash with saturated NaCl (3 x 50 mL). Collect the organic layer,
concentrate in vacuo and purify by chromatography on silica gel eluting with
hexane/EtOAc (20:1) to obtain the desired intermediate (1.5 g, 53%).
5-(2,2,2-Trifluoro-l,l-dimethvl-ethoxv)-pyridine-2-carbonitrile: Add 2-
trifluoromethyl-2-propanol (1.1 g, 8.3 mmol) slowly to a slurry of sodium hydride (202

mg, 60% mineral oil, washed with hexane) in HMPA (3 mL) under nitrogen. Stir the
slurry for 15 min, then add 5-fluoro-pyridine-2-carbonitrile (510 mg, 4.2 mmol). Stir the
slurry for 16 h at ambient temperature. Adjust the mixture to pH 9 with sodium carbonate
then extract with diethyl ether (3 x 50 mL). Collect the organic layer, dry over Na2SO4
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (95/5 to 80/20) to obtain the desired intermediate (768 mg, 79%). GC-MS
mJz: 230 (M*).
2-Aminomethvl-5-(2,2,2-trifluoro-l,l-dimethvl-ethoxv)-pvridine: Add 5-(2,2,2-
trifluoro-l,l-dimethyl-ethoxy)-pyridine-2-carbonitrile (580 mg, 2.5 mmol), 10 % Pd/C
(Degussa type E101, 50% water by wt, 400 mg) and trifluoroacetic acid (2 mL) in ethanol
(20 mL) to a pressure vessel. Pressurize the vessel to 50 psi with hydrogen for 1 h. Filter
the mixture through Celite® and wash the cake with warm ethanol followed by DCM
under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product as the
trifluoroacetic acid salt. Prepare the free base with SCX chromatography, then purify
using silica gel chromatography eluting with DCM/2M ammonia in methanol (20:1) to
obtain the title compound (261 mg, 45%). MS (ES+) m/r. 235 (M+H)+.
Preparation 100
(±)-2-Aminomethyl-5-(2,2,2-trifluoro-1 -methyl-ethoxy)-pyridine

(±)-5-(2JJ-Trifluoro-l-methyl-ethoxy)-pvridine-2-carbonitriIe: Add 1,1,1-trifluoro-
2-propanol (971 mg, 8.5 mmol) slowly to a slurry of sodium hydride (205 mg, 60%
mineral oil, washed with hexane) in HMPA (8 mL) under nitrogen at 0°C. Allow the
slurry to warm to ambient temperature and stir for 5 min. Add 5-chloro-pyridine-2-
carbonitrile (590 mg, 4.2 mmol), then heat the mixture at 90°C for 4 h. Adjust the
mixture to pH 9 with sodium carbonate then extract with diethyl ether (2 x 50 mL). Dry
the combined organic extracts over Na2SO4 and concentrate in vacuo. Purify by

chromatography on silica gel eluting with hexane/EtOAc (95/5 to 80/20) to obtain the
desired intermediate (818 mg, 89%). GC-MS m/z: 216(M+).
(±)-2-Aminomethyl-5-(2^,2-trifluoro-l-methvl-ethoxv)-pyridine: Add (±)-5-(2,2,2-
trifluoro-l-methyI-ethoxy)-pyridine-2-carbonitriIe (810 mg, 3.7 mmol), 10 %Pd/C
(Degussa type El01, 50% water by wt, 300 mg), and trifluoroacetic acid (4 mL) in
methanol (50 mL) to a pressure vessel. Pressurize the vessel to 40 psi with hydrogen for
0.25 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed
by DCM under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product
as a trifluoroacetic acid salt. Prepare the free base with SCX ion chromatography, then
purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol
(20:1) to obtain the title compound (676 mg, 82%). GC-MS m/z: 220 (M*).

2-Bromo-5-fluoro-pyridine: Cool 48% hydrobromic acid (44 mL, 4.4 equiv.) in an
ice/acetone bath to -5°C, then add 2-amino-5-fluoropyridine (10.0 g, 89.2 mmol, 1.0
equiv.) portion wise over 10 min and maintain the temperature below 5°C throughout
addition. Add bromine (14 mL, 3 equiv.) at 0°C over 2 h and maintain the temperature at
0°C throughout the addition. Stir the mixture for 30 min, then add a solution of sodium
nitrite (15.4 g) in water (30 mL) via addition funnel over 2 h and maintain the temperature
below 0°C throughout the addition. Stir the mixture for 30 min., then add a solution of
NaOH (34 g) in water (34 mL) over 1 h and maintain the temperature below 10°C. Stir
the mixture for 3 min. Extract with diethyl ether (5 x 250 mL), dry the combined organic
extracts over Na2SC>4 and concentrate in vacuo to give the desired intermediate (12.1 g,
77%).

(5-Fluoro-pyridin-2-vl)-methanol: At -78°C under nitrogen, add w-butyllithium (2.5 M
in hexane, 16.4 mL, 40.9 mmol) via syringe to a solution of 2-bromo-5-fluoro-pyridine
(6.0 g, 34.1 mmol) in toluene (220 mL), while keeping the reaction temperature below -
60°C. Stir the mixture at -78°C and then add DMF (3.4 mL, 44.3 mmol) and stir for 1 h
at this temperature. Warm to -10°C and quench with methanol (10 mL). Concentrate the
mixture to half of the volume in vacuo. Dilute with methanol (150 mL), cool the mixture
to -78°C and add sodium borohydride (3.2 g, 85.2 mmol) portion wise over 5 min. Warm
the mixture to ambient temperature and stir for 2 h. Quench with water (10 mL) and
remove the organic solvent in vacuo to obtain an oil/water mixture. Extract with diethyl
ether (3 x 100 mL), dry the combined organic extracts, wash with brine, dry and
concentrate in vacuo to obtain the desired intermediate as an oil (3.9 g, 91%).
Methanesulfonic acid (5-fluoro-pvridin-2-vr)methyl ester Add methanesulfonyl
chloride (1.8 mL, 23.5 mmol) to a solution of (5-fluoro-pyridin-2-yl)-methanoI (2.5 g,
19.7 mmol) and triethylamine (8.2 mL, 59.0 mmol) in DCM (150 mL) at 0°C under
nitrogen. Stir the mixture for 30 min and concentrate in vacuo. Dilute with water (20
mL) and extract the mixture with EtOAc (3 x 50 mL). Combine the organic extracts and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
to obtain the desired intermediate (2.2 g, 54%).
2-AminomethyI-5-fluoro-pyridine: Dissolve methanesulfonic acid (5-fluoro-pyridin-2-
yl)-methyl ester (1.5 g, 7.3 mmol) in DMF (5mL) and add sodium azide (950 mg, 14.6
mmol). Stir the mixture for 30 min, then dilute with hexane/EtOAc (1:1, 50 mL). Wash
the mixture with 10% aqueous NaCl (3x10 mL). Dry the combined organic extracts
over Na2SO4 and remove half of the solvent in vacuo. Add EtOAc (20 mL) and a
suspension of 10% Pd/C (200 mg) in EtOAc (2 mL). Stir the mixture for 1 h at ambient
temperature in a pressurized vessel under 50 psi of hydrogen. Filter the slurry through
Celite® and concentrate in vacuo to obtain 2-aminomethyl-5-fluoro-pyridine (613 mg,
60% yield, 80% purity by GC/MS). GC-MS mJr. \26 (M+).


Preparation 102
3-Aminomethyl-5-fluoro-pyridine
In a Parr Bottle add 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105 mol),
ethanol (336 mL), triethylamine (24 mL), and 5% Pd/C (4 g). Place on a Parr Shaker
Apparatus under 60 psi hydrogen for 1 h at ambient temperature. Filter the reaction
mixture and bubble ammonia gas into filtrate for 10 min. Add Raney® nickel (5.2 g) and
place on a Parr Shaker Apparatus under 500 psi hydrogen for 18 h at 60-70°C. Filter the
reaction mixture and concentrate in vacuo. Dissolve in methanol and add IN hydrogen
chloride in ether until form a precipitate. Cool in an ice bath, filter off the precipitate,
wash the solid several times with ether, and dry to give the title compound as the
hydrochloridesalt(12g,70%). MS(ES+)m/z: 127(M+H)+. Dissolve the hydrochloride
salt in water, add 0.1 N aqueous NaOH to adjust to pH 10, extract with DCM, dry the
organic layer over Na2SO4, filter and concentrate to give the title compound.
Preparation 103
3-Aminomethyl-4-trifluoromethyl-pyridine

Add 4-trifluoromethyl-nicotinonitrile (1.0 g, 5.8 rnmol) and ethanol wet Raney®
activated nickel (0.2 g) to a Parr pressure vessel. Immediately add, at ambient
temperature, 2B-ethanol (25 mL) previously saturated with ammonia gas and seal the
vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with
hydrogen (400 KPa), seal the vessel, agitate the reaction and heat to 40°C. Continue the
reaction for 20 h then turn off the heat and allow the reaction mixture to cool to ambient
temperature. Vent the excess hydrogen from the vessel and purge the vessel with
nitrogen. Filter the reaction mixture to remove the Raney® nickel, wash with ethanol and

concentrate in vacuo. Purify by SCX chromatography to give the title compound (560
mg, 55%). MS (ES+) m/z: 177 (M+H)+.
Preparation 104
2-Aminomethyl-6-fluoropyridine Dihydrochloride

3-FIuoropYridine-JV-Oxide: Dissolve 3-fluoropyridine (2.5 g, 25.749 mmol) in
anhydrous DCM (75 mL). Add /M-CPBA (70% suspension, 12.696 g, 51.499 mmol) and
stir at ambient temperature overnight. Wash the reaction mixture with saturated aqueous
NaHCCh, dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with DCM and DCM/methanol (97:3) to obtain the
desired intermediate as a solid (1.413 g, 49%). MS (ES+) m/z: 115 (M+H)+.
2-Cvano-3-fluoropvridine: Dissolve 3-fluoropyridine-^V-oxide (1.0 g, 8.687 mmol) in
anhydrous acetonitrile (100 mL). Add triethylamine (1.319 g, 1.82 mL, 13.031 mmol),
trimethylsilylcyanide (3.447 g, 4.63 mL, 34.749 mmol) and heat the mixture to reflux
overnight. Cool to ambient temperature and concentrate in vacuo. Dissolve the residue in
EtOAc and wash with saturated aqueous NaHCOj. Dry the organic layer over NajSQt,
filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0 and 17:3) to give the desired intermediate as a solid (746 mg, 70%).
GC-MS m/z: 122 (M^.
2-Aminomethvl-3-fluoropyridinedihydrochloride: Dissolve 2-cyano-3-fluoropyridine
(300 mg, 2.457 mmol) in absolute ethanol (12 mL). Add 10% Pd/C (93 mg) and
concentrated HC1 (0.614 mL, 7.37 mmol). Hydrogenate at 40 psi overnight. Filter
through Celite® and concentrate in vacuo to give the title compound as a solid (440 mg,
90%). MS (ES+) m/z: 127 (M+H)+.
Preparation 105
2-Aminomethyl-6-fluoropyridine Dihydrochloride


2-Cvano-6-fluoropyridine: Dissolve 2,6-difluoropyridine (12 g, 104.2 mmol) in
anhydrous DMSO (5 mL). Add a solution of sodium cyanide (1.3 g, 26.53 mmol) in
DMSO (60 mL) over 12 h using a syringe pump. Heat the mixture to 100°C overnight.
Cool to ambient temperature, dilute with EtOAc (500 mL), and wash with brine. Dry the
organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0 and 4:1) to give the desired intermediate as a
solid (723 mg, 22%). GC-MS m/z: 122 (Ivf).
2-Aminomethyl-6-fluoropvridine Dihvdrochloride: Dissolve 2-cyano-6-fluoropyridine
(300 mg, 2.46 mmol) in absolute ethanol (12 mL). Add 10% Pd/C (93 mg) and
concentrated HC1 (0.614 mL, 7.37 mmol). Hydrogenate at 40 psi overnight. Filter
through Celite® and concentrate to give the title compound as a solid (356 mg, 73%).
MS (ES+) m/z: 127 (M+H)+.
Preparation 106
4-Aminomethyl-Ar-(pyridin-2-yl-methyl)-benzamide

Use the General Procedure 6-2, using 2-(aminomethyl)pyridine (181 mg, 0.172
mL, 1.67 mmol) and 4-(/er/-butoxycarbonylamino-methyl)-benzoic acid (420 mg, 1.67
mmol) to give the title compound as a solid (427 mg, 100 %). MS (ES+) m/z: 242
(M+H)+.



The compounds of Preparations 107-117 may be prepared essentially as described
in Preparation 106 by using 4-(terf-butoxycarbonylamino-methyl)-benzoic acid and the
appropriate amine. Overall yields and MS (ES+) data are shown in the Table below.


Add sodium cyanoborohydride (452 mg, 7.2 mmol) to a solution of 3-
fluoroacetophenone (500 mg, 3.6 mmol) and ammonium acetate (2.8 g, 36 mmol) in
methanol (11 mL). Stir the mixture for 96 h at ambient temperature under a nitrogen
atmosphere. Adjust to pH 2 with 2M hydrogen chloride in diethyl ether. Concentrate the
slurry in vacuo, dilute the residue with DCM and wash with 5N aqueous NaOH followed
by saturated aqueous NaHCC>3. Dry the organic layer, concentrate in vacuo to half of the
volume, and load the solution onto a SCX column (pre-wash column with methanol
followed by DCM, then elute with 2M ammonia in methanol). Concentrate the fractions
to half of the volume to remove ammonia, add excess of 2M hydrogen chloride in diethyl
ether and concentrate to obtain the hydrochloride salt (70:30 mixture of title compound
and dimer). Purify by chromatography on silica gel eluting with DCM/2M ammonia in
methanol (20:1) to obtain the title compound (323 mg, 51%). MS (ES+) m/z: 140 (M+H)+


Set-up flask equipped with condenser, mechanical stirrer and addition funnel. Add
3-fluoroacetophenone (25 g, 0.18 mol) and formic acid (4.2 g, 0.09 mol) via addition
funnel to a flask containing formamide (32.6 g, 0.72 mol) at 140°C over 15 min, and then
heat the mixture to 160°C. Add formic acid successively (4.2 g, 0.5 equiv.) via addition
funnel to the flask every hour for 4 h while maintaining the reaction temperature at
160°C. Cool the reaction mixture, extract with toluene (3 x 100 mL), and concentrate the
organic layer in vacuo. Add aqueous HC1 (37%, 40 mL) to the residue and heat to reflux
for 2 h. Cool to ambient temperature and wash the aqueous mixture with toluene (2 x 100
mL), then basify the aqueous mixture with 5N aqueous NaOH (120 mL). Extract the
basic mixture with EtOAc (3 x 100 mL), dry the combined organic extracts over NaaSQ*
and filter. Acidify the filtrate with 2M hydrogen chloride in diethyl ether to pH 2 and
concentrate in vacuo to a solid. Suspend the solid in diethyl ether, filter and wash with
diethyl ether. Dry the solid in a vacuo-oven at 50°C to obtain (±)-l-(3-
fluorophenyl)ethylamine hydrochloride (21.5 g, 68%). MS (ES+) m/z: 140 (M+H)+.
Dissolve (±)-l-(3-fluorophenyl)ethylamine hydrochloride (42.5 g, 0.24 mol) in
THF (520 mL) and saturated aqueous NaHCO3 (430 mL). Add di-/ert-butyl-dicarbonate
(69 g, 0.31 mol) and stir for 16 h at ambient temperature. Separate the organic layer,
dilute with EtOAc (300 mL) and wash with 2N aqueous NaOH (1 x 400 mL) and water (2
x 200 mL). Concentrate the organic layer in vacuo. Purify by chromatography on silica
gel eluting with hexane/EtOAc (9:1) to obtain (±)-JV-[l-(3-fluorophenyl)ethyl]-carbamic
acid fer/-butyl ester (56 g, 97%). GC-MS m/z: 183 [(M-C4H9)+].
Separate the racemic mixture of (±)-iV-[l-(3-fluorophenyl)ethyl]-carbamic acid
tert-butyl ester by normal phase chiral chromatography (Chiralcel OD 8 x 34 cm, elute
with 95:5, heptane/isopropanol). Using the General Procedure 1-4, deprotect the desired

isomer [20.7 g, >95% ee (Chiralcel OD, 4.6 x 250 mm, eluent: 95:5 heptane/isopropanol
with 0.2% DMEA, 1.0 mL/min)] to obtain the title compound (9.4 g, 78%). MS (ES+)
m/z: 140 (M+H)+.
Preparation 120
(±)-l-(2-Fluorophenyl)ethylamine

Add sodium cyanoborohydride (1.8 g, 29 mmol) to a solution of 2-fluoro-
acetophenone (2.0 g, 14.5 mmol) and ammonium acetate (11.2 g, 145 mmol) in methanol
(45 mL). Stir the mixture for 20 h at ambient temperature under a nitrogen atmosphere.
Adjust the mixture to pH 1 with 2M hydrogen chloride in diethyl ether. Concentrate the
slurry in vacuo, dilute the residue with DCM and wash with 5N aqueous NaOH. Dry the
organic layer, concentrate carefully, as the amine is volatile, under reduced pressure to
one third of the volume, and load the material onto an SCX column (pre-wash column
with methanol, followed by DCM, elute with 2M ammonia in methanol). Concentrate the
fraction to one half of the volume to remove the ammonia, then add excess 2M hydrogen
chloride in diethyl ether and concentrate to obtain the hydrochloride salt. Purify by
chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to
obtain the title compound (280 mg, 13%). MS (ES+) m/z: 140 (M+H)+.
Preparation 121
l-(2-Fluorophenyl)ethylamine, Isomer 1

Use a method similar to the General Procedure 6-3, using 2-fluoroacetophenone
(1.4 g, 9.9 mmol) and (/?)-(+)-2-methyl-2-propanesulfinamide (1.0 g, 8.2 mmol). Purify
by chromatography on silica gel eluting with hexane/EtOAc/2M ammonia in methanol

(90:9:1 to 50:45:5). Add 4M hydrogen chloride in dioxane to obtain the title compound
as the hydrochloride (600 mg, 35%). MS (ES+) m/z: 140 (M+H)+. Dissolve the
hydrochloride in an aqueous solution of cesium carbonate (1.5 equiv.) and extract with
toluene to obtain the free base.


The compounds of Preparations 122-141 may be prepared essentially as described
in Preparation 121 by using (7?)-(+)-2-methyl-2-propanesulfinamide or (S)-(-)-2-methyl-2-
propanesulfinamide and the appropriate acetophenone. Overall yields and mass spectrum
data are shown in the Table below.



Slurry 2',5'-difluoroacetophenone (0.9 g, 5.76 mmol), ammonium acetate (4.44 g,
57.5 mmol) and sodium cyanoborohydride (755 mg, 12 mmol) in anhydrous methanol (25
mL) and stir for 18 h at ambient temperature. Acidify with 5N aqueous HC1 (5 mL),
dilute, extract with ethyl ether (3 x 150 mL), basify aqueous layer with 5N aqueous
NaOH, extract with DCM (3 x 75 mL), wash the organic layer with brine, dry over
MgSOt, filter and concentrate in vacuo. Purify by SCX chromatography to give a mixture
of (±)-l-(2,5-difluorophenyl)ethylamineandbis-[l-(±)-2,5-difluorophenyl)ethyl]-amine
(total 400 mg, crude weight). MS (ES+) m/z: 158 (M+H)+ and m/z: 298 (M+H)+.
Preparation 145
(±)-1 -(3,5-Difluoro-4-methoxyphenyl)ethylamine

Slurry 3',5'-difluoro-4'-methoxyacetophenone (1.0 g, 5.0 mmol), ammonium
acetate (4.14 g, 50 mmol) and sodium cyanoborohydride (630 mg, 20 mmol) in anhydrous
methanol (35 mL) and stir for 18 h at ambient temperature. Acidify with IN aqueous HC1
(5 mL), dilute, extract with ethyl ether (3 x 150 mL), basify aqueous with IN aqueous
NaOH, extract with DCM (3 x 50 mL), wash the organic extracts with brine, dry over
MgSCU, filter and concentrate in vacuo. Purify by SCX chromatography to give crude the
title compound as a yellow oil (380 mg).
Preparations 146 and 147
l-(4-Phenoxyphenyl)-ethylamine, Isomer 1 and Isomer2


Mix 4-phenoxyacetophenone (5.3 g, 25 mmol), ammonium acetate (14.5 g, 187.5
mmol) and sodium cyanoborohydride (3.2 g, 50 mmol) in anhydrous methanol (200 mL).
Stir for 18 h at ambient temperature. Acidify with IN aqueous HC1 (10 mL), dilute,
extract with ethyl ether (3 x 150 mL), dry over MgSCU, filter and concentrate in vacuo.
Purify by chromatography on si lica gel eluting sequentially with hexane/EtOAc (4:1, 1:1
and 0:1) and EtOAc/methanol (1:1) to give(±)-l-(4-phenoxyphenyl)-ethylamine (1.6 g,
30%). Dissolve the racemate (1.1 g, 5.2 mmol) in DCM (100 mL), add triethylamine
(1.6mL, 11.4 mmol) followed by di-ter/-butyl-dicarbonate (1.7 g, 7.8 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give (±)-a-methyl-(4'-
phenoxy)-benzylamino]carbamic acid ter/-butyl ester as an off-white solid (1.3 mg, 81%).
Separate via chiral chromatography (heptane/isopropanol/DMEA 95:5:0.2, 4.6 x 250 mm
Chiralpak AD, 1 mL/min, UV detector at 260 nm) to give [a-methyl-(4'-
phenoxy)benzylamino]carbamic acid terf-butyl ester, isomer 1 (315 mg, chiral HPLC: tR =
7.35 min; 99.1% ee) and [a-methyl-(4'-phenoxy)benzyl-aminocarbamic acid tert-butyl
ester, isomer 2 (400 mg, chiral HPLC: tR = 8.7 min; 97.2% ee). Dissolve [a-methyl-(4'-
phenoxy)benzylamino]carbamic acid tert-butyl ester isomer 1 or isomer 2 in
DCM/trifluoroacetic acid (1:1, 20 mL) to give, after solvent evaporation and
chromatography over SCX column, l-(4-phenoxyphenyl)-ethylamine, isomer 1
(Preparation 146) and l-(4-phenoxyphenyl)-ethylamine, isomer 2 (Preparation 147). MS
(ES+)/M/Z:214(M+H)+.
Preparation 148
(5-Fluoro-indan-l-yl)amine, Isomer 1

Use a method similar to the General Procedure 6-3 to react 5-fluoro-indan-l-one
(1.5 g, 9.9 mmol) and (i?)-(+)-2-methyl-2-propanesulfinamide (1.0 g, 8.3 mmol). Purify
by chromatography on silica gel eluting with hexane/EtOAc (5:2). Add 4M hydrogen
chloride in dioxane to obtain the title compound as the hydrochloride (254 mg, 16%). MS
(ES+) m/z: 152 (M+H)+. Dissolve the hydrochloride in an aqueous solution of cesium
carbonate (1.5 equiv.) and extract with toluene to obtain the free base.

Preparation 149
1-Phenyl-cyclopropylamine

Dissolve 1 -phenyl-cyclopropanecarboxylic acid (2.5 g, 15.4 mmol) in a mixture of
sulfuric acid (12.5 mL) and DCM (25 mL). Add sodium azide (2.3 g, 35.4 mmol) by
small portions at ambient temperature. Heat the reaction mixture at 50°C for 8 h, cool to
0°C and slowly add 2M aqueous NaOH until pH 11. Extract the reaction mixture with
DCM (3 x 100 mL), combine the organic extracts and dry over anhydrous Na2SC»4.
Evaporate the solvent and purify by chromatography on silica gel eluting with DCM and
DCM/2M ammonia in methanol (9:1) to obtain the title compound as a brown oil (1.1 g,
54%). MS (ES+) mJr. 134 (M+H)+.
Preparation 150
l-(2,4-Dichlorophenyl)-cyclopropylamine

Use a method similar to Preparation 149, using 1-(2,4-dichlorophenyl)-
cyclopropanecarboxylic acid (3.5 g, 15.4 mmol), to obtain the title compound as a yellow
oil (1.0 g, 32%). MS (ES+) m/z: 203 (M+H)+.
Preparation 151
4-Methylamino-benzo[l ,3]dioxole

Benzofl31dioxol-4-vl-methanol: Dissolve benzo[l,3]dioxole-4-carbaldehyde (2.0 g,
13.3 mmol) in anhydrous THF (30 mL) and treat with sodium borohydride (0.5 g, 13.3

mmol) at O°C. Stir the reaction mixture for 30 min at ambient temperature and quench
with water (30 mL). Extract the reaction mixture with DCM (3x10 mL), combine the
organic extracts and dry over anhydrous Na2SO4. Remove the solvent to obtain the
desired intermediate as a colorless oil (1.9 g, 94%).
4-Chloromethyl-benzo[l,31dioxole: Dissolve benzo[l,3]dioxol-4-yl-methanol (1.9 g,
12.5 mmol) in thionyl chloride (3 mL, 41.1 mmol) and reflux the reaction mixture for 1 h.
Concentrate in vacuo to obtain the desired intermediate as a yellow oil (1.9 g, 91%) that
was used without further purification. GC-MS m/z: 170 (M+).
4-Mettivlamino-benzo[Uldioxole: Dissolve 4-chloromethyl-benzo[l,3]dioxole (1.9 g,
11.1 mmol) in methanol (5 mL), cool the solution to 0°C and saturate with anhydrous
ammonia for 15 min. Keep the reaction mixture at 0°C for 18 h. Evaporate the solvent
and purify by SCX chromatography to obtain the title compound as a yellow oil (0.6 g,
36%). GC-MS m/z: 151 (Ivf).
Preparation 152
6-Bromomethyl-benzothiazole

Benzothiazole-6-carboxylic acid methyl ester: Add l-methyl-3-nitro-l-
nitrosoguanidine (5.0 g, 33.9 mmol) to a mixture of diethyl ether (20 mL) and IN aqueous
NaOH (20 mL) at ambient temperature. Separate the organic layer and add it slowly to a
solution of benzothiazole-6-carboxylic acid (1.0 g, 5.58 mmol) in THF (50 mL) at 0°C.
Evaporate the solvent to obtain the desired intermediate as a yellow solid (1.1 g, 100%).
MS (ES+) m/z: 194(M+H)+.
BenzothiazoI-6-yl-methanol: Add slowly a solution of benzothiazole-6-carboxylic acid
methyl ester (0.5 g, 2.59 mmol) in anhydrous THF (10 mL) to a suspension of lithium

aluminum hydride (0.1 g, 2.85 mmol) in anhydrous THF (20 mL) at -10°C and stir for 20
min at -10°C. Treat the reaction mixture with 2N aqueous NaOH until a granular
precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and
purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1, 7:3, 3:2
and 1:1) to obtain the desired intermediate as a yellow oil (0.4 g, 99%). MS (ES+) m/z:
166(M+H)+.
6-Broniomethvl-benzothiazole: Dissolve benzothiazol-6-yl-methanol (0.4 g, 2.55
mmol) in diethyl ether (10 mL) and add slowly a solution of phosphorus tribromide (0.7
g, 2.55 mmol) in diethyl ether (5 mL). Stir the reaction mixture for 2 h at ambient
temperature, wash with brine, dry the organic phase over anhydrous Na2SC»4, evaporate
the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0,
9:1 and 4:1) to obtain the title compound as a white solid (0.5 g, 86%). MS (ES+) m/z:
229 (M+H)+.
Preparation 153
6-Bromomethyl-2-cyclohexyl-benzothiazole

Cvclohexanecarboximidic acid ethyl ester, hvdrochloride: Combine
cyclohexanecarbonitrile (1.0 g, 9.20 mmol), ethanol (0.4 g, 9.20 mmol) and 4N hydrogen
chloride in dioxane (8 mL) and stir the reaction mixture for 17 h at ambient temperature.
Evaporate the solvent and triturate the residue with diethyl ether to obtain the desired
intermediate as a white solid (1.4 g, 80%).
2-Cvclohexyl-6-methvl-benzothiazole: Combine 2-amino-5-methyl-benzenethiol zinc
salt (1.0 g, 2.91 mmol, prepared as described in Synth. Commun. 1980,10, 167-173),
cyclohexanecarboximidic acid ethyl ester hydrochloride (1.1 g, 5.82 mmol), methanol (20

mL) and reflux the reaction mixture for 17 h. Evaporate the solvent and purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the
desired intermediate as a white solid (1.15 g, 85%).
6-BromomethvI-2-cvclohexyl-benzothiazole: Combine 2-benzyl-6-methyl-
benzothiazole (0.6 g, 2.42 mmol), NBS (0.5 g, 2.54 mmol), AIBN (40 mg, 0.24 mmol),
carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient
temperature, dilute with chloroform and wash with water. Dry the organic extracts over
anhydrous Na2SC>4, concentrate in vacuo and purify by chromatography on silica gel
eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid
(0.4 g, 53%). MS (ES+) m/z: 311 (M+H)+.
Preparation 154
6-Bromomethyl-2-phenyl-benzothiazole

6-Methvl-2-phenvl-benzothiazole: Combine 2-amino-5-methyl-benzenethiol zinc salt
(1.0 g, 2.91 mmol, prepared as described in Synth. Commun. 1980,10, 167-173), ethyl
benzimidate hydrochloride (1.1 g, 5.82 mmol), methanol (20 mL), and reflux the reaction
mixture for 17 h. Evaporate the solvent and purify by chromatography on silica gel
eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a white
solid (1.1 g, 85%). MS (ES+) m/z: 226 (M+H)+.
6-Bromomethvl-2-phenyl-benzothiazole: Combine 6-methyl-2-phenyl-benzothiazole
(0.2 g, 0.98 mmol), NBS (0.2 g, 1.02 mmol), AIBN (20 mg, 0.10 mmol), carbon
tetrachloride (5 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature,
dilute with chloroform and wash with water. Dry the organic extracts over anhydrous
Na2SC>4, concentrate and purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0, 9:1, 8:2 and 7:3) to obtain the title compound as a white solid (0.2 g,
69%).

Preparation 155
2-Benzyl-6-bromornethyl-benzothiazole

2-Phenyl-acetimidic acid ethyl ester, hydrochloride: Combine benzyl cyanide (1.0 g,
8.50 mmol), ethanol (0.4 g, 8.50 mmol) and 4N hydrogen chloride in dioxane (8 mL) and
stir the reaction mixture at ambient temperature for 17 h. Evaporate the solvent and
triturate the residue with diethyl ether to obtain the desired intermediate as a white solid
(1.7 g, 100%).
2-Benzyl-6-methyl-benzothiazole: Combine 2-amino-5-methyl-benzenethiol zinc salt
(1.0 g, 2.91 mmol, prepared as described in Synth. Commun. 1980,10, 167-173), 2-
phenyl-acetimidic acid ethyl ester hydrochloride (1.16 g, 5.82 mmol), methanol (20 mL)
and reflux the reaction mixture for 17 h. Evaporate the solvent and purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the
desired intermediate as a white solid (1.0 g, 72%). MS (ES+) m/z: 240 (M+H)+.
2-Benryl-6-bromomethyl-benzothiazole: Combine 2-benzyl-6-methyl-benzothiazole
(0.6 g, 2.51 mmol), NBS (0.5 g, 2.63 mmol), AIBN (40 mg, 0.25 mmol), carbon
tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient
temperature, dilute with chloroform and wash with water. Dry the combined organic
extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on
silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white
solid (0.2 g, 69%). MS (ES+) m/z: 319 (M+H)+.
Preparation 156
5-Bromomethyl-benzoxazole


5-Methyl-benzoxazole: Combine 2-amino-4-methyl-phenol (1.0 g, 8.12 mmol),
[(ditnethylaminomethylene-aminomethylene)dimethylainmonium chloride (Gold's
reagent) (1.6 g, 9.91 mmol), anhydrous 1,4-dioxane (25 mL) and reflux for 17 h. Cool the
reaction mixture to ambient temperature, evaporate the solvent and purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired
intermediate as a yellow oil (0.7 g, 65%).
5-Bromomethvl-bcnzoxazol: Combine 5-methyl-benzoxazole (0.5 g, 3.75 mmol), NBS
(0.7 g, 3.93 mmol), AffiN (60 mg, 0.37 mmol), chloroform (10 mL) and reflux for 1 h.
Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with
water. Dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to
obtain the title compound as a white solid (0.1 g, 13%).
Preparation 157
5- Methylamino-2-phenyl-benzoxazole

2-rPhenyl-benzoxazol-5-vlmethyl)-carbamic acid 2-trimethvlsilanyl-ethyl ester:
Combine (2-phenyl-benzoxazol-5-yl)-acetic acid (1.0 g, 3.95 mmol), triethylamine (0.5 g,
4.34 mmol), and anhydrous toluene (20 mL), heat to reflux and slowly add
diphenylphosphoryl azide (1.2 g, 4.15 mmol) in anhydrous toluene (8 mL). Continue to
reflux for 3 h, cool to ambient temperature, add 2-trimethylsilylethanol (0.9 g, 7.89 mmol)
to the reaction mixture and continue to reflux for 3 h. Evaporate the solvent and purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to obtain
the desired intermediate as a yellow solid (0.4 g, 26%).

5- Methylamino-2-phenyl-benzoxazole: Dissolve (2-phenyl-benzoxazol-5-yl-methyl)-
carbamic acid 2-trimethylsilanyl-ethyl ester (0.4, 0.99 mmol) in anhydrous THF (5 mL)
and treat with 1M tetrabutylammonium fluoride in THF (1.5 mL, 1.54 mmol). Heat the
mixture at reflux for 30 min, evaporate the solvent and purify by SCX chromatography to
obtain the title compound as a yellow oil (0.1 g, 27%).
Preparation 158
4-Aminomethyl-1 -methylindole

l-Methylindole-4-carbonitrile: Add slowly a solution of indole-4-carbonitrile (1.0 g,
7.04 mmol) in anhydrous DMF (5 mL) to a suspension of sodium hydride (60%
dispersion in mineral oil, 0.6 g, 8.64 mmol) in anhydrous DMF (2 mL) at 0°C and warm
the reaction mixture to ambient temperature. Add iodomethane (0.7 mL, 10.6 mmol) and
stir the reaction for 1 h at ambient temperature. Dilute the reaction mixture with 1M
aqueous NH4OH (30 mL) and extract with diethyl ether (3x10 mL). Combine the
organic extracts, dry over anhydrous Na2SO4, concentrate in vacuo and purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1,4:1 and 7:3) to obtain
the desired intermediate as a yellow oil (1.0 g, 87%). GC-MS m/z: 156 (M"1).
4-Aminomethvl-l methvlindole: Dissolve l-methylindole-4-carbonitrile (1.0 g, 6.18
mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in
THF (12.4 mL, 12.37 mmol) at ambient temperature. Heat the reaction mixture at 50°C
for 17 h and cool to ambient temperature. Quench the reaction mixture with water until a
granular precipitate starts to form and filter through a pad of Celite®. Evaporate the
solvent and purify by SCX chromatography to obtain the title compound as a yellow oil
(0.9 g, 91%). GC-MS m/z: 160 (M*).
Preparation 159
6-Aminomethyl-1 -methylindole


l-Methylindole-6-carbonitrHe: Add slowly a solution of indole-6-carbonitrile (1.0 g,
7.04 mmol) in anhydrous DMF (5 mL) to a suspension of sodium hydride (60%
dispersion in mineral oil, 0.6 g, 14.1 mmol) in anhydrous DMF (2 mL) at 0°C and warm
the reaction mixture to ambient temperature. Add iodomethane (0.7 mL, 1.06 mmol) and
stir the reaction mixture for 1 h at ambient temperature. Dilute the reaction mixture with
1M aqueous NH4OH (30 mL) and extract with diethyl ether (3 x 10 mL). Combine the
organic layers, dry over anhydrous Na2SC>4, remove the solvent and purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1,4:1 and 7:3) to obtain
the desired intermediate as a yellow oil (1.0 g, 87%). MS (ES+) m/r. 156 (M+H)+.
6-Aminomethvl-l-methvlindole: Dissolve l-methylindole-6-carbonitrile (0.97 g, 6.18
mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in
THF (1.24 mL, 1.24 mmol) at ambient temperature. Heat the reaction mixture at 50°C for
17 h and cool to ambient temperature. Quench the reaction mixture with water until a
granular precipitate starts to form and filter through a pad of Celite®. Evaporate the
solvent and purify by SCX chromatography to obtain the title compound as a yellow oil
(0.9 g, 91%). GC-MS m/z: 160 (M*).
Preparation 160
6-Aminomethyl-benzofuran

Dissolve benzofuran-6-carbonitrile (0.5 g, 3.28 mmol) in anhydrous THF (10 mL)
and add slowly to 1M lithium aluminum hydride in THF (6.56 mL, 6.56 mmol) at
ambient temperature. Heat the reaction mixture at 50°C for 17 h and cool to ambient
temperature. Quench the reaction mixture with water until a granular precipitate starts to
form and filter through a pad of Celite®. Evaporate the solvent and purify by SCX
chromatography to obtain the title compound as a yellow oil (0.4 g, 79%).

Preparation 161
4-Aminomethyl-benzofuran

Benzofiiran-4-carbonitrile: Combine 4-bromo-benzofuran (1.0 g, 5.07 mmol),
copper(I) cyanide (0.9 g, 10.2 mmol), anhydrous DMF (16 mL) and reflux for 17 h. Cool
the reaction mixture to ambient temperature, treat with 50% (v/v) aqueous
ethylcncdiamine (25 mL). Extract the reaction mixture with diethyl ether (3 x 15 mL),
combine the organic extracts, wash with brine (15 mL) and dry over anhydrous Na2SO4.
Evaporate the solvent and purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil (0.3
g, 39%).
4-Aminomethyl-benzofuran: Dissolve benzofiiran-4-carbonitrile (0.3 g, 1.96 mmol) in
anhydrous THF (5 mL) and add slowly to 1M lithium aluminum hydride in THF (3.91
mL, 3.91 mmol) at ambient temperature. Heat the reaction mixture at 50°C for 5 h and
cool to ambient temperature. Quench the reaction mixture with water until a granular
precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and
purify by SCX chromatography to obtain the title compound as a brown oil (0.4 g, 79%).
GC-MS m/z: 147 (Ivf).
Preparation 162
4-Aminomethyl-benzo[Z>]thiophene

Add lithium aluminum hydride (1M solution in THF, 7.5 mL) to
benzo[6]thiophene-4-carbonitrile (prepared as described in WO 0168653) (0.6 g, 3.8

mmol) at 0°C in THF (38 mL). After 17 h at ambient temperature, cool to 0°C and add
sequentially water (1.89 mL), 2N aqueous NaOH (1.89 mL) and water (2.69 mL). Filter
the solids and evaporate the filtrate to obtain the crude amine. Purify by SCX
chromatography. Rinse the column with methanol, add a solution of the crude amine in
methanol, wash the column with methanol and then elute with IN ammonia in methanol.
Concentrate to give the title compound (0.57 g, 93%). GC-MS m/z: 163 (IVT).
Preparation 163
6-Aminomethyl-benzo[6]thiophene

BenzofAlrhiophen-6-carbonitrile: Heat copper(I) cyanide (0.84 g, 9.4 mmol) and 6-
bromobenzo[Z>]thiophene (prepared as described in WO 01/23381) (1.0 g, 4.7 mmol) at
160°C for 13 h. Cool the mixture to 0°C, add 33% aqueous ethylenediamine (20 mL) and
dilute with ether. Wash the organic mixture with brine, dry over NajSCu and evaporate.
Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:3) to give the
desired intermediate (0.58 g, 78%). GC-MS m/z: 159 (St).
6-Aminomethyl-benzof^lthiophene: Add 1M lithium aluminum hydride in THF (7.3
mL) to benzo[&]thiophene-6-carbonitrile (0.6 g, 3.6 mmol) at 0°C in THF (36 mL). After
15 h at ambient temperature, cool to 0°C and add sequentially water (1.82 mL), 2N
aqueous NaOH (1.82 mL) and water (2.60 mL). Filter the solid and evaporate the filtrate
to obtain the crude amine. Purify by SCX chromatography. Rinse the column with
methanol, add a solution of the crude amine in methanol, wash the column with methanol
and then elute with IN ammonia in methanol. Concentrate in vacuo to give the title
compound (0.55 g, 92%).
Preparation 164
8-Bromomethyl-quinoline


Combine 8-methyl-quinoline(1.0 g, 6.99 mmol), NBS (1.3 g, 7.13 mmol),
benzoyl peroxide (6.0 mg, 0.03 mmol), carbon tetrachloride (30 mL) and reflux for 17 h.
Cool the reaction mixture to ambient temperature and evaporate the solvent. Dissolve the
residue in chloroform (30 mL), wash the organic solution with saturated aqueous
NaHCC>3 (2x10 mL), brine (10 mL) and dry over anhydrous Na2SC>4. Evaporate the
solvent and purify by chromatography on silica gel eluting with DCM to obtain the title
compound as a white solid (1.3 g, 83%). MS (ES+) m/z: 223 (M+H)+.
Preparation 165
2-Aminomethyl-quinoline

Combine quinoline-2-carbonitrile (0.2 g, 1.29 mmol), Raney® 3201 nickel (slurry
in water, 0.05 g), 2N ammonia in methanol (10 mL) and hydrogenate at 50 psi for 15 min.
Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by
SCX chromatography to obtain the title compound as a yellow oil (0.2 g, 98%). MS
(ES+)/w/z:159(M+H)+.
Preparation 166
3-Aminomethyl-quinoiineDihydrochloride

Combine quinoline-3-carbonitrile (1.0 g, 6.49 mmol), 10% Pd/C (0.2 g), 5% TFA
in methanol (100 mL) and hydrogenate at 30 psi for 2 h. Filter the reaction mixture
through a pad of Celite® and evaporate the solvent. Dissolve the residue in ethanol (10
mL), treat with IN hydrogen chloride in diethyl ether (5 mL) and allow the mixture to

stand at 5°C for 18 h. Filter the precipitate, wash with ethanol and dry under vacuo to
obtain the title compound as a white solid (0.6 g, 53%).
Preparation 167
2-Aminomethyl-isoquinoIineDihydrochloride

Combine isoquinoline-3-carbonitrile (1.0 g, 6.49 mmol), 10% Pd/C (0.2 g), 5%
TFA in methanol (95 mL) and hydrogenate at 30 psi for 17 h. Filter the reaction mixture
through a pad of Celite® and evaporate the solvent. Dissolve the residue in ethanol (10
mL), treat with IN hydrogen chloride in diethyl ether (5 mL) and allow to stand at 5 °C
for 18 h. Filter the precipitate, wash with ethanol and dry under vacuo to obtain the title
compound as a white solid (0.6 g, 55%).
Preparation 168
6-Aminomethyl-quinoline

6-Ouinolinecarboxamide: Combine 6-quinolinecarboxylic acid (2.0 g, 11.6 mmol), 1,1-
carbonyldiimidazol (3.8 g, 23.45 mmol) in DCM (50 mL) and stir at ambient temperature
for 1 h. Saturate the reaction mixture with anhydrous ammonia and continue to stir for 1
h. Quench the reaction mixture with water (100 mL) and extract with chloroform (3 x 50
mL). Combine the organic extracts, dry over anhydrous Na2SO4 and evaporate the
solvent to obtain the desired intermediate as a white solid (1.6 g, 78%).
6-Quinolineearbonitrile: Dissolve 6-quinolinecarboxamide (1.5 g, 8.95 mmol) in DCM
(50 mL), add triethylamine (2.7 g, 26.8 mmol) and cool the reaction mixture to 0°C. Add
trifluoroacetic acid anhydride (2.4 g, 11.16 mmol) to the reaction mixture and stir for 10

min at 0 °C. Quench the reaction mixture with water (20 mL) and separate the organic
layer. Extract aqueous layer with DCM (2x15 mL). Combine the organic extracts and
dry over anhydrous Na2SO4. Evaporate the solvent to obtain the desired intermediate as a
white solid (1.0 g, 73%). GC-MS m/z: 154 (M+).
6-AminomethyI-quinoline: Combine 6-quinolinecarbonitrile (1.0 g, 6.49 mmol),
Raney® 3201 nickel (slurry in water, 0.2 g), 2N ammonia in methanol (20 mL) and
hydrogenate at 50 psi for 1 h. Filter the reaction mixture through a pad of Celite®,
remove the solvent and purify by SCX chromatography to obtain the title compound as a
yellow oil (0.8 g, 78%).
Preparation 169
(±)-2-(l-Aminoethyl)-5-methylthiophene

(±>-2-(l-Hvdroxvcthyl)-5-nicthvlthiophene: Add sodium borohydride (270 mg, 7.13
mmol) to a solution of 2-acetyl-5-methyIthiophene (1.0 g, 7.13 mmol) in methanol (40
mL). Stir the mixture for 1 h at room temperature. Remove the solvent in vacuo and
partition the residue between water and DCM. Separate the organic phase, dry over
Na2SC"4, filter and concentrate to obtain the desired intermediate as an oil (0.995 g, 98%)
that was used without further purification. GC-MS m/z 142 (M*).
(±)-2-(l-AzidoethvD-5-methvlthiophene: Add DBU (1.228 g, 1.2 mL, 8.07 mmol) to a
solution of (±)-2-(l-hydroxyethyl)-5-methylthiophene (0.955 g, 6.72 mmol) and
diphenylphosphoryl azide (2.22 g, 1.74 mL, 8.07 mmol) in anhydrous toluene. Stir at
room temperature for 18 h. Dilute the mixture with EtOAc and wash with water and 0.5N
aqueous HC1. Dry the organic phase over Na2SC>4, filter and concentrate. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain the
desired intermediate as an oil (0.875 g, 78%). GC-MS m/z 167 (M*).

f±V-2-(l-Aminoethvl)-5-methylthiophene: Add lithium aluminum hydride (29 mg, 0.72
mmol) to a solution of (±)-2-(l-azidoethyl)-5-methylthiophene (100 mg, 0.59 mmol) in
anhydrous THF (5 mL). Stir at room temperature overnight. Work-up the mixture with
EtOAc and water. Filter the mixture over Celite®. Separate and wash the organic phase
with brine. Dry over Na2SO4, filter and concentrate in vacuo. Purify by SCX
chromatography. Rinse with DCM/methanol (1:1), load the crude mixture in methanol
and elute sequentially with methanol and IN ammonia in methanol to obtain the title
compound as an oil (80 mg, 95%). GC-MS m/z 141 (VT).
Preparations 170 and 171
l-(5-Phenyl-thiophen-2-yl)ethylamine, Isomers 1 and 2

ALK5-Phenvlthiophen-2-Yl)-methYlene]-2-methvlpropanesulfinainide: To a solution
of 5-phenyl-2-thiophenecarboxaldehyde (1.25 g, 6.64 mmol) in anhydrous THF (50 mL),
add titanium(IV) ethoxide (3.03 g, 2.78 mL, 13.28 mmol) and (/?)-(+)-2-methyl-2-
propanesulfinamide (0.965 g, 7.968 mmol) under nitrogen. Heat the reaction at 80°C
overnight. Cool the mixture to room temperature and dilute with EtOAc. Add water and
filter the resulting precipitate over Celite®. Separate and dry the organic phase over
Na2SC>4, filter and concentrate in vacuo to obtain the desired intermediate as a yellow
solid (1.93 g, 100% yield) that was used without purification.

A^-H-(5-Phenvlthiophen-2-vl)ethvll-2-methvlpropanesulfinamide ("Isomer 1) and N-
[l-(5-phenvlthiophen-2-vl)ethvll-2-methylpropanesulfinamide (Isomer 2): Add
slowly methyllithium (8.1 mL, 12.92 mmol, 1.6 M solution in ether) to a solution of N-
[(5-phenylthiophen-2-yl)-methylene]-2-methylpropanesulfinamide (1.883 g, 6.46 mmol)
in anhydrous THF (50 mL) at -40°C. Warm the reaction to -20°C and stir for 2 h. Warm
to 0°C and stir for an additional 2 h. Add saturated aqueous NH4CI and extract with
EtOAc. Dry the organic phase over Na2SC>4, filter and concentrate in vacua. Purify by
chromatography on silica gel eluting with hexane/EtOAc (7:3 and 1:1) to obtain N-[l-(5-
phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 1) (575 mg, 30% yield)
and Ar-n-^-phenylthiophen^-ytyethyl^-methylpropanesulfinamide (Isomer 2) (847 mg,
44% yield).
l-(5-Phenvl-thiophen-2-vl)ethvlamine (Isomer 1, Preparation 170) Add 4N hydrogen
chloride in dioxane (0.837 mL, 3.349 mmol) to a stirred solution of iV-[l-(5-
phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 1) (515 mg, 1.675
mmol) in methanol (8 mL) at room temperature. Stir for 2 h and remove the solvent in
vacuo to obtain a solid that was washed with ethyl ether. Dissolve the solid in DCM and
wash with saturated aqueous NaHCC>3. Dry the organic phase over Na2SO4, filter and
concentrate in vacuo to obtain the desired intermediate (236 mg, 69% yield).
l-(5-Phenvl-thiophen-2-vl)ethyIamine (Isomer 2, Preparation 171) Add 4N hydrogen
chloride in dioxane (1.112 mL, 4.449 mmol) to a stirred solution of AT-[l-(5-
phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 2) (684 mg, 2.225
mmol) in methanol (10 mL) at room temperature. Stir for 2 h and remove the solvent in
vacuo to obtain a solid that was washed with ethyl ether. Dissolve the solid in DCM and
wash with saturated aqueous NaHCC>3. Dry the organic phase over Na2SC>4, filter and
concentrate in vacuo to obtain the desired intermediate (347 mg, 77% yield).
Example 49
6-(2-Benzoylamino-ethylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[ Hydrochloride


Dissolve 6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[J]azepine (70 mg, 0.208 mmol) in DCM (4 mL). Add benzoyl
chloride (24 uL, 0.208 mmol), and triethylamine (44 |oL, 0.312 mmol) and stir at ambient
temperature for 24 h under nitrogen atmosphere. Dilute with DCM and add 1M aqueous
HC1. Extract the aqueous layer with DCM. Dry the organic layer over MgSCv and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
(1:0, 7:3 and 1:1) to obtain 6-(2-benzoylamino-ethylamino)-7-chloro-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[J]azepine.
Use a method similar to the General Procedure 1-1, using 6-(2-benzoylamino-
ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyI)-2,3,4,5-tetrahydro-l^-benzo[rf]azepine, to
give the free base of the title compound. Use a method similar to the General Procedure
2-2 to give the title compound (77 mg, 90% overall). HPLC: tR= 2.64 min (20-80% of
Solvent B in 7.5 min. Solvent A: water, 0.1% TFA. Solvent B: acetonitrile, 0.1% TFA.
Column: C18 Metachem, 5 micron, 4.6x50).
Examples 50-52 may be prepared essentially as described in Example 49 by using
6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepineor6-(3-amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[(i]azepine and the appropriate benzoyl chloride. Overall yields and
MS (ES+) data are shown in the Table below.



ND = Not determined
Example 53
7-Chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethylamino}-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine Hydrochloride

Dissolve nicotinic acid (28.2 mg, 0.23 mmol) in DCM (3 mL). Add EDC (40 mg,
0.208 mmol), HOBT (28.1 mg, 0.2081mmol) and stir at ambient temperature for 10 min.
Add 6-(2-amino-ethylamino)-7-chIoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//'-
benzo[|azepine (70 mg, 0.208 mmol) and stir at ambient temperature for 10 hr. Dilute
with DCM, add water and extract the aqueous layer three times with DCM. Wash
combined organic extracts with IN aqueous NaOH, and brine. Dry the organic layer over
MgSCu, concentrate in vacuo and purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0, 1:1, 3:7 and 1:9) to obtain 7-chloro-6-{2-[(pyridine-3-carbonyl)-
amino]-ethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[£/]azepine.
Use a method similar to the General Procedure 1-1, using 7-chloro-6-{2-
[(pyridine-3-carbonyl)-amino]-ethylamino}-3-(2,2,2-trifluoroaceryl)-2,3,4,5-tetrahydro-
1 W-benzo[rf]azepine, to give the free base of the title compound. Use a method similar to

the General Procedure 2-2 to give the title compound as a solid (92 mg, 98%). HPLC: tR=
1.38 min (20-80% of Solvent B in 7.5 min. Solvent A: water, 0.1% TFA. Solvent B:
acetonitrile, 0.1% TFA. Column: C18 Metachem, 5 micron, 4.6x50).
Example 54
7-Chloro-6-[3-(3-phenyl-ureido)-propylamino]-2,3,4,5-tetrahydro-li7-benzo[ Hydrochloride

Combine phenyl isocyanate (15 uL, 0.137 mmol) and 6-(3-amino-propylamino)-7-
chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ mmol) in DCM and stir for 16 h. Concentrate, add DCM, filter and collect the solid to
obtain 7-chloro-6-[3-(3-phenyl-ureido)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[]azepine (18 mg, 28%).
Use a method similar to the General Procedure 1-1, using 7-chloro-6-[3-(3-phenyl-
ureido)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 i/-benzo[rf]azepine, to
give the free base of the title compound. Use a method similar to the General Procedure 2-
2 to give the title compound (14 mg, 23%). MS (ES+) m/z: 373 (M+H)+.
Example 55
6-(2-Phenoxy-ethylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Hydrochloride

Use a method similar to the General Procedure 5-1, using 3-(2,2,2-trifluoroacetyl)-
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cQazepine (100 mg, 0.23
mmol) and phenoxyethylamine (63 mg, 0.4 mmol) to give, after chromatography on silica
gel eluting with hexane/EtOAc (85:15) followed by SCX chromatography, 6-(2-phenoxy-

ethylamino)-3-(2,2,2-trif1uoroacetyl)-2,3,4,5-tetrahydro-li/-benzo[t/|azepine as a yellow
oil. MS (ES+) m/z: 379 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 6-(2-phenoxy-
ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[f/|azepine (75 mg, 0.19
mmol). Purify by SCX chromatography to give the free base of the title compound. Use a
method similar to the General Procedure 2-2 to give the title compound as a white solid.
MS (ES+) m/z: 283 (M+H)+
Examples 56-61 may be prepared essentially as described in Example 55 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine and the appropriate amine. The yields for the Stepl (General Procedure
5-1) and MS (ES+) data are shown in the Table below.



ND = Not determined
Example 62
7-Chloro-6-[(2-ethoxyethyl)amino]-2,3,4,5-tetrahydro-l^-benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-1, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(200 mg, 0.47 mmol) and 2-ethoxyethyl amine (105 ^L, 1.0 mmol) to give, after
chromatography on silica gel eluting with hexane/EtOAc (95:5) and additional SCX
chromatography, 7-chloro-6-[(2-ethoxyethyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[c/]azepine (32 mg, 19%). MS (ES+) m/z: 365 (M+H)+.

Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[(2-
ethoxyethyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rflazepine(30
mg, 0.08 mmol). Purify by SCX chromatography to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
as an oil (23.8 mg, 75% over 2 steps). MS (ES+) m/z: 269 (M+H)+.
Examples 63-68 may be prepared essentially as described in Example 62 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyIoxy-2,3,4,5-tetrahydro-l//-
benzo[t/]azepine and the appropriate amine. The yields for the Step 1 (General Procedure
5-1), optical rotations and MS (ES+) data are shown in the Table below.




Example 69
6-(2-Fluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepineHydrochloride

Use a method similar to the General Procedure 5-1, using 3-(2,2,2-trifluoroacetyl)-
6-trifluoromethyIsulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[]azepine (100 mg, 0.26
mmol) and 2-fluorobenzylamine (88 JIL, 0.77 mmol) to give, after chromatography on
silica gel eluting with hexane/EtOAc (9:1), 6-(2-fluorobenzylamino)-3-(2,2,2-
trifluoroacetyI)-2,3,4,5-tetrahydro-l//-benzo[]azepine as a yellow oil (45 mg, 48%). MS
(ES+) m/z: 367 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 6-(2-
fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//Lbenzo[d]azepine(40
mg, 0.11 mmol). Purify by SCX chromatography to give the free base of the title
compound as a yellow oil (28 mg, 94 %). Use a method similar to the General Procedure
2-2 to give the title compound as an off-white solid (29 mg, 95%). MS (ES+) m/z: 271
(M+H)+.
Example 70 may be prepared essentially as described in Example 69 by using 3-
(2,2,2-trifluoroacetyl)-6-trifluoromethylsuIfonyloxy-2,3,4,5-tetrahydro-l//-

benzo[rf]azepine and 2,6-difluorobenzylamine. The yield for the Step 1 (General
Procedure 5-1) and MS (ES+) data are shown in the Table below.

Example 71
7-Chloro-6-(2-fluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[t/]azepine Hydrochloride

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/7-benzo[rf]azepine
and 2-fluorobenzyl amine. Purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1 and 4:1) to give 7-chloro-6-(2-fluorobenzylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine as a yellow solid. MS (ES+) m/r.
401 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(2-
fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[f/]azepine.
Purify by SCX chromatography to give the free base of the title compound as a yellow oil.
Use a method similar to the General Procedure 2-2 to give the title compound as a light
yellow solid. MS (ES+) m/z: 305 (M+H)+.

Examples 72-80 may be prepared essentially as described in Example 71 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine and the appropriate amine. MS (ES+) data are shown in the Table below.



Example 81
6-(4-rert-Butylbenzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[c(]azepine Succinate
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine
(300 mg, 0.7 mmol) with 4-(/erNbutyl)benzyl amine (375 \xL, 2.1 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by SCX
chromatography to give 6-(4-/ert-butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-li/-benzo[cr|azepine as a colorless oil (240 mg, 78%). MS (ES+) m/r.
439 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 6-(4-tert-
butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine (235 mg, 0.54 mmol). Purify by SCX chromatography to give the free
base of the title compound (161 mg, 87%). Use a method similar to the General Procedure
2-1 to give the title compound as an off-white gum (190 mg, 88%). MS (ES+) m/r. 343
(M+H)+.
Examples 82-88 may be prepared essentially as described in Example 81 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-
benzo[c/|azepine and the appropriate amine. MS (ES+) data are shown in the Table below.




Example 89
7-Chloro-6-(4-cyanobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[ CN

Use a method similar to the General Procedure 5-1 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[J)azepine
(504 mg, 1.2 mmol), 4-cyanobenzylamine (476 mg, 3.6 mmol), palladium(II) acetate (29
mg, 0.1 mmol), BINAP (148 mg, 0.2 mmol) and cesium carbonate (540 mg, 1.7 mmol) in

toluene (5 mL). Purify by chromatography on silica gel eluting with isohexane/EtOAc
(1:0 to 1:1) to give 7-chloro-6-(4-cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine as a white gum (108 mg, 22%). MS (ES+) m/z: 408
(M+H)+.
Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-6-(4-
cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l#-benzo[rf]azepine(98
mg, 0.2 mmol). Purify by preparative liquid chromatography eluting with a gradient of
water/acetonitrile (19:1 to 1:19) to give the free base of the title compound (31 mg, 42%).
MS (ES+) m/z: 312 (M+H)+. Use a method similar to the General Procedure 2-1, using 7-
chloro-6-(4-cyanobenzylarnino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (31 mg, 0.1
mmol) to give the title compound as a beige solid (41 mg, 95%). MS (ES+) m/z: 312
(M+H)+.
Example 90
7-Chloro-6-(3-phenyl-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepineSuccinate




Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[i/|azepine
(0.3 g, 0.706 mmol) with 3-phenyl-benzylamine (0.388 g, 2.117 mmol) using
palladium(II) acetate (32 mg; 0.141 mmol), tris(dibenzylideneacetone)dipalladium(0) (65
mg, 0.070 mmol), BINAP (264 mg, 0.424 mmol) and cesium carbonate (460 mg, 1.412
mmol) in toluene (12 mL). Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0, 19:1) to give 7-chIoro-6-(3-phenyl-benzylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-li/-benzo[flf|azepine as an oil (0.257 g, 79%). MS
(ES+) m/z: 459 (M+H)+.

Use a method similar to the General Procedure 1-2, using 7-chloro-6-(3-phenyl-
benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[t/]azepine (237 mg,
0.516 mmol), to give the free base of the title compound as an oil (188 mg, 100%) that
was used without further purification.
Use a method similar to the General Procedure 2-1, using 7-chloro-6-(3-phenyl-
benzylamino)-2,3,4,5-tetrahydro-l/f-benzo[ title compound as a white solid (191 mg, 77%). MS (ES+) m/z: 363 (M+H)+.
Example 91
7-Chloro-6-(4-chlorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rflazepineSuccinate

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine
(700 mg, 1.6 mmol) with 4-chlorobenzylamine (354 mg, 2.5 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) and then SCX
chromatography to give 7-chloro-6-(4-chlorobenzylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l#-benzo[]azepine (459 mg, 69%). MS (ES+) m/z: 417 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-(4-
chlorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[fiT|azepine.
Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol
(95:5) to give the free base of the title compound. MS (ES+) m/z: 321 (M+H)+. Use a
method similar to the General Procedure 2-1 to obtain the title compound.
Examples 92-98 may be prepared essentially as described in Example 91 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l^-

benzo[d]azepine and the appropriate amine. The yields for the Step 1 (General Procedure
5-3) and MS (ES+) data are shown in the Table below.

Examples 99-106 may be prepared essentially as described in Example 91 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
1/7-benzofrflazepine and the appropriate amine. The yields for the Step 1 (General
Procedure 5-3) and MS (ES+) data are shown in the Table below.


Example 106
7-Chloro-6-(2-fluoro-4-phenoxy-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[c/Jazepine
Succinate


Using a method similar to the General Procedure 5-3, couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
(1.1 g, 2.5 mmol) with 2-fluoro-4-phenoxy-benzylamine (550 mg, 2.5 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) and then SCX
chromatography to obtain 7-chloro-6-(2-fluoro-4-phenoxy-benzylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[|azepine. MS (ES+) m/z: 493 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(2-
fluoro-4-phenoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[i/|azepine. Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (95:5) to give the free base of the title compound (468 mg, 47% overall).
MS (ES+) m/z: 397 (M+H)+. Use a method similar to the General Procedure 2-1 to obtain
the title compound.
Example 107
7-Chloro-6-[2-fluoro-4-(3'-fluorophenoxy)-ben2ylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Use a method similar to the Example 106, using 7-chloro-3-(2,2,2-trifluoroacetyl)-
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf)azepine (426 mg, 1.0
mmol) and 2-fluoro-4-(3'-fluorophenoxy)-benzylamine (340 mg, 1.4 mmol) to give the
free base of the title compound (162 mg, 39%). MS (ES+) m/z: 415 (M+H)+. Use a
method similar to the General Procedure 2-1 to obtain the title compound.

Examples 108-121 may be prepared essentially as described in Example 107 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
lH-benzo[d\azep\ne and the appropriate amine. The yields for the Step 1 (General
Procedure 5-3) and MS (ES-i-) data are shown in the Table below.


Ex. R Compound Yield
(%) MS (ES+)
m/z
108 2-F 7-Chloro-6-[4-(2' -fluorophenoxy)-
benzylamino]-2,3>4,5-tetrahydro-l//-
benzo[t/Jazepine Succinate 44 397
(M+H)+
109 3-F 7-Chloro-6-[4-(3'-fluorophenoxy)-
benzylamino]-2,3,4,5 -tetrahydro-1H-
benzoff^azepine Succinate 23 397
(M+H)+
110 4-F 7-Chloro-6-[4-(4' -fluorophenoxy)-
benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[c/|azepine Succinate 50 397
(M+H)+
111 3-C1 7-Chloro-6-[4-(3' -chlorophenoxy)-
benzylamino]-2,3,4,5-tetrahydro-l//-
benzofrflazepine Succinate 45 413
(M+H)+
112 3,5-diF 7-Chloro-6-[4-(3\5'-
difluorophenoxy)-benzylam ino] -
2,3,4,5-tetrahydro-ltf-
benzo[c/|azepine Succinate 36 415
(M+H)+
113 4-CH3 7-Chloro-6-[4-(4'-methylphenoxy)-
benzylamino]-2,3,4,5-tetrahydro-l//-
benzo^azepine Succinate 54 393
(M+H)+
114 3-CH3 7-Chloro-6-[4-(3' -methylphenoxy)-
benzylamino]-2,3,4,5-tetrahydro-lH-
benzo[]azepine Succinate 45 393
(M+H)+
115 2-CH3 7-Chloro-6-[4-(2'-methylphenoxy>
benzylamino]-2,3,4,5-tetrahydro-li/-
benzo[t/]azepine Succinate 54 393
(M+H)+
116 3-'Pr 7-Chloro-6-[4-(3'-
isopropylphenoxy)-benzylamino]-
2,3,4,5-tetrahydro-l/f-
benzo[|azepine Succinate 49 421
(M+H)+
117 2-'Pr 7-Chloro-6-[4-(2'- 40 421





Example 122
7-Chloro-6-[4-(3'-cyanobenzyIoxy)-benzyIamino]-2,3,4,5-tetrahydro-l//-benzo[*/]azepine
Succinate




Mix7-chloro-6-(4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[]azepine (150 mg, 0.38 mmol), 3-cyanobenzyl bromide (90 mg,
0.46 mmol), podwered potassium carbonate (105 mg, 0.76 mmol), powdered potassium
iodide (6.6 mg, 0.04 mmol) and acetone (30 mL). Stir and heat to reflux under nitrogen
for 16 hr. Dilute with acetone, filter, concentrate in vacuo and purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0 and 4:1) to obtain 7-chIoro-6-[4-(3'-
cyanobenzyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzofrfjazepine (72.4 mg, 37%). MS (ES+) m/z 514 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[4-(3'-
cyanobenzyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine. Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (95:5) to give the free base of the title compound (42 mg, 71%). MS (ES+)

m/z: 418 (M+H)4. Use a method similar to the General Procedure 2-1 to obtain the title
compound.
Examples 123-126 may be prepared essentially as described in Example 122 by
using 7-chloro-6-(4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[ shown in the Table below.

Example 127
7-Chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-2,3,4,5-tetrahydro-
l//-benzo[

Use a method similar to the General Procedure 4-1 to react 7-chloro-6-(3-chloro-
4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ (438 mg, 1.01 mmol) and 1-bromopinacolone (217 mg, 1.21 mmol). Purify by
chromatography on silica gel eluting with EtOAc/hexane (1:4) to give 7-chloro-6-[3-
chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf)azepine as a colorless oil (441 mg, 82%). MS (ES+) m/r. 531
(M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[3-
chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4)5-
tetrahydro-l//-benzo[c/lazepine (441 mg, 0.83 mmol). Purify by chromatography on
silica gel eluting with DCM/2M ammonia in methanol (93:7) to give the free base of the
title compound (278 mg, 95%). MS (ES+) m/r. 435 (M+H)+. Use a method similar to the
General Procedure 2-1 to give the title compound.
Example 128
7-Chloro-6-(3-chloro-4-benzyloxy-benzylamino)-2,3,4,5-tetrahydro-li¥-benzo[rf]azepine
Succinate


The title compound may be prepared essentially as described in Example 127,
using 7-chloro-6-(3-chloro-4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[J]azepine and benzyl bromide (64%). MS (ES+) m/z: 427 (M+H)+.
Example 129
(±)-7-Chloro-6-[4-(l-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[
o
Use a method similar to the General Procedure 5-3, to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cnazepine
(851 mg, 2.0 mmol) and (±) 4-(l-phenyl-ethoxy)-benzylamine (721 mg, 2.6 mmol).
Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (±)-7-
chloro-6-[4-(l-phenyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[c/]azepme (702 mg, 69%). MS (ES+) m/z: 503 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect (±)-7-chloro-6-[4-
(l-phenyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[]azepine (702 mg, 1.40 mmol). Purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (92:8) to give the free base of the title compound
(368 mg, 65 %). MS (ES+) m/z: 407 (M+H)+. Use a method similar to the General
Procedure 2-1 to obtain the title compound.
Examples 130 and 131
(-)-7-Chloro-6-[4-(l-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[cf]azepine Succinate and (+)-7-Chloro-6-[4-(l-phenyl-ethoxy)-benzylamino]-
2,3,4,5-tetrahydro-l//-benzo[t/]azepine Succinate


Separate the two enantiomers of Example 129 by chiral HPLC [Chiralcel OJ-H
column, acetonitrile/methanol (20:80) with 0.2% DMEA; flow rate 1 mL/min; Isomer 1:
tR=5.0 min, Isomer 2: tR=6.5 min].
Use a method similar to the General Procedure 2-1 to prepare the succinate of
each enantiomer: (-)-7-chloro-6-[4-(l-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine Succinate, [a]20D -17.4° (c 0.5, CH3OH), and (+)-7-chloro-6-[4-(l-
phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[cT|azepine Succinate, [a]20D
+18.2° (c 0.5, CH3OH).
Example 132
7-Chloro-6-[4-(3,3-dimethylbutoxy)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine Mesylate

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[*/]azepine
(426 mg, 1.0 mmol) and 4-(3,3-dimethylbutoxy)-benzylamine (325 mg, 1.5 mmol). Purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) and then SCX
chromatography to obtain 7-chloro-6-[4-(3,3-dimethylbutoxy)-benzylamino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine. MS (ES+) m/z: 483 (M+H)+.

Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[4-
(3,3-dimethylbutoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[cf]azepine. Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (95:5) to give the free base of the title compound (161 mg, 42% overall). MS
(ES+) m/z: 387 (M+H)4". Use a method similar to the General Procedure 2-4 to obtain the
title compound.
Example 133
7-Chloro-6-(4-cyclohexylmethoxy-benzylamino)-2,3,4,5-tetrahydro-l/7-beiizo[^azepine
Mesylate

(CH3SO3H)X
The title compound may be pre
pared essentially as described in Example 132, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[t/]azepine
and 4-cyclohexylmethoxy-benzylamine ( 27% yield, MS (ES+) m/z 399 (M+H)*).
Example 134
7-Chloro-6-(3-pyrrolidinyl-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate


Use a method similar to the General Procedure 5-1, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c?]azepine
(300 mg, 0.7 mmol) and 3-(pyrrolidin-l-yl)benzylamine (300 mg, 1.7 mmol) to give, after
chromatography on silica gel eluting with hexane/EtOAc (19:1, 9:1, 4:1 and 3:2), 7-
chloro-6-(3-pyrrolidinyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[]azepine as a yellow oil (195 mg, 62%). MS (ES+) m/z: 452 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(3-
pyrrolidinyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine (195 mg, 0.43 mmol). Purify by SCX chromatography to give the free
base of the title compound (136 mg, 89%). Use a method similar to the General
Procedure 2-1, using 7-chloro-6-(3-pyrrolidinyl-benzylamino)-2,3,4,5-tetrahydro-l#-
benzo[rf]azepine (130 mg, 0.37 mmol), to give the title compound as an off-white gum
(111 mg, 61%). MS (ES+) m/z: 356 (M+H)+.
Example 135
6-(4-Memoxybenzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rfjazepine
Hydrochloride

Use a similar method to the General Procedure 1-1, using 6-(4-
methoxybenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (0.1 g, 0.24 mmol) to give the free base of the title compound. Use a
similar method to the General Procedure 2-2 to give the title compound (75 mg, 80%).
HRMS calcd forCi8H2iClN2O 317.1421, found 317.1410.

Example 136
7-Chloro-6-[4-(2,2,3,3-tetrafluoropropoxy)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(500 mg, 1.2 mmol) with 4-(2,2,3,3-tetrafluoropropoxy)-benzylamine (835 mg, 3.5 mmol)
in toluene (10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc
(10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol
followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia
in methanol (1:1) and concentrate in vacuo] to obtain 7-chloro-6-[4-(2,2,3,3-
tetrafluoropropoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine(600
mg,99%).
Use a method similar to the the General Procedure 1-3 to deprotect 7-chloro-6-[4-
(2,2,3,3-tetrafluoropropoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lflr-
benzo[rf|azepine (600 mg, 1.2 mmol). Purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (99:1 to 90:10) to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
(390 mg, 62 %). MS (ES+) m/z: 417 (M+H)+.
Examples 137-138 may be prepared essentially as described in Example 136 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
l//-benzo[d]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.



Examples 139 and 140
(-)-7-Ch lora-6-[4-(2,2,2-trifIuoro-1 -methyl-ethoxy)-benzylamino] -2,3,4,5-tetrahydro-1H-
benzo[rf]azepine Succinate and (+)-7-Chloro-6-[4-(2,2,2-trifluoro-l-methyl-ethoxy)-
benzyIamino]-2,3,4,5-tetrahydro-lit/-benzo[c(]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(500 mg, 1.2 mmol) with (±)-4-(2,2,2-trifluoro-l-methyl-ethoxy)-benzylamine (515 mg,
2.3 mmol) in toluene (10 mL). Purifyby chromatography on silica gel eluting with
hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column
with methanol followed by DCM, load material dissolved in DCM, then elute with
DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give (±)-7-chloro-6-
[4-(2,2,2-trifluoro-l-methyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[
Use a method similar to the General Procedure 1-3 to deprotect (±)-7-chloro-6-[4-
(2,2,2-trifluoro-l-methyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l/f-benzo[ gel eluting with DCM/2M ammonia in methanol (99:1 to 90:10) to give (±)-7-chloro-6-
[4-(2,2,2-trifluoro-l-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-li7-
benzo[rf]azepine. Use a method similar to the General Procedure 2-1 to obtain (±)-7-
chloro-6-[4-(2,2,2-trifluoro-l-methyl-ethoxy)-benzylamino]-2,3>4,5-tetrahydro-l//-
benzo[rf]azepine Succinate.
Separate the two enantiomers of (±)-7-chloro-6-[4-(2,2,2-trifluoro-l-methyl-
ethoxy)-benzylamino]-2,3,4,5-tetrahydro-l/f-benzo[rf]azep»ne succinate by normal phase
chiral chromatography (Chiralpak AD 8x30 cm, elute with 85:15 heptane/3 A ethanol with
0.2% DMEA).
Use a method similar to the General Procedure 2-1 to obtain (-)-7-chloro-6-[4-
(2,2,2-trifluoro-1 -methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro- l//-benzo[tf]azepine
Succinate [137 mg, 71% recovery, 98% ee (Chiralpak AD, 4.6x150 mm, eluent: 85:15
heptane/isopropanol with 0.2% DMEA, 0.6 mL/min)]. MS (ES+) m/r. 399 (M+H)+.
[ Use a method similar to the General Procedure 2-1 to obtain (+)-7-chloro-6-[4-
(2,2,2-trifluoro-l-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-l/f-benzo[cQazepine
Succinate [133 mg, 69% recovery, 97% ee (Chiralpak AD, 4.6x150 mm, eluent: 85:15
heptane/isopropanol with 0.2% DMEA, 0.6 mL/min)]. MS (ES+) m/z: 399 (M+H)+.
[a]20D+9.2°(c0.5,MeOH).
Example 141
6-(4-Acetyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l/f-benzo[]azepine Succinate


Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
(200 mg, 0.47 mmol) with 4-(2-methyl-[l,3]dioxolan-2-yl)-benzylamine (prepared by
following the procedure described in J. Med. Chem. 1978, 21, 507) (182 mg, 0.94 mmol).
Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1 and 9:1) to
give 6-{4-(2-methyl-[ 1,3]dioxolan-2-yl)benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l/f-benzo[rflazepine as an oil (150 mg, 68%). GC-MS m/z 468 (\T).
Dissolve 6-{4-(2-methyl-[l,3]dioxolan-2-yl)benzylamino}-7-chloro-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine (150 mg, 0.32 mmol) in methanol
(5 mL) and add IN aqueous HC1 (1 mL). Stir the solution at ambient temperature for 2 h.
Remove the solvent, dissolve the residue in DCM and wash with saturated aqueous
NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to obtain
6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[cf]azepine as an oil (107 mg, 79%). GC-MS m/z 424 (M+).
Use a method similar to the General Procedure 1-2, using 6-(4-acetyl-
benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ (100 mg, 0.23 mmol), to give the free base of the title compound as an oil (76 mg, 99%)
that was used without further purification.
Use a method similar to the General Procedure 2-1, using 6-(4-acetyl-
benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (76 mg, 0.23 mmol), to
give the title compound as a white solid (102 mg, 97%). MS (ES+) m/z: 329 (M+H)+.

Example 142
6-(3-Acetylbenzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[£/]azepine Succinate
O

Use a method similar to Example 141, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[d]azepine and 3-(2-methyl-
[l,3]dioxolan-2-yl)-benzylamine (prepared by following the procedure described in J.
Med. Chem. 2000, 43, 3315), to give the title compound as a solid. MS (ES+) m/zr. 329
(M+H)+.
Example 143
7-Chloro-6-[4-(l-hydroxyiminoethyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Add hydroxylamine hydrochloride (19 mg, 0.27 mmol) and pyridine (0.04 mL,
0.54 mmol) to a solution of 6-(4-acetylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-lfl-benzo[rf]azepine (115 mg, 0.27 mmol) in ethanol (10 mL). Heat
the mixture to reflux for 2 h. Remove the solvent in vacuo and partition the residue
between DCM and 0.1N aqueous HC1. Dry the organic phase over Na2SC>4, filter and
concentrate. Dissolve the oil into the minimum amount of ether and add hexane to
precipitate the solid. Filter to obtain 7-chloro-6-[4-(l-hydroxyiminoethyl)-benzylamino]-

3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[i/]azepine as a solid (112 mg, 94%)
that was used without farther purification. MS (ES+) m/z: 440 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(l-
hydroxyiminoethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine (100 mg, 0.23 mmol), to give 7-chloro-6-[4-(l-hydroxyiminoethyl)-
benzylamino]-2,3,4,5-tetrahydro-l//-benzo[cfJazepine as an oil (61 mg, 78%) that was
used without further purification.
Use a method similar to the General Procedure 2-1, using 7-chloro-6-[4-(l-
hydroxyirninoethyl)benzylamino]-2,3,4,5-tetrahydro-lfl'-benzo[rf]azepine(58 mg, 0.17
mmol) to give the title compound as a white solid (68 mg, 87%). MS (ES+) m/z: 344
(M+H)+.
Example 144
6-(4-Benzoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf)azepine Succinate




Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[flT|azepine
(272 mg, 0.64 mmol) with 4-(aminomethyl)benzophenone (prepared by following the
procedure described in J. Biol. Chem. 1993,268 (19), 14230) (270 mg, 1.3 mmol). Purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1,17:3 and 4:1) to
give 6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-
benzo[t/)azepine as an oil (300 mg, 96%).

Use a method similar to the General Procedure 1-2, using 6-(4-benzoyl-
benzylamino)-7-chloro-3-(2)2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//Lbenzo[ (80 mg, 0.16 mmol), to give 6-(4-benzoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-
benzofrfjazepine as an oil (47 mg, 73%) that was used without further purification.
Use a method similar to the General Procedure 2-1, using -(4-benzoyl-
benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (45 mg, 0.11 mmol), to
give the title compound as a white solid (37 mg, 63%). MS (ES+) m/r. 391 (M+H)+.
Example 145
7-Chloro-6-[4-(l-hydroxyiminobenzyl)-benzylamino]-2,3,4,5-tetrahydro-l/f-
benzo[t/]azepine Succinate




HO2CCH2CH2CO2H
Add hydroxylamine hydrochloride (52 mg, 0.75 mmol) and pyridine (0.1 mL) to a
solution of 6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[JJazepine (91 mg, 0.19 mmol) in ethanol (10 mL). Heat the mixture
to reflux overnight. Remove the solvent in vacuo and partition the residue between DCM
and 0. IN aqueous HC1. Dry the organic phase over Na2SC>4, filter and concentrate.
Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0,4:1 and 3:1) to
give7-chloro-6-[4-(l-hydroxyiminobenzyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[d]azepine as a mixture of E/Z isomers (93 mg, 99%).
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(l-
hydroxyiminobenzyl)benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-
benzo[t/]azepine (97 mg, 0.19 mmol), to give 7-chloro-6-[4-(l-hydroxyiminobenzyl)-

benzylatnino]-2,3,4,5-tetrahydro-l//-benzo[c/|azepine as an oil (68 mg, 87%) that was
used without further purification.
Use a method similar to the General Procedure 2-1, using 7-chloro-6-[4-(l-
hydroxyiminobenzyI)benzylamino]-2,3,4,5-tetrahydro-li/-benzo[V/|azepine (65 mg, 0.16
mmol), to give the title compound as a white solid (67 mg, 80%). MS (ES+) m/z: 406
(M+H)+.
Example 146
7-Chloro-6-[4-(pyridin-4-yl)-benzylamino]-2,3,4,5-tetrahydro-l/7-benzo[ Succinate

Use a method similar to the General Procedure 5-3, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[i/lazepine
(178 mg, 0.426 mmol) and a solution of 4-(pyridin-4-yl)-benzylamine (116 mg, 0.63
mmol) in THF/toluene (1:1,8 mL). Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0,7:3 and 1:1) to give 7-chloro-6-[4-(4-pyridin-4-yl)-benzylarnino]-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine as an oil (120 mg, 63%).
MS (ES+) m/z: 460 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(pyridin-
4-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[^azepine(153
mg, 0.33 mmol), to give 7-chloro-6-[4-(pyridin-4-yl)-benzylamino]-2,3,4,5-tetrahydro-
l/f-benzofrfjazepine as an oil (110 mg, 91%) that was used without further purification.
Use a method similar to the General Procedure 2-1, using 7-chloro-6-[4-(pyridin-4-yl)-

benzylamino]-2,3,4,5-tetrahydro-l//-benzo[c/jazepine (105 mg, 0.289 mmol) to give the
title compound as a white solid (123 mg, 88%). MS (ES+) m/z: 364 (M+H)+.
Examples 147-149 may be prepared essentially as described in Example 146 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyIoxy-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.

Example 150
(-)-7-Chloro-6-[4-(4-phenyl-4,5-dihydro-l//-imidazol-2-yl)-benzylamino]-2,3,4,5-
tetrahydro- l//-benzo[

Mix 7-chloro-6-(4-cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[ (600 tng, 4.4 mmol, prepared as described in J. Org. Chem. 1997, 62, 3586) andp-
toluenesulfonic acid monohydrate (102 mg, 0.53 mmol) in a sealed tube equipped with a
magnetic stirrer. Heat the mixture to 200°C for 16 h. Cool the mixture to ambient
temperature. Dilute with DCM (50 mL) and wash with saturated aqueous NaHCO? (10
mL). Collect the organic fraction and concentrate in vacuo. Purity by chromatography on
silica gel eluting with DCM/2M ammonia in methanol (98:2 to 80:20).
Use a method similar to the General Procedure 2-3 to give title compound as the
hydrochloride. Use reverse phase HPLC [Column: Symmetry C18, 10x300 mm, flow =
25 mL/min, water with 0.1% TFA / Acetonitrile (9:1 to 2:3)] followed by SCX
chromatography to obtain the free base of the title compound. Use a method similar to the
General Procedure 2-3 to obtain the title compound (38 mg, 16%). MS (ES+) m/z: 431
(M+H)+. [a]20D -20° (c 0.5, MeOH).
Example 151
7-Chloro-6-[4-(l-methyl-l//-imidazol-2-yl)-benzylamino]-2,3,4,5-tetrahydro-l/f-
benzo[£(]azepine Succinate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyIoxy-2,3,4,5-tetrahydro-l//-benzo[^azepine
(455 mg, 1.1 mmol) with 4-(l-methyl-li/-imidazol-2-yl)-benzylamine (240 mg, 1.3
mmol) in toluene (8 mL). Purify by chromatography on silica gel eluting with
hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column
with methanol followed by DCM, load material dissolved in DCM, then elute with
DCM/2M ammonia in methanol (1:1) and concentrate in vacud] to obtain 7-chloro-6-[4-
(l-methyl-l^-imidazol-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (429 mg, 93%). MS (ES+) m/z: 463 (M+H)+.
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-[4-(l-
methyl-l//-imidazol-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lfl-
benzo[]azepine. Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (99:1 to 90:10) to give the free base of the title compound. Use a method
similar to the General Procedure 2-1 to give the title compound (350 mg, 73 %). MS
(ES+) m/z: 367 (M+H)+.
Example 152
7-Chloro-6-(4-ethanesulfonyl-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[ar]a2epine
Hydrochloride


Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[J]azepine
(0.2 g, 0.35 mmol) and 4-ethanesulfonyl-benzylamine (0.2 g, 1.06 mmol) to give 7-
chloro-6-(4-ethanesulfonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/)azepine as a colorless oil.
Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-2 to
form the hydrochloride salt. Purify by reverse phase preparative HPLC (Zorbax SB-
Phenyl 21.2x250 mm, 5 micron, 22 mL/min of 0.1% HC1 in water/acetonitrile (9:1 to 1:1)
over 30 min, detector at 230 nm) to obtain the title compound as a white solid (57 mg,
36%).
MS (ES+) m/z: 379 (M+H)+.
Example 153
7-Chloro-6-[4-(2-propanesulfonyl)-ben2ylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

The title compound may be prepared essentially as described in Example 152,
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
l//-benzo[cQazepine and 4-(2-propanesulfonyl)-benzylamine(l 1% yield, MS (ES+) m/z
393 (M+H)+).
Example 154
7-Chloro-6-(4-methoxycarbonyl-benzylamino)-2,3,4,54etrahydro-l//-benzo[//Jazepine
Succinate


Treat 4-aminomethyl-benzoic acid methyl ester hydrochloride (0.2 g, 0.71 mmol)
with K2CO3 (1.0 g, 0.71 mmol) in a mixture of toluene/water (1:1,2 mL). Separate the
organic layer, dry over anhydrous Na2SO4 and use as a toluene solution for the next step.
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c/Iazepine
(0.1 g, 0.24 mmol) and 4-aminomethyl-benzoic acid methyl ester (0.2 g, 0.71 mmol) to
give7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l/f-benzo[)azepine as a colorless oil.
Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-1 to
obtain the title compound as a white solid (20 mg, 18%). MS (ES+) m/r. 345 (M+H)+.
Example 155
6-(4-Carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rfjazepine
Hydrochloride

Combine 7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[|azepine (70 mg, 0.16 mmol), potassium carbonate (0.87 g,
6.3 mmol), methanol (2 mL), water (2 mL) and heat at 50°C for 3 h. Purify by SCX

chromatography to obtain 6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine as a yellow oil.
Use a method similar to the General Procedure 2-2 to form the hydrochloride salt.
Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2x250 mm, 5 micron,
22 mL/min of 0.1% HC1 in water/acetonitrile (9:1 to 1:1) over 30 min, detector at 230
nm] to obtain the title compound as a white solid (30 mg, 46%). MS (ES+) mfz: 331
(M+H)+.
Example 156
7-Chloro-6-(4-methylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride




Combine 3-(/er/-butoxycarbonyl)-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-
tetrahydro-l#-benzo[]azepine (0.1 g, 0.3 mmol), methylamine hydrochloride (31 mg,
0.46 mmol), triethylamine (0.1 g, 0.9 mmol), HATU (0.2 g, 0.5 mmol), anhydrous DMF
(3 mL) and stir at ambient temperature for 17 h. Partition the reaction mixture between
brine (5 mL) and diethyl ether (5 mL), separate the organic layer and dry over anhydrous
Na2SO4. Evaporate the solvent to obtain 3-(terf-butoxycarbonyl)-7-chloro-6-(4-
methylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-l/f-benzo[fl0azepine as a yellow oil
(0.1 g, 93%). MS (ES+) m/z: 344 (M+H-Boc)'.
Use a method similar to the General Procedure 1-5 and purify the residue by SCX
chromatography to obtain the free base of the title compound as a yellow oil. Use a
method similar to the General Procedure 2-2 to form the hydrochloride salt. Purify by
reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2x250 mm, 5 micron, 22 mL/min

of 0.1% HC1 in water/acetonitrile (9:1 to 1:1) over 30 min, detector at 230 nm] to obtain
the title compound as a white solid (0.9 g, 65%). MS (ES+) m/r. 344 (M+H)+.
Examples 157-158 may be prepared essentially as described in Example 156 by
using 3-(/er/-butoxycarbonyI)-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-
l//-benzo[d]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.

Example 159
6-(4-/er/-Butylcarbamoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[«/|azepine
Hydrochloride

Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[|azepine
(0.2 g, 0.35 mmol) and 4-aminometyl-N-/ert-butyl-benzamide (0.2 g, 1.06 mmol), to give

6-(4-ter/-butylcarbamoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine as a colorless oil.
Use a method similar to the General Procedure 1 -1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-2 to
form the hydrochloride salt and purify by reverse phase preparative HPLC [Zorbax SB-
Phenyl 21.2x250 mm, 5 micron, 22 mL/min of 0.1% HC1 in water/acetonitrile (9:1 to 1:1)
over 30 min, detector at 230 nm] to obtain the title compound as a white solid (65 mg,
41%). MS (ES+) m/z: 386 (M+H)+.
Examples 160-161 may be prepared essentially as described in Example 159 by
using 7-chloro-3-(2,2^2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
l//-benzo[]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.



7-Chloro-6-[4-(cyclohexylaminocarbonyl-)3-fluoro-benzylamino]-2,3,4,5-tetrahydro-l/7-
benzo[rf]azepine Succinate
Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(500 mg, 1.17 mmol) with 4-aminomethyl-Ar-cyclohexyl-2-fluoro-benzamide (441 mg,
1.76 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1,
10:1, 7:1 and 5:1) to give 7-chloro-6-[4-(cyclohexylarninocarbonyl-)3-fluoro-
benzy!amino]-3-(2,2,2-trifluoroaceryl)-2,3,4,5-tetrahydro-l//-tenzo[^azepine as an oil.
Use a method similar to the General Procedure 1-3 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (1:0, 20:1. 10:1 and 7:1)
followed by reverse phase semi-prep HPLC [SymmetryPrep C18, 7 Dm, 19x300 mm
column eluting with acetonitrile/0.1 % trifluoroacetic acid in water (1:9 to 8:2) at 20
mL/min] and SCX chromatography to give the free base of the title compound.
Use a method similar to the General Procedure 2-1 to give the title compound as a
yellow solid (97 mg, 15%). MS (ES+) m/z: 430 (M+H)+.
Example 163
7-Chloro-6-[4-(2,2,2-trifluoroethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//L
benzofrfjazepine Succinate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluorotnethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c0azepine
(250 mg, 0.59 mmol) with 4-aminomethyJ-iV-(2,2,2-trifluoroethyl)-benzamide (273 mg,
1.17 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1,
10:1, 7:1 and 5:1) to give 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethyl-
aminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[rfjazepine as an oil.
Use a method similar to the General Procedure 1-3 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (1:0,20:1. 10:1 and 7:1) to give
the free base of the title compound. Use a method similar to the General Procedure 2-1 to
give the title compound as a white solid (191 mg, 61%). MS (ES+) m/z: 412 (M+H)+.
Examples 164-177 may be prepared essentially as described in Example 163 by
using 7-chloro-3-(2,2,2-trifluoroacetyI)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
l//-benzo[c/]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.






Examples 178 and 179
(-)-7-Chloro-6-[4-(2,2,2-trifluoro-l-methy]-ethylaminocarbonyl)-benzylaniino]-2,3,4,5-
tetrahydro-li/-benzo[c/]azepine Succinate and (+)-7-Chloro-6-[4-(2,2,2-trifluoro-l-
methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-lfl-benzo[ Succinate

Dissolve (±)-7-chloro-6-[4-(2,2,2-trifluoro-1 -methyl-ethylaminocarbonyl)-
benzylamino]-2,3,4,5-tetrahydro-l/f-benzo[£/|azepine (472 mg, 1.11 mmol) in DCM (50
mL) and add di-terf-butyl-dicarbonate (300 mg, 1.34 mmol) and a solution of sodium
carbonate (2 g) in water (50 mL). Stir the reaction at room temperature for 2 h then dilute
with DCM, wash with water, dry over Na2SC>4, filter and concentrate. Purify by
chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) to give (±)-3-
rert-butoxycarbonyl-7-chloro-6-[4-(2,2,2-trifluoro-l-methyl-ethylaminocarbonyl)-
benzylamino]-2,3,4,5-tetrahydro-benzo[rf]azepine (330 mg, 57%).
Separate the two enantiomers by chiral HPLC [Chiralpak AD column, 8x30 cm,
eluting with 0.2% DMEA in heptane/isopropanol (9:1)].
Use a method similar to the General Procedure 1-5 to deprotect the first eluting
compound and purify by SCX chromatography to give (-)-7-chloro-6-[4-(2,2,2-trifluoro-

l-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine.
Use a method similar to the General Procedure 2-1 to give (-)-7-chloro-6-[4-(2,2,2-
trifluoro-l-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine succinate as a white solid (50 mg, 15%). MS (ES+) m/z: 426 (M+H)+;
[a]20D -3.3° (c 0.5, CH3OH).
Use a method similar to the General Procedure 1-5 to deprotect the second eluting
compound and purify by SCX chromatography to give (+)-7-chloro-6-[4-(2,2,2-trifluoro-
1 -methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1 /7-benzo[*/]azepine.
Use a method similar to the General Procedure 2-1 to give (+)-7-chloro-6-[4-(2,2,2-
trifluoro-l-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzofrflazepine succinate as a white solid (55 mg, 16%). MS (ES+) m/z: 426 (M+H)+;
[a]20D +4.4° (c 0.5, CH3OH).
Examples 180 and 181
(+)-7-Chloro-6-[4-(l-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-
tetrahydro-l/f-benzo[c(]azepine Succinate and (-)-7-Chloro-6-[4-(l-methyl-3,3>3-
trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[tf|azepine
Succinate

Dissolve (±)-7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-( 1 -methyl-3,3,3-trifluoro-
propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l/f-benzo[]azepine(985 mg,
2.24 mmol) in DCM (50 mL) and add di-/erf-butyl-dicarbonate (605 mg, 3.36 mmol) and
a solution of sodium carbonate (2 g) in water (50 mL). Stir the mixture at room
temperature for 1 h then dilute with DCM, wash with water, dry over Na2SO4, filter and
concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1,

5:1 and 3:1) to give (±)-3-terr-butoxycarbonyl-7-chloro-6-[4-(l-methyl-3,3,3-trifluoro-
propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-benzo[]azepine.
Separate the two enantiomers by chiral HPLC [Chiralpak AD column, 8x30 cm,
eluting with heptane/isopropanol/0.2% DMEA in methanol (90:5:5)].
Use a method similar to the General Procedure 1-5 to deprotect the first eluting
compound and purify by SCX chromatography to give (+)-7-chloro-6-[4-(l-methyl-3,3,3-
trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l/f-benzo[]azepine.
Use a method similar to the General Procedure 2-1 to give (+)-7-chloro-6-[4-(l-methyl-
3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine succinate as a white solid (186 mg, 15%). MS (ES+) m/z: 440 (M+H)+;
[a]20D +6.5° (c 0.5, CH3OH).
Use a method similar to the General Procedure 1-5 to deprotect the second eluting
compound and purify by SCX chromatography to give (-)-7-chIoro-6-[4-(l-methyl-3,3,3-
trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[ Use a method similar to the General Procedure 2-1 to give (-)-7-chloro-6-[4-(l-methyl-
3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine succinate as a white solid (191 mg, 15%). MS (ES+) m/z: 440 (M+H)+;
[a]2OD-5.2° (c 0.5, CH3OH).
Example 182
(i?)-(+)-7-Chloro-6-[4-(l-phenyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-
l//-benzo[]azepine Succinate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
txifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine
(250 mg, 0.59 mmol) with (/?)-4-aminomethyl-JV-(l-phenyl-ethyl)-benzamide (298 mg,
1.17 mmol) in toluene (15 mL). Purify by chromatography on silica gel eluting with
hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give (fl)-(+)-7-chloro-6-[4-(l-phenyl-
ethylcaminocarbonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)- 2,3,4,5-tetrahydro-l//-
benzo[rf]azepine as an oil.
Use a method similar to the General Procedure 1-3 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (1:0, 20:1. 10:1 and 7:1) to give
the free base of the title compound. Use a method similar to the General Procedure 2-1 to
give the title compound as a yellow solid (158 mg, 49%). MS (ES+) m/r. 434 (M+H)+;
[a]20D +18.7° (c 0.5, CH3OH).
Example 183
(5)-(-)-7-Chloro-6-[4-(l-phenyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-
l//-benzo[rf|azepine Succinate




Use a method similar to the Example 182, using 7-chloro-3-(2,2,2-trifluoroacetyl)-
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine (250 mg, 0.59
mmol) and (S)-4-aminomethyI-Ar-(l-phenyl-ethyl)-benzamide (298 mg, 1.17 mmol) to
give the title compound as a white solid (95 mg, 29%). MS (ES+) m/z: 434 (M+H)+;
[oc]20D -20.1° (c 0.5, CH3OH).

Example 184
7-Chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-17?-
benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-3, react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c?]azepine
(250 mg, 0.588 mmol) with 4-aminomethyl-iV-(2-thiophen-2-yl-ethyl)-benzamide (306
mg, 1.176 mmol) using palladium(II) acetate (26 mg, 0.118 mmol),
tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.059 mmol), BINAP (220 mg, 0.353
mmol) and cesium carbonate (383 mg, 1.176 mmol) in dioxane (6 mL). Purity by
chromatography on silica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to give 7-
chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine as an oil (233 mg, 91%). MS (ES+) m/z: 535
(M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-{4-[(2-
thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l/f-benzo[rf]azepine (223 mg, 0.416 mmol), to give 7-chloro-6-{4-[(2-
thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-lfl-benzo[cr|azepineas
an oil (145 mg, 79%) that was used without any further purification.
Use a method similar to the General Procedure 2-1, using 7-chloro-6-{4-[(2-
thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-l//-benzo[c/|azepine
(145 mg, 0.330 mmol), to give the title compound as a solid (123 mg, 67%). MS (ES+)
m/z: 440 (M+H)+.

Examples 185-194 may be prepared essentially as described in Example 184 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
l//-benzo[c/]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.





Example 195
7-Chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[J]azepine Hydrochloride




Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[rf]azepine

(200 mg, 0.471 mmol) and 4-aminomethyl-AT-(2-pyridin-2-yl-ethyl)-benzamide (241 mg,
0.942 mmol) using palladium(H) acetate (21 mg, 0.094 mmol),
tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.047 mmol), BINAP (176 mg, 0.283
mmol) and cesium carbonate (307 mg, 0.942 mmol) in dioxane (5 mL). Purify by
chromatography on silica gei eluting with hexane and hexane/EtOAc/DCM/methanol
(7:1:1:1) to give 7-chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylarnino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[cflazepine as an oil (107 mg, 43%). MS
(ES+) m/z: 531 (M+H)+.
Use a method similar to the General Procedure 1 -2, using 7-chIoro-6-[4-(2-
pyridin-2-yl-ethylcarbamoyl)-benzy!amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (107 mg, 0.202 mmol), to give 7-chloro-6-[4-(2-pyridin-2-yl-
ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[|azepine as an oil (85 mg,
97%) that was used without any farther purification.
Use a method similar to the General Procedure 2-2, using 7-chloro-6-[4-(2-
pyridin-2-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[(i]azepine(85
mg, 0.195 mmol), to give the title compound as a solid (103 mg, 97 %). MS (ES+) m/z:
435 (M+H)+.
Example 196

Using a method similar to the General Procedure 5-2, react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
7-Chloro-6-[4-(piperidine-1 -carbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-
benzo[]azepine Succinate

(500 mg, 1.17 mmol) with 4-(piperidin-l-ylcarbonyl)-benzyIamine (308 mg, 1.41 mmol).
Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and
5:1) to give 7-chloro-6-[4-(piperidine-l-carbonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[c/|azepine as an oil.
Use a method similar to the General Procedure 1-3 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (1:0, 20:1. 10:1 and 7:1) to give
the free base of the title compound. Use a method similar to the General Procedure 2-1 to
give the title compound as a yellow solid (284 mg, 47%). MS (ES+) m/z: 398 (M+H)+.
Example 197
7-Chloro-6-[2-(cyclohexylaminocarbonyl-pyridin-5-yImethyl)-amino]-2,3,4,5-tetrahydro-
l//-benzo[]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[]azepine
(348 mg, 0.82 mmol) with 5-aminomethyl-pyridine-2-carboxylic acid cyclohexylamide
(200 mg, 0.86 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc
(20:1, 10:1, 7:1 and 5:l)togive7-chloro-6-[2-(cyclohexylaminocarbonyl-pyridin-5-
ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)- 2,3,4,5-tetrahydro-l.//-benzo[c/]azepine as oil.
Use a method similar to the General Procedure 1-3 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (1:0, 20:1. 10:1 and 7:1) to give
the free base of the title compound.
Use a method similar to the General Procedure 2-1 to give the title compound as a
yellow solid (147 mg, 34%). MS (ES+) m/z: 413 (M+H)+.

Example 198
7-Chloro-6-[2-(4-fluoro-benzylaminocarbonyl)-pyridin-5-ylmethyI]-amino]-2,3,4,5-
tetrahydro-li/-benzo[£/]azepine Succinate

The title compound may be prepared essentially as described in Example 197,
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
li/-benzo[*/]azepine and 5-aminomethyl-pyridine-2-carboxylic acid 4-fluoro-benzylamide
(28% yield, MS (ES+) m/z 439).
Example 199
7-Chloro-6-(4-terf-butylthiocarbamoyl-benzyIamino)-2,3,4,5-tetrahydro-li¥-
benzo[|azepine Hydrochloride

Combine 6-(4-fert-butylcarbamoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l/f-benzo-
[rf]azepine (0,3 g, 0.67 mmol), 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-
2,4-disulfide (Lawesson's reagent) (0.3, g, 0.67 mmol) and anhydrous 1,4-dioxane (10
mL) in a sealed tube and heat at 100°C for 5 h. Cool the reaction mixture to ambient
temperature, evaporate the solvent and purify the residue by SCX

Example 200
(5)-(-)-7-Chloro-6-[l-(4-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-lF-
benzo[cf|azepine Succinate

F

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[]azepine
(7.0g, 16.4mmol) with (5)-l-(4-fluorophenyl)ethylamine (6.9 g, 49.3 mmol) in toluene
(175 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to
1:1) followed by SCX chromatography [pre-wash column with methanol followed by
DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol
(1:1) and concentrate in vacua] to give 7-chloro-6-[l-(iS)-(4-fluorophenyl)-ethylamino]-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lW-benzo[(flazepine (3.96 g, 58%). GC-MS
m/z: 414 (M*).
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-[l-(5)-
(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (3.92 g, 9.5 mmol) and purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (99:1 to 80:20) to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 and crystallize the solid
from ethanol and methyl-*-butyl ether. Filter and dry the solid in a vacuum oven at 60°C
overnight to obtain the title compound (3.4 g, 83 %). MS (ES+) m/z: 319 (M+H)+; [a]20D
-102.8° (c 0.5, MeOH).
Examples 201-209 may be prepared essentially as described in Example 200 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[cOazepine and the appropriate amine. The yields for the Step 1

(General Procedure 5-2), optical rotation and MS (ES+) data are shown in the Table
below.









Example 210
(+)-7-Chloro-6-[(2-trifluoromethoxy-phenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Oxalate




Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4>5-tetrahydro-l//-benzo[]azepine
(0.15 g, 0.35 mmol) with l-(2-trifluoromethoxyphenyl)-ethylamine Isomer 2 at 90°C for
15 h. Use a method similar to the General Procedure 1-2 and purify by reverse phase
preparative HPLC to give the free base of the title compound. Use a method similar to the
General Procedure 2-5 to give the title compound (27 mg, 16 %). HPLC tR = 4.2 min
(Chiralpak AD 4.6x150 mm, 3 micron column, 1.0 mL/min of 94.8/5/0.2
heptane/ethanol/dimethyethylamine isocratic; detector is at 225 nm); HRMS calcd for
C19H20CIF3N2O 385.1294, found 385.1285; [a]20D+95.4° (c 0.5, MeOH).
Example 211
(±)-7-Chloro-6-[l-(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l/jr-benzo[c/]azepine
Succinate




Add palladium(II) acetate (27 mg, 0.12 mmol), BINAP (146 mg, 0.24 mmol),
cesium carbonate (270 mg, 0.8 mmol) and (±)-l-(3-fluorophenyl)-ethylamine (230 mg,
1.6 mmol) to a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rfJazepine (250 mg, 0.6 mmol)
in toluene (9 mL). Degas the slurry and fill with nitrogen. Heat the mixture to 95°C for
16 h. Add additional palladium(II) acetate (0.1 equiv.) and BINAP (0.2 equiv.) and
continue heating the reaction for an additional 24 h. Cool the mixture, dilute with EtOAc
(50 mL) then filter through Celite®. Concentrate the filtrate and purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX
chromatography to obtain (±)-7-chloro-6-[l-(3-fluorophenyl)-ethylamino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine (138 mg, 56%). GC-MS m/z: 414
(M+).
Use a method similar to the General Procedure 1-3 to deprotect (±)-7-chloro-6-[l-
(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf|azepine (132 mg, 0.3 mmol) and purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (99:1 to 90:10) to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
(98 mg, 70 %). MS (ES+) m/z: 319 (M+H)+.
Example 212
(+)-7-Chloro-6-[l-(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[rflazepine
Succinate




Separate the two enantiomers of (±)-7-chloro-6-[l-(3-fluorophenyl)-ethylamino]-
2,3,4,5-tetrahydro-l//-benzo[c/]azepine succinate by normal phase chromatography
(Chiralpak AD 2x25 cm, elute with 95:5 heptane/isopropanol with 0.2 % DMEA).

Use a method similar to the General Procedure 2-1 to obtain the title compound
[23 mg, 30% recovery, 99% ee (Chiralpak AD, 4.6x250 mm, eluent: 95:5
heptane/isopropanol, with 0.2% DMEA, 1.0 mL/min)]. MS (ES+) m/z: 319 (M+H)+;
[a]2°D +64° (c 0.5, MeOH).
Example 213
(-)-7-Chloro-6-[ 1 -(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l //-benzo[rf]azepine
Succinate

NH HOOC(CH3)2COOH
Add tris(dibenzylideneaeetone)dipalladium(0) (3.4 g, 3.8 mmol), BINAP (4.7 g,
7.5 mmol), cesium carbonate (8.6 g, 26.3 mmol) and 1 -(3-fluorophenyl)-ethylamine
Isomer 2 (5.8 g, 41.3 mmol) to a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l./7-benzo[d]azepine (8.0 g, 18.8 mmol)
in toluene(225 mL). Degas the slurry and fill with nitrogen. Heat the mixture to 95 °C
for 8 h. Add additional tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv.), and
BINAP (0.2 equiv.). Continue heating the reaction for an additional 16 h. Cool the
mixture, dilute with EtOAc (200 mL) then filter thru Celite®. Concentrate in vacuo and
purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) followed by
SCX chromatography to obtain 7-chloro-6-[l-(3-fluorophenyl)-ethylamino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[tf|azepine (6.0 g, 78%). GC-MS m/z: 414
(M+).
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-[l-(3-
fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[d]azepine (6.0 g, 14.4 mmol). Purify by chromatography on silica gel eluting with
DCM/2M ammonia in methanol (99:1 to 90:10) to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 and crystallize the solid
from ethanol and methyl-f-butyl ether. Filter and dry the solid under vacuum at 60°C

overnight to obtain the title compound [5.3 g, 84 % yield, 99% ee (Chiralpak AD,
4.6x250 mm, eluent: 95:5 heptane/EtOH, with 0.2% DMEA, 1.0 mL/min)]. MS (ES+)
m/z: 319 (M+H)+; [a]20D-90.6° (c 0.5, MeOH).
Example 214
(±)-7-Chloro-6-[l-(2-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[t/)azepine
Succinate




Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydrc~l#-benzo[c/]azepine
(250 mg, 0.6 mmol) with (±)-l-(2-fluorophenyl)-ethylamine (206 mg, 1.5 mmol) in
toluene (5 mL). Purify the residue by chromatography on silica gel eluting with
hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with
methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M
ammonia in methanol (1:1) and concentrate in vacuo] to obtain (±)-7-chloro-6-[l-(2-
fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine (86 mg, 35%). GC-MS m/z: 414 (M+).
Use a method similar to the General Procedure 1-3 to deprotect (±)-7-chloro-6-[l-
(2-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine (85 mg, 0.2 mmol) and purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (99:1 to 90:10) to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
(70 mg, 80 %). MS (ES+) m/z: 319 (M+H)+.
Examples 215-216 may be prepared essentially as described in Example 214 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[^lazepine and the appropriate amine. The yields for the Step 1

(General Procedure 5-1), optical rotation and MS (ES+) data are shown in the Table
below.

Example 217
(S)-(-)-7-Chloro-6-(l-phenyI-ethylamino)-2,3,4,5-tetrahydro-l//-benzo[c/|azepine
Succinate

Add palladium(II) acetate (396 mg, 1.8 mmol), BINAP (2.2 g, 3.5 mmol), cesium
carbonate (8.0 g, 24.6 mmol), and l.S-(-)-methylbenzylamine (6.4 g, 52.9 mmol) to a
solution of 7-chloro-6-trifluoromethanesulfonyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-lH-benzo[c/]azepine (7.5 g, 17.6 mmol) in toluene(173 ml). Degas the slurry
and fill with nitrogen. Heat the mixture to 95°C for 16 h. GC/MS shows some starting
material still present after 16 h, so add additional palladium(II) acetate (0.1 equiv.),
BINAP, and lS-(-)-methylbenzylamine (1.0 equiv..). Continue heating the reaction for an
additional 24 h. Cool the mixture, dilute with EtOAc (250 ml) then filter through
Celite®. Concentrate in vacua and purify by chromatography on silica gel eluting with
hexane/EtOAc/methanol (84:15:1) followed by SCX chromatography to give (S)-7-

chloro-6-(l-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-
benzo[ Use a method similar to the General Procedure 1-1 to deprotect (S)-7-chloro-6-(l-
phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H-benzo[rf]azepine (4.3
g, 10.8 mmol). Purify by chromatography on silica gel eluting with DCM/2M ammonia in
methanol (99/1 to 80/20) to give the free base of the title compound. Use a method
similar to the General Procedure 2-1 and crystallize the solid from ethanol and methyl-/-
butyl ether. Filter and dry the solid in a vacuum oven at 70°C overnight to obtain the title
compound (3.6 g, 80%). MS (ES+) m/z: 301 (M+H)+. [a]\ -95.6° (c 0.5, MeOH).
Examples 218-227 may be prepared essentially as described in Example 217 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4>5-
tetrahydro-l//-benzo[]azepine and the appropriate amine. The yields for the Step 1,
optical rotation or enantiomeric excess (determined by chiral HPLC) and MS (ES+) data
are shown in the Table below.





Example 228
(-)-7-Chloro-6-[l-(3-chloro-4-fluoro-phenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-
benzo[£/]azepine Succinate
F

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[|azepine
(426 mg, 1.0 mmol) with l-(3-chloro-4-fluoro-phenyl)-ethylamine Isomer 1 (226 mg, 1.3
mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:7) to give
7-chloro-6-[l-(3-chloro-4-fluoro-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[cf)azepine as a yellow oil (293 mg, 65%).
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-(3-
chloro-4-fluoro-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/|azepine Isomer 1 (293 mg, 0.65 mmol). Purify by chromatography on silica gel
eluting with DCM/2M ammonia in methanol (94:6) to give the free base of the title
compound as an oil (157 mg, 68%). MS (ES+) m/z: 353 (M+H)+. Use a method similar to
preparation E-l to convert the free base to the title compound. [CX]20D -115.9° (c 0.5,
MeOH).
Examples 229-235 may be prepared essentially as described in Example 228 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[d]azepine and the appropriate amine. The yields for the Step 1
(General Procedure 5-3), optical rotation and MS (ES+) data are shown in the Table
below.


Example 236
(±)-7-Chloro-6-[l-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l/f-benzo[^azepine
Succinate


Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[|azepine
(852 mg, 2.0 mmol) and (±)-4-chloro-(a-methyl)benzylamine (622 mg, 4.0 mmol). Purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain (±)-7-
chloro-6-[l-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
ltf-benzo[]azepine (326 mg, 38%). MS (ES+) m/z: 431 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect (±)-7-chloro-6-[l-
(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzofrfjazepine. Purify by chromatography on silica gel eluting with DCM/2M
ammonia in methanol (95:5) to give the free base of the title compound (61 mg, 100%).
MS (ES+) m/z: 335 (M+H)+. Use a method similar to the General Procedure 2-1 to obtain
the title compound.
Examples 237 and 238
(-)-7-Chloro-6-[l-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-lfl-benzo[J]azepine
Succinate and (+)-7-Chloro-6-[ 1 -(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro- \H-
benzo[Jlazepine Succinate

Submit (±)-7-chloro-6-[l-(4-chlorophenyl)-ethylarnino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-li/-benzo[ (Chiralpak AD, 4.6x150 mm, eluting with heptane/ethanol (9:1) with 0.2% DMEA,
lmL/min) to provide the two enantiomers: 7-chloro-6-[l-(4-chlorophenyl)-ethylamino]-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[aT]azepine Isomer 1 (102 mg, tR =
5.25 min) and 7-chloro-6-[l-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[rf)azepine Isomer 2 (110 mg, tR = 6.40 min).

Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-(4-
chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[ ammonia in methanol (95:5) to give 7-chloro-6-[l-(4-chlorophenyl)-ethylamino]-2,3,4,5-
tetrahydro-l//-benzo[rfjazepine Isomer 1 (Example 237, 82 mg, 100%). MS (ES+) m/r.
335 (M+H)+. Use a method similar to the General Procedure 2-1 to obtain the title
compound. [ct]20D -127.7° (c 0.5, CH3OH).
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-(4-
chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l#-
benzofcQazepine Isomer 2. Purify by chromatography on silica gel eluting with DCM/2M
ammonia in methanol (95:5) to give 7-chloro-6-[l-(4-chlorophenyl)-ethylamino]-2,3,4,5-
tetrahydro-l//-benzo[ 335 (M+H)+. Use a method similar to the General Procedure 2-1 to obtain the title
compound. [a]"D +133.6° (c 0.5, CH3OH).
Examples 239 and 240
7-Chloro-6-[l-(2,5-difluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[*/]azepine
Succinate Isomer 1, and 7-chloro-6-[l-(2,5-difluorophenyl)-ethylamino]-2,3»4,5-
tetrahydro-l//-benzo[J)azepine Succinate Isomer 2

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[d]azepine
(550 mg, 1.27 mmol) and crude (±)-a-methyl-(2',5'-difluoro)benzylamine (400 mg).
Separate the two enantiomers by chiral chromatography (eluent: 75.20:5
heptane/isopropanol/methanol, 4.6x250 mm Chiralpak AD, 1 mL/min, uv 260 nm) to
obtain 7-chloro-6-[l-(2,5-difluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-

tetrahydro-l//-benzo[cOazepine Isomer 1 [150 mg, 29%; chiral HPLC: tR = 4.5 min; MS
(ES+) m/z: 433 (M+H)+] and 7-chloro-6-[l-(2,5-difluoropheny!)-ethylamino]-3-(2,2,2-
trifluoroacetyI)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Isomer 2 [130 mg, 25%; chiral
HPLC: tR = 5.5 min; MS (ES+) m/z: 433 (M+H)*], both as opaque oils which solidify
upon standing to off-white waxy solids.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-
(2,5-difluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Isomer 1 (140 mg, 0.32 mmol). Purify by SCX chromatography to give
7-chloro-6-[l-(2,5-difluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[rf)azepine
Isomer 1 (102 mg, 95%) as a yellow oil. Use a method similar to the General Procedure
2-1 to obtain the Isomer 1 of the title compound (130 mg, 95%) as an off-white solid. MS
(ES+) m/z: 337 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-
(2,5-difluorophenyl)-ethylamino]-3-(2>2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[]azepine Isomer 2 (125 mg, 0.29 mmol). Purify by SCX chromatography to give
7-chloro-6-[l-(2,5-difluorophenyI)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Isomer 2 (87.7 mg, 90%) as a yellow oil. Use a method similar to the General Procedure
2-1 to obtain the Isomer 2 of the title compound (117 mg, 99%) as an off-white solid. MS
(ES+) m/z: 337 (M+H)+.
Example 241
(-)-7-Chloro-6-[l-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[d]azepine
benzo[)azepine Succinate

(300 mg, 0.7 mmol) and crude a-methyl-(3',5'-difluoro-4'-methoxy)benzylamine (380
mg). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed
by chiral chromatography [heptane/isopropanol/dimethylethylamine (90:10:0.2), 4.6x250
mm Chiralpak AD, 1 mL/min, uv 250 nm] to give 7-chloro-6-[l-(3,5-difluoro-4-
methoxy-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[tf|azepine Isomer 1 [59 mg, 18% yield, 99% ee, chiral HPLC: tR = 6.0 min; MS
(ES-)/w/z: 461 (M-H)"] and 7-chloro-6-[l-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Isomer 2 [50 mg, 15%
yield, 99% ee, chiral HPLC: tR = 7.7 min; MS (ES-) m/z: 461 (M-H)"]. Use a method
similar to the General Procedure 1-1 to deprotect 7-chloro-6-[l-(3,5-difluoro-4-methoxy-
phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-benzo[rflazepine
Isomer 2 (50 mg, 0.14 mmol). Purify by SCX chromatography to give 7-chloro-6-[l-(3,5-
difluoro-4-methoxy-phenyl)-ethylamino]-2,3,4,5-tetrahydro-li/-benzo[rf]azepine Isomer
2 (35 mg, 70%) as a yellow oil. Use a method similar to the General Procedure 2-1, using
7-chloro-6-[l-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-2,3,4>5-tetrahydro-l//-
benzo[rf]azepine Isomer 2 (35 mg, 0.10 mmol), to give the title compound (44 mg, 97%)
as an off-white powder. MS (ES+) m/z: 367 (M+H)+; [a]20D -107.0° (c 0.5, CH3OH).
Example 242
(+)-7-Chloro-6-[(2-methylphenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[J]azepine
Oxalate

Usa a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[^/lazepine
(0.15 g, 0.35 mmol) with (#)-l-(2-methyl)-ethylamine (162 mg, 1.2 mmol) at 90°C for 17
h. Deprotect according to the General Procedure 1-2. Purify by reverse phase preparative
HPLC and form the oxalate salt according to the General Procedure 2-5 to give the title
compound (72 mg, 51 %). HPLC tR = 4.0 min (Chiralpak AD 4.6x150 mm, 3 micron

column, 1.0 mL/min of 89.8:10:0.2 heptane/isopropanol/DMEA, isocratic; detector is at
225 nm); HRMS calcd for C19H23CIN2 315.1628, found 315.1623. [ CH3OH).
Example 243
(+)-7-Chloro-6-(indan-l-ylamino)-2,3,4,5-tetrahydro-l//-benzo[]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cr]azepine
(200 mg, 0.5 mmol) with (7?)-l-aminoindan (188 mg, 1.4 mmol) in toluene (5 mL).
Purify by chromatography on silica gel eluting with hexane / EtOAc (9:1 to 1:1) followed
by SCX chromatography [pre-wash column with methanol followed by DCM, load
material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and
concentrate in vacuo] to give 7-chloro-6-(indan-l-ylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-ltf-benzo[rf]azepine (129 mg, 67%). GC-MS m/z: 408 (M+).
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(indan-
l-ylamino)-3-(2,2,2-trifluoroacetyl)-23,4,5-tetrahydro-l#-benzo[]azepine (125 mg, 0.3
mmol) and purify by chromatography on silica gel eluting with DCM/2M ammonia in
methanol (99:1 to 80:20) to give the free base of the title compound. Use a method
similar to the General Procedure 2-1 to give the title compound (104 mg, 78 %). MS
(ES+) m/z: 313 (M+H)+. [a]20D +73.9° (c 0.5, MeOH).

Example 244
(+)-7-Chloro-6-(5-fluoro-indan-l-ylamino)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine
(210 mg, 0.5 mmol) with 5-fluoro-indan-ylamine Isomer 1 (161 mg, 1.1 mmol) in toluene
(10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1)
followed by SCX chromatography to obtain 7-chloro-6-[l-(3,5-bis-trifluoromethyl-
pheny])-ethylamino]- 3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 H-benzo[rf]azepine
Isomer 1 (616 mg, 99%).
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-(5-
fluoro-indan-ylamine)-3-(2^2,2-trifluoroacetyl)-23,4,5-tetrahydro-lH-benzo[ Isomer 1 (200 mg, 0.5 mmol). Purify by chromatography on silica gel eluting with
DCM/2M ammonia in methanol (99/1 to 90/10) to give the free base of the title
compound. Use Preparation E-l to give the title compound (140 mg, 66 %). MS (ES+)
mJr. 331 (M+H)+. [cc]20D + 80.0° (C1 0.5, MeOH)
Example 245
(±)-7-Chloro-6-(2,3-dihydro-benzofuran-3-ylamino)-2,3,4,5-tetrahydro-l#-
benzo[rf]azepine Succinate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[J]azepine
(0.15 g, 0.35 mmol) with 2,3-dihydro-benzofuran-3-ylamine (prepared as described in
WO 0069816) (0.14 g, 1.1 mmol) at 90°C for 18 h.
Use a method similar to the General Procedure 1-2 and purify by reverse phase
preparative HPLC [Zorbax SB-Phenyl 4.6x150 mm, 5 micron column, 1 mL/min of 0.1%
TFA in water/ACN (9:1 to 1:9) over 30 min, detector at 230 and 254 nm].
Use a method similar to the General Procedure 2-1 to give the title compound (4.3
mg, 3%). HRMS calcd for C,gH,9ClN2O 315.1264, found 315.1256.
Example 246
7-Chloro-6-(indan-2-yl-amino)-2,3,4,5-tetrahydro-l//-benzo[]azepine Succinate

Use a method similar to the General Procedure 5-3, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[f/jazepine
(426 mg, 1.0 mmol) and 2-aminoindane (400 mg, 3.0 mmol), to give 7-chloro-6-(indan-2-
yl-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[c/lazepine as a slightly
yellow oil (354 mg, 86%). MS (ES+) m/r. 409 (M+H)+.
Using a method similar to the General Procedure 1-1, deprotect 7-chloro-6-(indan-
2-yl-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[flriazepine(354mg,
0.87 mmol) to obtain 7-chloro-6-(indan-2-yl-amino)-2,3,4,5-tetrahydro-l/f-
benzo[]azepine as a pale-yellow oil (166 mg, 61%). MS (ES+) m/z: 313 (M+H)+. Use a
method similar to the General Procedure 2-1 to give the title compound.

Example 247
(-)-7-Chloro-6-[(A^-methyl)-l-phenylethylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate

Dissolve (-)-7-chloro-6-( 1 -phenyl-ethylamine)-3-(2,2,2-trifiuoroacetyl)-2,3,4,5-
tetrahydro-l/f-benzo[rf]azepine (192 mg) in DCE (5 mL) and add acetic acid (0.33 mL,
5.8 mmol), formaldehyde (37% solution; 0.5 mL) and sodium triacetoxyborohydride (570
mg, 2.7 mol) and stir the reaction at ambient temperature for 16 h. Dilute the reaction
with DCM and wash with IN aqueous NaOH. Dry the organic layers over Na2SO4, filter
and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc
(20:1,10:1 and 5:l)togive(-)-7-chloro-6-(methyl-l-phenylethylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ Use a method similar to the General Procedure 1-3 to deprotect (-)-7-chloro-6-
(methyl-l-phenylethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//'-
benzofflfjazepine and purify by SCX chromatography to give the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
as a white solid (176 mg, 85%). MS (ES+) m/z: 315 (M+H)+. [a]20D -5.4° (c 0.5,
CH3OH).
Example 248
7-Chloro-6-[(A'-methyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[i/]azepine Succinate


Dissolve 6-benzylamino-7-chloro-2,3,4,5-tetrahydro-l//-benzo[d]azepine (330
mg, 0.86 mmol) in DCM (3 mL) and add triethylamine (250 ~L, 1.8 mmol) followed by
di-terr-butyl-dicarbonate (260 mg, 1.2 mmol). Stir at ambient temperature for 1 h. Pour
the mixture into water (250 mL), extract with DCM (3x25 mL) and concentrate in vacuo
to give, after chromatography on silica gel eluting with hexane/EtOAc (9:1), 6-
benzylamino-3-te«-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf|azepine as a
colorless oil (260 mg, 78%).
Dissolve 6-ben2ylamino-3-/ert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-li7-
benzo[]azepine (50 mg, 0.11 mmol) in acetonitrile (3 mL) and add a solution of
formaldehyde in water (37%, 85 uL, 0.97 mmol) followed by sodium cyanoborohydride
(16.5 mg, 0.26 mmol). Heat the solution to reflux 1 h, cool to ambient temperature, add
glacial acetic acid (0.25 mL) and stir 72 h. Pour the mixture into water (100 mL)
containing methanol (1 mL), extract with DCM (3x20 mL), wash the organic extracts
with brine, dry over MgSCu, filter and concentrate in vacuo. Dissolve the resulting
residue in DCM (5 mL), and add trifluoroacetic acid (2 mL). Stir for 2 h at ambient
temperature and evaporate the solvent. Purify by SCX chromatography. Use a method
similar to the General Procedure 2-1 to give the title compound (45 mg, 95%). MS (ES+)
m/z: 301 (M+H)+.
Example 249
7-Chloro-6-[(Ar-methyl)-3-fluorobenzylamino]-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Succinate
The title compound may be prepared essentially as described in Example 248 by
using 7-chloro-6-(3-fluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[aT]azepine (85%
yield and MS (ES+) m/z 319 (M+H)+).

Example 250
7-Chloro-6-(l-phenyl-cyclopropylamino)-2,3,4,5-tetrahydro-l//-benzo[£/]azepine
Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]a2epine
(0.2 g, 0.47 mmol) with 1-phenyl-cyclopropylamine (0.2 g, 1.41 mmol) using
tris(dibenzylideneacetone)dipalladium(0) (43.0 nig, 0.05 mmol), BINAP (0.1 g, 0.15
mmol) and cesium carbonate (0.3 g, 0.97 mmol) at 90°C for 17 h to obtain 7-chloro-6-(l-
phenyl-cyclopropylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine as a colorless oil.
Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-1 to
obtain the title compound as a white solid (85 mg, 33%).
Example 251 may be prepared essentially as described in Example 250 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-
benzo[ steps) is shown in the Table below.


Example 252
(±)-7-Chloro-6-(2,3-dihydro-benzofuran-3-yl-methylamino)-2,3,4,5-tetrahydro-l//-
benzo[]azepine Succinate



Use a method similar to the General Procedure 5-2 to couple 2,3-dihydro-
benzofuran-3-yl-methylamine (prepared as described in WO 0069816) (0.14 g, 1.1 mmol)
with 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
ltf-benzo[rf]azepine (0.15 g, 0.35 mmol) at 90°C for 18 h.
Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine.
Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 4.6x150 mm 5 micron
column, 1 mL/min of 1% TFA in water/ACN (9:1 to 1:9) over 30 min, detector at 230
and 254 nm]. Use a method similar to the General Procedure 2-1 to give the title
compound (4.3 mg, 3%).
Example 253
7-Chloro-6-[(2,3-dihydrobenzo[b]furan-5-yl)-methylamino]-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine Succinate




Suspend commercially available 2,3-dihydrobenzo[2>]furan-5-yl-methylamine
hydrochloride (1.0 g, 5.4 mmol) in DCM (100 mL). Add IN aqueous NaOH (15 mL) and
stir until all solids dissolve. Add two spatulas of NaCl. Stir the mixture and extract twice
with DCM. Combine the organic layers, dry over Na2SO4, and concentrate in vacuo to

obtain 2,3-dihydrobenzo[&]furan-5-yl-methylamine (650 mg, 81%). MS (ES+) m/z: 133
(M+H-NH3)+.
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-17/-benzo[rf]azepine
(426 mg, 1.0 mmol) with 5-aminomethyl-2,3-dihydrobenzo[&]furane (223 mg, 1.5 mmol).
Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain
7-chloro-6-[(2,3-dihydrobenzo[b]fiiran-5-yl)-methylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l/f-benzotJlazepine (244 mg, 58%). MS (ES+) m/z: 425 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[(2,3-
dihydrobenzo[b]furan-5-yl)-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine. Purify by chromatography on silica gel eluting with DCM/2M
ammonia in methanol (95:5) to give the free base of the title compound (105 mg, 32%).
MS (ES+) m/z: 329 (M+H)+. Use a method similar to the General Procedure 2-1 to obtain
the title compound.
Examples 254-260 may be prepared essentially as described in Example 253 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine and the appropriate amine. The yields for the Step 1
(General Procedure 5-3) and MS (ES+) data are shown in the Table below.








Example 261
7-Chloro-6-(naphthalen-2-yl-methylamino)-2,3,4,5-tetrahydro-l//-benzo[t/lazepine
Succinate

Use a method similar to the General Procedure 5-2 to couple 2-
aminomethylnaphthalene (prepared as described in WO 9509159) (0.17 g, 1.1 mmol)
with7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (0.15 g, 0.35 mmol) at 90°C for 18 h.

Use a method similar to the General Procedure ] -2 to give the free base of the title
compound. HRMS calcd for C2iH2iClN2 337.1471, found 337.1461. Use a method
similar to the General Procedure 2-1 to give the title compound (104 mg, 66 % overall).
Example 262
7-Chloro-6-[(quinolin-6-yl-methyI)-amino]-2,3,4,5-tetrahydro-l//-benzo[t/|azepine
Hydrochloride

Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-
trifluoroacetyl^-trifluoromethanesulfonyloxy^.S^.S-tetrahydro-l^f-benzof^azepine
(0.2 g, 0.35 mmol) and 6-aminomethyl-quinoline (0.2 g, 1.06 mmol) with
tris(dibenzylideneacetone)dipalladium(0) (32.0 mg, 0.04 mmol), BINAP (44.0 mg, 0.07
mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90°C for 17 h, to obtain 7-chloro-6-
[(quinolin-6-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzofrfjazepine as a colorless oil.
Use a method similar to the General Procedure l-l to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-2 to
form the hydrochloride salt and purify by reverse phase preparative HPLC [Zorbax SB-
Phenyl 21.2x250 mm, 5 micron column, 22 mL/min of 0.1% HC1 in water/acetonitrile
(9:1 to 1:1) over 30 min, detector at 230 nm) to obtain the title compound as a white solid
(50 mg, 56% overall). MS (ES+) m/z: 338 (M+H)+.
Examples 263-266 may be prepared essentially as described in Example 262 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-

tetrahydro-l//-benzo[cQazepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.

Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine
(0.2 g, 0.35 mmol) and 6-aminomethyl-benzofuran (0.2 g, 1.06 mmol) with
tris(dibenzylideneacetone)dipalladium (0) (32.0 mg, 0.04 mmol), BINAP (88.0 mg, 0.11
mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90°C for 17 h, to obtain 6-

[(benzofuran-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[tf]azepine as a colorless oil.
Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-1 to
obtain the title compound as a white solid (72 mg, 46% overall). MS (ES+) m/z: 327
(M+H)+.
Examples 268-271 may be prepared essentially as described in Example 267 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l.//-benzo[*/|azepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.


Example 272
6-[(Benzothiazol-6-yl-methyl)-amino]-7-chloro-2,3,4,5-tetrahydro-l//-benzo[d]azepine
Oxalate



Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[d] azepine (0.1 g, 0.35 mmol), 6-
bromomethyl-benzothiazole (80 mg, 0.35 mmol), and potassium carbonate (47.0 mg, 0.35
mmol) in anhydrous DMF (1 mL) in a sealed tube. Heat at 150°C for 3 h to obtain 6-
[(benzothiazol-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l#-benzo[rfjazepine as a colorless oil.
Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-5 to
obtain the title compound as a white solid (25 mg, 16% overall). MS (ES+) m/z: 344
(M+H)+.
Example 273
7-Chloro-6-[(quinolin-8-yl-methyl)-amino]-2,3,4,5-tetrahydro-l//-beiizo[ Hydrochloride

Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-ltf-benzo[rf] azepine (0.1 g, 0.35 mmol), 8-
bromomethyl-quinoline (83.6 mg, 0.038 mmol), cesium carbonate (0.2 g, 0.68 mmol) and
anhydrous acetonitrile (1 mL) in a sealed tube and heat at 50°C for 12 h to obtain 7-

chloro-6-[(quinolin-8-yl-methyl)-amino)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l#-benzo[c/]azepine as a colorless oil.
Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-2 to
form the hydrochloride salt and purify by reverse phase preparative HPLC [Zorbax SB-
Phenyl 21.2x250 mm, 5 micron column, 22 mL/min of 0.1% HC1 in water/acetonitrile
(9:1 to 1:1) over 30 min, detector at 230 nm) to obtain the title compound as a white solid
(13 mg, 8% overall). MS (ES+) m/z: 338 (M+H)+.
Example 274
7-Chloro-6-[(2-cyclohexyl-benzothiazol-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-lH-
benzo[rf)azepine Succinate

Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf] azepine (60 mg, 0.21 mrnol), 6-
bromomethyl-2-cyclohexyl-benzothiazole (0.1 g, 0.31 mmol), potassium carbonate (58
mg, 0.42 mmol) and anhydrous toluene (2 mL) in a sealed tube and heat at 100°C for 72 h
to obtain 7-chloro-6-[(2-cyclohexyl-benzothiazol-6-yl-methyl)-amino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-1 to
obtain the title compound as a white solid (40 mg, 35% overall). MS (ES+) m/z: All
(M+H)+.

Examples 275-277 may be prepared essentially as described in Example 274 by
using 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[d]azepine
and the appropriate bromide. Overall yields and MS (ES+) data are shown in the Table
below.

Example 278
7-Chloro-6-[( 1 -methyl-indol-4-y 1-methy l)-am ino]-2,3,4,5 -tetrahydro-1 H-bcnzo[ d] azepine
Succinate

Using a method similar to the General Procedure 5-1, couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetra-hydro-l//-benzo[rf]azepine
(0.1 g, 0.24 mmol) with 4-arninornethyl-l-methylindole (0.1 g, 0.71 mmol) to obtain 7-
chloro-6-[(l-methyl-indol-4-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine as a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the free base of the
title compound as a yellow oil. Use a method similar to the General Procedure 2-1 to
obtain the title compound as a white solid (0.1 g, 91% overall). MS (ES+) m/z: 340
(M+H)+.
Examples 279-280 may be prepared essentially as described in Example 278 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[cf]azepine with the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2(3,4,5-tetrahydro-l//-benzo[rfIazepine
(500 mg, 1.17 mmol) with pyridin-2-ylmethylamine (254 mg, 2 equiv.) using palladium
acetate (0.1 equiv.), B1NAP (0.3 equiv.) and cesium carbonate (1.4 equiv.) in toluene (5

mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc
(10:1, 5:1, 3:1, and 1:1) to give 7-chloro-6-( pyridin-2-ylmethylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as an oil.
Use a method similar to the General Procedure 1-3 to deprotect 7-chIoro-6-(
pyridin-2-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/7-
benzo[cGazepine. Purify by SCX chromatography followed by silica gel chromatography
eluting with DCM/2M ammonia in methanol (1:0,40:1, 20:1 and 10:1) to give the free
base of the title compound. Use a method similar to the General Procedure 2-2 to give
the title compound as an off white solid (207 mg, 55% overall). MS (ES+) m/z: 288
(M+H)+.
Example 282
7-Chloro-6-(pyridin-4-ylmethylamino)-2,3,4,5-tetrahydro-l//-benzo[t/]azepine
Hydrochloride
may be prepared essentially as described in Example 281 by using 7-chloro-3-(2,2,2-
trifluoroacetyl)-64rifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/7-benzo[c/]azepine
and pyridin-4-ylmethylamine (28% yield, and MS (ES+) 288 (M+H)+).
Example 283
(±)-7-Chloro-6-[(l-pyridin-4-yl-ethyl)-amino]-2,3,4,5-tetrahydro-l//-benzo[(/|azepine

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate

(400 mg, 0.94 mmol) and (±)-l-pyridin-4-yl-ethylamine (prepared as described in Bull.
Kor. Chem. Soc. 1998,19 (8), 891-893) (172 mg, 1.41 mmol). Purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give (±)-7-chloro-6-[(l-
pyridin-4-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/T-
benzo[c?]azepine.
Use a method similar to the General Procedure 1-1 to give the free base of the title
compound (73 mg, 26%). Use a method similar to the General Procedure 2-1, using (±)-
7-chloro-6-[(l-pyridin-4-yl-ethyl)-amino]-2,3,4,5-tetrahydro-l//-benzo[|azepine(73mg,
0.243 mmol), to give the title compound (31 mg, 31%). MS (ES+) m/z: 302 (M+H)+.
Examples 284-287 may be prepared essentially as described in Example 283 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[]azepine and the appropriate amine. The yields for the Step 1
(General Procedure 5-3) and MS (ES+) data are shown in the Table below.



Example 288
7-Chloro-6-[(5-fluoro-pyridin-2-ylrnethyl)-amino]-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine Succinate

Use a method similar to the General Procedure 5-1 to couple 2-aminomethyl-5-
fluoro-pyridine (230 mg, 1.8 mmol) and a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (500 mg, 1.2 mmol)
in toluene (4 tnL). Purify by chromatography on silica gel eluting with hexane/EtOAc
(9:1 to 1:1) followed by SCX chromatography to give 7-chloro-6-[(5-fluoro-pyridin-2-
ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[cGazepine(302
mg, 64%). GC-MS m/z: 402 (M+).
Dissolve 7-chloro-6-[(5-fluoro-pyridin-2-ylmethyl)-amino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine (297 mg, 0.74 mmol) in ethanol
(5 mL). Add 5N aqueous NaOH (10 equiv.) and stir for 1 h at ambient temperature.
Concentrate in vacua and purify by SCX chromatography followed by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (99:1 to 9:1) to obtain the free
base of the title compound. Use a method similar to the General Procedure 2-1 and
crystallize the solid from methanol and diethyl ether. Dry the solid in a vacuum oven at
60°C overnight to obtain the title compound (181 mg, 58%). MS (ES+) m/z: 306
(M+H)+.

Example 289
7-Chloro-6-{t5-(2>2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-6-
trifluoromethanesulfonyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (370 mg, 0.9 mmol) with 2-aminomethyl-5-(2,2,2-trifluoroethoxy)-
pyridine (180 mg, 0.9 mmol) in toluene (8 mL). Purify by chromatography on silica gel
eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-
wash column with methanol followed by DCM, load material dissolved in DCM, then
elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain 7-
chloro-6-{[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[rf]azepine.
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-{[5-
(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-lH-benzo[rf]azepine. Purify by chromatography on silica gel elutin with
DCM/2M ammonia in methanol (99/1 to 90/10) to obtain the free base of the title
compound. Use a method similar to the General Procedure 2-1 to give the title compound
(184 mg, 42 %). MS (ES+) m/z: 386 (M+H)+.
Examples 290-291 may be prepared essentially as described in Example 289 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[*/]azepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.


Examples 292 and 293
(-J-T-Chloro-e-ifS^Z^^-trifluoro-l-methyl-ethoxyJ-pyridin^-ylmethyn-amino}^^^^-
tetrahydro-l//-benzo[t/]azepine Succinate and (+)-7-Chloro-6-{[5-(2,2,2-trifluoro-l-
methyl-ethoxy)-pyridin-2-y lmethyl]-amino} -2,3,4,5 -tetrahydro-1 #-benzo[d]azepine
Succinate

Separate the two enantiomers of (±)-7-chloro-6-{[5-(2,2,2-trifluoro-l-methyl-
ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-l//-benzo[^azepine succinate by
normal phase chiral HPLC (Chiralcel OD 8x35 cm, elute with 4:1 heptane/3A-ethanol
with 0.2 % DMEA). Purify each enantiomer by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (20:1). Use a method similar to the General
Procedure 2-1 to obtain the title compounds: (-)-7-Chloro-6-{[5-(2,2,2-trifluoro-l-methyl-
ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine succinate

(Example 292, 75 mg, 38%), 95% ee [Chiralpak AD, 4.6x150 mm, eluent: 85/15
heptane/3 A ethanol with 0.2% DMEA, 0.6 mL/min)]; MS (ES+) m/z: 400 (M+H)+. [a]20D
-12.1° (c 0.5, MeOH). (+)-7-Chloro-6-{[5-(2,2,2-trifluoro-l-methyl-ethoxy)-pyridin-2-
ylmethyl]-amino}-2,3,4,5-tetrahydro-l//-benzo[rf]azepine succinate (Example 293, 72
mg, 37%), 93% ee [Chiralpak AD, 4.6x150 mm, eluent: 85/15 heptane/3A ethanol with
0.2% DMEA, 0.6 mL/min)]. MS (ES+) m/z: 400 (M+H)+. [a]20D +7.4° (c 0.5, MeOH).
Example 294
(±)-7-Chloro-6-[(l-thiophen-2-yl-ethyI)-amino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(200 mg, 0.47 mmol) with (±)-l-thiophen-2-yl-ethylamine (prepared as described in J.
Amer. Chem. Soc. 1942, 64,477-479) (200 mg, 1.57 mmol). Purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to give (±)-7-chloro-6-[(l-
thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[tf]azepine (126 mg, 67%).
Use a method similar to the General Procedure 1-1, using (±)-7-chloro-6-[(l-
thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-
benzo[rf]azepine (126 mg, 0.313 mmol), to give the free base of the title compound (73
mg, 77%). Use a method similar to the General Procedure 2-1, using (±)-7-chloro-6-[(l-
thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-l//-benzo[i/]azepine (73 mg, 0.241 mmol)
to give the title compound (100 mg, 50% overall). MS (ES+) m/z: 307 (M+H)+.

Example 295
(+)-7-Chloro-6-[( 1 -thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-l tf-benzo[d]azepine
Succinate, Isomer 1

Separate the two enantiomers of (±)-7-chloro-6-[(l-thiophen-2-yl-ethyl)-amino]-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine by chiral preparative
HPLC (Chiralpak AD, 8x30 cm; eluent: 9:1 heptane/isopropanol with 0.2% DMEA; flow:
350 mL/min at 240 nm (UV), -650 mg load] to obtain 7-chIoro-6-[(l-thiophen-2-yl-
ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/y-benzo[(/]azepine Isomer 1,
ee=100% [Analytical Column: Chiralpak AD, 4.6x250mm; eluent: 9:1
heptane/isopropanol with 0.2% DMEA; flow: 1 mL/min at 250nm (UV).
Use a method similar to the General Procedure 1-1, using 7-chloro-6-[(l-
thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[|azepine Isomer 1, to give 7-chloro-6-[(l-thiophen-2-yl-ethyl)-amino]-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine Isomer 1. Use a method similar to the General Procedure
2-1, using 7-chloro-6-[(l-thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine Isomer 1 (73 mg, 0.241 mmol) to give the title compound (100 mg,
98%). MS (ES+) m/z: 307 (M+H)+. [cc]20D +115.0° (c 0.5, MeOH).
Example 296
(±)-7-Chloro-6-[l-(5-methylthiophen-2-yl)ethylamino]-2,3>4>5-tetrahydro-l//-
benzo[i/|azepine Succinate


Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine
(96 mg, 0.227 mmol) with (±)-2-(l-aminoethyl)-5-methylthiophene (48 mg, 0.34 mmol)
using palladium(II) acetate (10 mg, 0.0454 mmol), BINAP (60 mg, 0.0908 mmol) and
cesium carbonate (148 mg, 0.454 mmol) in toluene (10 mL). Purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0, 19:1) to give (±)-7-chloro-6-[l-(5-
methylthiophen-2-yl)ethylamino]-3-(2>2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[d]azepine as an oil (47 mg, 50%). GC-MS m/z 416 (M"").
Use a method similar to the General Procedure 1-2, using (±)-7-chloro-6-[l-(5-
methylthiophen-2-yl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (47 mg, 0.113 mmol) to give (±)-7-chloro-6-[l-(5-methylthiophen-2-
yl)ethylamino]-2,3,4,5-tetrahydro-l//-benzo[c/]azepine as an oil (30 mg, 83%) that was
used without further purification. Use a method similar to the General Procedure 2-1 to
give the title compound as a white solid (36 mg, 88%). MS (ES+) m/z: 321 (M+H)+.
Example 297
(+)-7-Chloro-6-tl-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-l//-
benzo[c(]azepine Succinate

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine
(0.328 g, 0.773 mmol) with l-(5-phenyl-thiophen-2-yI)ethylamine Isomer 1 (0.236 g,
1.16 mmol) using palladium(II) acetate (69 mg, 0.309 mmol), tris(dibenzylideneacetone)-
dipalladium(O) (142 mg, 0.155 mmol), BINAP (578 mg, 0.928 mmol) and cesium
carbonate (504 mg, 1.546 mmol) in toluene (10 mL). Purify by chromatography on silica
gel eluting with hexane/EtOAc (1:0 and 19:1) to give 7-chloro-6-[l-(5-phenyl-thiophen-

2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-Iiy-benzo[rf]azepineIsomer
l(89mg,34%).
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[l-(5-
phenyl-thiophen-2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[t/)azepine Isomer 1 (89 mg, 0.186 mmol) to give 7-chloro-6-[l-(5-phenyl-
thiophen-2-yl)-emylamino]-2,3,4,5-tetrahydro-l.H-benzo[]azepine Isomer 1 (65 mg,
92%) as an oil that was used without further purification. Use a method similar to the
General Procedure 2-1, using 7-chloro-6-[l-(5-phenyl-thiophen-2-yl)-ethylamino]-
2,3,4,5-tetrahydro-I//-benzo[rf]azepine Isomer 1 (65 mg, 0.17 mmol), to give the title
compound as a white solid (58 mg, 68%). MS (ES+) m/z: 383 (M+H)+; [a]20D +159.0° (c
0.5, MeOH).
Example 298
(-)-7-Chloro-6-[l-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-lW-
benzo[t/]azepine Succinate

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[rf|azepine
(0.484 g, 1.138 mmol) with l-(5-phenyI-thiophen-2-yl)ethylamine Isomer 2 (0.347 g,
1.71 mmol) using palladium(II) acetate (102 mg, 0.45 mmol), tris(dibenzylideneacetone)-
dipalladium(O) (209 mg, 0.228 mmol), BINAP (851 mg, 1.366 mmol) and cesium
carbonate (741 mg, 2.276 mmol) in toluene (12 mL). Purify by chromatography on silica
gel eluting with hexane:EtOAc (1:0 and 19:1) to give 7-chloro-6-[l-(5-phenyl-thiophen-
2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 //-benzo[cf)azepine Isomer
2 (247 mg, 63 %).

Use a method similar to the General Procedure 1-2, using 7-chloro-6-[ 1-(5-
phenyl-thiophen-2-yI)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lW-
benzo[c/]azepine Isomer 2 (247 mg, 0.516 mmol) to give 7-chloro-6-[l-(5-phenyl-
thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-ltf-benzo[ 93%) as an oil that was used without further purification. Use a method similar to the
General Procedure 2-1, using 7-chloro-6-[l-(5-phenyl-thiophen-2-yl)-ethylamino]-
2,3,4,5-tetrahydro-l#-benzo[c/]azepine Isomer 2 (184 mg, 0.48 mmol) to give the title
compound as a white solid (200 mg, 83%). MS (ES+) m/z: 383 (M+H)+; [a]20D -196.5° (c
0.5, MeOH).
Example 299
(±)-7-Chloro-6-[(l-thiophen-3-yl-ethyl)-amino]-2,3,4,5-tetrahydro-lJ7-benzo[i/]azepine
Succinate
s-

Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[d]azepine
(200 mg, 0.47 mmol) with (±)-l-thiophen-3-yl-ethylamine (prepared as described in J.
Heterocycl. Chem. 1988, 25, 1571-1581) (90 mg, 0.70 mmol). Purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0,9:1 and 4:1) to give (±)-7-chloro-6-(l-
thiophen-3-yl-ethylamino)-3-(2,2,2-trifluoroacetyI)-2,3,4,5-tetrahydro-l/^
benzo[]azepine (100 mg, 53%).
Use a method similar to the General Procedure 1-1, using (±)-7-chloro-6-(l-
thiophen-3-yl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lfl-
benzo[]azepine (100 mg, 0.248 mmol), to give the free base of the title compound (74
mg, 98%). Use a method similar to the General Procedure 2-1, using (±)-7-chloro-6-(l-
thiophen-3-yl-ethylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (74 mg, 0.242 mmol)
to give the title compound (108 mg, 54% overall). MS (ES+) m/z: 307 (M+H)+.

Example 300
7-Chloro-6-[(5-methylfuran-2-ylmethyl)-amino]-2,3,4,5-tetrahydro-li/-benzo[c/]azepine
Hydrochloride

Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-
2,3,4,5-tetrahydro-l//-benzo[cf)azepine (100 mg, 0.24 mmol), 2-(di-ter/-butylphosphino)-
biphenyl (6.8 mg, 0.023 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012
mmol) and potassium phosphate (70 mg, 0.33 mmol) in a pressure tube and degas.
Dissolve the mixture in dry toluene (2 mL) and degas. Add a solution of 5-
methylfurfurylamine (30 mg, 0.27 mmol) in toluene (1 mL) and degas. Stir at 90°C for
24 h. Cool to ambient temperature, dilute with ethyl ether and filter through Celite®.
Concentrate and purify by chromatography on silica gel eluting with hexane/EtOAc
(20:1). Remove the solvent and add 7M ammonia in methanol (4 mL). Stir at ambient
temperature for 24 h. Concentrate and purify by SCX chromatography to give the free
base of the title compound. Use a method similar to the General Procedure 2-2 to obtain
the title compound as a solid (56 mg, 66%). MS (ES+) m/z: 291 (M+H)+.
Examples 301-302 may be prepared essentially as described in Example 300 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[]azepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.



Example 303
7-Chloro-6-(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-lH-benzo[rf]azepine
Hydrochloride

Thiazole-5-carbaldehvde: Add DMSO slowly to a solution of oxalyl chloride (1.6 g, 13
mmol) in anhydrous DCM (30 mL) under nitrogen at -78 °C and stir for 10 min. Add
dropwise a solution of 5-hydroxymethylthiazole (1.15 g, 10 mmol) in DCM (10 mL) and
stir the mixture for 40 min. Add triethylamine and stir for 5 min and then quench the
reaction with water. Extract the mixture three times with ether, combine the organic
extracts, wash with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with EtOAc/hexane (2:5) to give thiazole-5-
carbaldehyde (337 mg, 29%).
3-ftert-ButoxvcarbonYl)-7-chloro-6-(thiazol-S-vlmethYleneamino>23,4,5-tetrahvdro-
1 j/-benzo|tflazepine: Dissolve 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3;4,5-
tetrahydro-l//-benzo[rf)azepine (285 mg, 0.97 mmol) in methanol (10 mL). Add 7N
ammonia in methanol (10 mL) and stir overnight at ambient temperature. Concentrate in
vacuo and dissolve the residue in THF (10 mL). Add saturated aqueous NaHCCh (5 mL)

and di-fert-butyl-dicarbonate (254 mg, 1.16 mmol). Stir the reaction mixture at ambient
temperature for 4 h. Dilute the mixture with water, extract three times with EtOAc,
combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo to give
crude material. Mix thiazole-5-carbaldehyde (165 mg, 1.45 mmol) with above crude
residue (0.97 mmol, assuming 100% conversion), acetic acid (87 mg, 1.45 mmol) and
1,2-dichloroethane (10 mL). Stir at ambient temperature for 20 min. Add sodium
triacetoxyborohydride and stir under nitrogen overnight. Quench the reaction with
saturated aqueous NaHCO3, separate the organic layer and extract the aqueous layer three
times with DCM. Combine the organic extracts, dry over Na2SC>4, filter and concentrate
in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3) to
afford the desired intermediate as a yellow oil (228 mg, 60% three steps). MS (ES+) m/z:
392 (M+H)3-(/-Butoxvcarbonvl)-7-chloro-6-(thiazol-5-vlmethvl-aminoV23,4,S-tetrahydro-l/r-
benzo\d\azepine: Dissolve 3-(/-butoxycarbonyl)-7-chloro-6-(thiazol-5-
ylmethyleneamino)-2,3,4,5-tetrahydro-l//-benzo[c/Jazepine (228 mg, 0.58 mmol) in
methanol (10 mL), add sodium borohydride (263 mg, 7 mmol) and reflux for 28 h. Cool
to ambient temperature, dilute with EtOAc and add slowly water. Separate the organic
layer, extract the aqueous layer three times with EtOAc. Combine the organic extracts,
dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with EtOAc/hexane (1:3) to give the desired intermediate as a colorless oil (134
mg, 58%). MS (ES+) m/z: 394 (M+H)+.
7-Chloro-6-('thiazoI-5-vlmethYl-amimo)-23,4,5-tetrahvdro-l/ir-benzo[rfl azepine
Hvdroehloride; Use a method similar to the General Procedure 1-6 to deprotect 3-(ferf-
butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine (134 mg, 0.34 mmol). Purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (94:6) to give 7-chloro-6-(thiazol-5-ylmethyl-
amino)-2,3,4,5-tetrahydro-l//-benzo[rf|azepine as an oil (90 mg, 90%). MS (ES+) m/z:
294 (M+H)+. Use a method similar to the General Procedure 2-2 to obtain the title
compound.

Example 304
7-Chloro-6-[(3-pyridyl)amino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoroinethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[(/]azepine
(300 mg, 0.7 mmol) with 3-aminopyridine (75 mg, 0.85 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 7-chloro-6-[(3-
pyridyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ white solid (20 mg, 8%). MS (ES+) m/r. 370 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[(3-
pyridyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-benzo[]azepine (20 mg,
0.05 mmol). Purify by SCX chromatography to give 7-chloro-6-[(3-pyridyl)amino]-
2,3,4,5-tetrahydro-lJ7-benzo[rf]azepine as a yellow oil (15 mg, 99%). Use a method
similar to the General Procedure 2-1, using 7-chloro-6-[(3-pyridyl)amino]-2,3,4,5-
tetrahydro-l/f-benzo[]azepine (15.1 mg, 0.05 mmol), to give the title compound as a
light yellow solid (20 mg, 97%). MS (ES+) m/z: 319 (M+H)+.
Example 305
7,9-Dichloro-6-(3,4-difluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

Dissolve 7-dichloro-6-(3,4-difluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[y/]azepine (150 mg, 0.36 mmol) in anhydrous toluene (20 mL). Add
N-chlorosuccinimide (140 mg, 1 mmol) and heat at 60°C for 4 h. Cool to room

temperature, pour reaction mixture into water (250 mL) and extract with EtOAc (3x50
mL). Wash combined organic extracts with water, brine, dry over Na2SO4, filter, and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
(4:1) to give 7,9-dichloro-6-(3,4-difluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l#-benzo[J]azepine (110 mg, 67%). MS (ES+) m/z: 453 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7,9-dichloro-6-
(3,4-difluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (120 mg, 0.26 mmol). Purify by SCX chromatography to give 7,9-
dichloro-6-(3,4-difluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a yellow
oil (81 mg, 88%). Use a method similar to the General Procedure 2-2, using 7,9-dichloro-
6-(3,4-difluorobenzylamino)-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine (75 mg, 0.21 mmol),
to give the title compound as a yellow gum (80 mg, 96%). MS (ES+) m/z: 357 (M+H)+.
Example 306
7-Chloro-9-fluoro-6-(3-fluorobenzylammo)-2,3,4,5-tetrahydro-l//-benzo[]azepine
Succinate

Use a method similar to the General Procedure 5-1 to couple 7-chloro-9-fluoro-3-
(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-
benzo[cf|azepine (130 mg, 0.3 mmol) with 3-fluorobenzylamine (100 DL, 0.89 mmol).
Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) followed
by SCX chromatography to give 7-chloro-9-fluoro-6-(3-fluorobenzylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a yellow oil (35 mg, 28%). MS
(ES+)m/z:401 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-9-fluoro-
6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(32 mg, 0.08 mmol). Purify by SCX chromatography to give 7-chloro-9-fluoro-6-(3-

fluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a yellow oil (10 mg, 45%).
Use a method similar to the General Procedure 2-1, using 7-chloro-9-fluoro-6-(3-
fluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (10 mg, 0.033 mmol), to give
the title compound as a light yellow solid (14 mg, 97%). MS (ES+) m/r. 323 (M+H)+.
Example 307
7-Fluoro-6-(4-fluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[]azepine Succinate

Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
(250 mg, 0.61 mmol) with 4-fluorobenzylamine (92 mg, 1.2 equiv.) using palladium(II)
acetate (0.1 equiv.), BINAP (0.3 equiv.) and cesium carbonate (1.4 equiv.) in toluene (5
mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1, 3:1
and 1:1) to give 7-fluoro-6-(4-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine as an oil.
Use a method similar to the General Procedure 1 -3 to deprotect 7-fluoro-6-(4-
fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-W-benzo[rf]azepine.
Purify by SCX chromatography to give the free base of the title compound. Use a
method similar to the General Procedure 2-1 to give the title compound as an off white
solid (14 mg, 6%). MS (ES+) m/z: 289 (M+H)+.
Example 308
6-Benzylamino-7-cyano-2,3,4,5-tetrahydro-l/f-benzo[t/]azepine Succinate


Use a method similar to the General Procedure 5-1 to couple 7-cyano-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[J]azepine
(125 mg, 0.3 mmol) with benzylamine (0.1 mL, 0.9 mmol) using palladium(II) acetate (7
mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) and cesium carbonate (137 mg, 0.4 mmol)
in toluene (3 mL). Purify by chromatography on silica gel eluting with heptane/EtOAc
(4:1 to 1:1) to give 6-benzylamino-7-cyano-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l#-benzo[rf]azepine as a clear oil (60 mg, 54%). MS (ES+) m/z: 374 (M+H)+.
Use a method similar to the General Procedure 1-2, using 6-benzylamino-7-
cyano-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[c(]azepine (56 mg, 0.15
mmol), to give 6-benzylamino-7-cyano-2,3,4,5-tetrahydro-l//-benzo[cT]azepine as a clear
oil (38 mg, 93%). MS (ES+) m/z: 278 (M+H)+. Use a method similar to the General
Procedure 2-1 to give the title compound as a white powder (39 mg, 71%). MS (ES+)
m/z: 278 (M+H)+.
Examples 309-310 may be prepared essentially as described in Example 308 by
using 7-cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-
li/-benzo[]azepine and the appropriate amine. Overall yields and MS (ES+) data are
shown in the Table below.


Example 311
6-(3-Fluorobenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydro-lf/-benzo[f/]azepine
Succinate

Use a method similar to the General Procedure 5-1 to couple 3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-l//-
benzo[ Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by
SCX chromatography to give 6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-7-
trifluoromethyl-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a yellow oil (55 mg, 53%). MS
(ES+) m/z: 435 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 6-(3-
fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (55 mg, 0.13 mmol). Purify by SCX chromatography to give 6-(3-
fluorobenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydro-l//-benzo[c/]azepine as a yellow
oil (34 mg, 81%). Use a method similar to the General Procedure 2-1 to give the title
compound as an off-white solid (33 mg, 72%). MS (ES+) m/z: 339 (M+H)+.
Example 312
(5)-(-)-6-[l-(4-Fluorophenyl)-ethylamino]-7-trifluoromethyl-2,3,4,5-tetrahydro-l//'-
benzo[Gflazepine Succinate


Use a method similar to the General Procedure 5-3 to couple 3-(2,2,2-
trifIuoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-l//-
benzo[cT|azepine (430 mg, 0.94 mmol) with (^)-l-(4-fluorophenyl)ethylamine (195 mg,
1.40 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to
give(5)-6-[l-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-
2,3,4,5-tetrahydro-l//-benzo[]azepine (279 mg, 66%). MS (ES+) m/z: 449 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect (5)-6-[l-(4-
fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (279 mg, 0.62 mmol). Purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (94:6) to obtain (S)-6-[l-(4-fluorophenyl)-
ethylamino]-7-trifluoromethyl-2,3,4,5-tetrahydro-l//-benzo[t/]azepine as a colorless oil
(190 mg, 87%). MS (ES+) m/z: 353 (M+H)+. Use a method similar to the General
Procedure 2-1 to give the title compound. [a]20D -96.7° (c 0.5, MeOH).
Example 313
(5)-7-Ethyl-6-[l-(4-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate

Use a method similar to the General Procedure 5-3 to couple 7-ethyl-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(335 mg, 0.8 mmol) and (5)-l-(4-fluorophenol)ethyl amine (557 mg, 4.0 mmol). Purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0,9:1 and 17:3) to give
(S)-7-ethyl-6-[l-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (127 mg, 39%). MS (ES+) m/z: 409 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect (S)-7-ethyl-6-[l-
(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacefyl)-2,3,4,5-tetrahydro-17/-

benzo[cf|azepine. Purify by chromatography on silica gel eluting with DCM/2M ammonia
in methanol (93:7) to give (5)-7-ethyl-6-[l-(4-fluorophenyl)-ethylamino]-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (70 mg, 72%). MS (ES+) m/z: 313 (M+H)+. Use a
method similar to the General Procedure 2-1 to obtain the title compound.
Example 314
7-Propyl-6-[(2-thienyl)methylamino]-2,3,4,5-tetrahydro-l//-benzo[rf|azepine
Hydrochloride

Use a method similar to the General Procedure 5-1 to couple 7-propyl-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
and 2-(aminomethyl)-thiophene. Purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1 and 4:1) to give 7-propyI-6-[(2-thienyl)methylamino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a yellow solid. MS (ES+) m/z:
397 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-propyl-6-[(2-
thienyl)methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l^r-benzo[c/]azepine.
Purify by SCX chromatography to give the free base of the title compound as a yellow
oil. Use a method similar to the General Procedure 2-2 to give the title compound as a
light yellow solid. MS (ES+) m/z: 301 (M+H)+.
General Procedure 7
Dissolve the appropriate substituted 3-ter/-butoxycarbonyl-6-dimethylcarbamoyl-
thio-2,3,4,5-tetrahydro-l//-benzo[c/]azepine (1.0 equiv) in methanol (0.1-0.2 M solution).
Add potassium hydroxide (32 equiv.) and heat the mixture at 50°C for 2-8 h. Cool the
reaction to ambient temperature and add the appropriate halide (1.0-5.0 equiv.). Stir the
mixture at ambient temperature for 0.5-16 h. Remove the solvent in vacuo and partition
the residue between DCM and water. Extract the aqueous phase with DCM, combine the

organic extracts, dry over Na2SO4, filter and concentrate. Purify by chromatography in
silica gel eluting with hexane/EtOAc mixtures to obtain the desired compound.
Preparation 172
3-te^Butoxycarbonyl-7-chloro-6^imethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[]azepine

7-ChIoro-6-dimethvlthiocarbamovloxv-3-f2t2J-trifluoroaceryl>-2v3,4,S-tetrahYdro-
1/y-benzoftflazepine: Place 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[)azepine (64.3 g, 219 mmol) in acetone (450 mL) and water (200
mL) with K2CO3 (91.8 g, 664 mmol) and dimethylthiocarbamoyl chloride (31.5 g, 255
mmol). Stir at ambient temperature for 1.25 h. Add additional dimethylthiocarbamoyl
chloride (3 g, 24 mmol) and stir for an additional 1.75 h at ambient temperature. Add
more dimethylthiocarbamoyl chloride (0.7 g, 5.7 mmol) and water (150 mL) to the
mixture and stir for 0.5 h at ambient temperature. Slowly add water (500 mL) to the
reaction over 2 h to promote crystallization and stir the resulting slurry at ambient
temperature for 1.5 h. Collect the solid by filtration to give the desired intermediate (76
g,91%).
3-/g/t-Butoxvcarbonvl-7-chloro-6-dimethYlcarbamoYlthio-23.4.5-tetrahvdro-l/?-
benzofrflazepine: Dissolve 7-chloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-
trifiuoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[fiflazepine (155 g, 407 mmol) in diphenyl
ether (1500 mL) and heat to 250°C for 2.5 h. Cool the reaction and dilute with methanol
(308 mL). Add IN aqueous NaOH (616 mL) and stir at 60°C for 4 h. Cool the reaction
to ambient temperature and extract between DCM (3 x 500 mL) and water (500 mL).
Combine the organic extracts and add to IN aqueous HC1 (1 L). Stir the reaction at
ambient temperature for 0.25 h then wash with hexane (5 x 400 mL). Adjust the pH of
the aqueous layer to 7.0 with 5N aqueous NaOH and mix the aqueous solution with DCM
(2.5 L). Cool the mixture in an ice bath and add K2CO3 (169 g, 1221 mmol) and di-f-

butyl dicarbonate (67.5 g, 390 mmol) and stir the reaction at ambient temperature for 0.5
h. Add di-r-butyl dicarbonate (16.35 g, 75 mmol) and stir for 0.3 h at ambient
temperature. Add di-/-butyl dicarbonate (0.1 g, 0.46 mmol) and stir for 0.25 h at ambient
temperature. Concentrate the mixture in vacuo to remove the volatiles and warm to 45°C.
Seed the mixture with a small amount of the title compound and stir for 1 h at 45°C. Cool
the reaction in an ice bath and stir for an additional 2 h. Collect the resultant solid by
filtration and rinse with cold hexane (100 mL). Concentrate the filtrate in vacuo,
recrystallize from DCM/heptane, and isolate the solids by filtration. Combine the solids
and dry in vacuo to give the title compound as a white crystalline solid (142 g, 91%). MS
(ES+) m/z 385 (M+H)+.
Preparation 173
3-/er/-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[]azepine and 3-/er?-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-l/f-benzo[J]azepine

7-Chloro-6-hvdroxv-3-(2J^2-trifluoroacetvl)-23.4,5-tetrahvdro-l^f-benzo[rflazepine
and 7,9-dichIoro-6-hydroxv-3-(2^.3-trifluoroaceryO-2,3,4,5-tetrahvdro-l//-
benzoUflazepine:
To a solution of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (0.961 g, 3.71 mmol) in toluene (30 mL) at 70 °C, add diisobutylamine
(52 |u.L, 0.30 mmol) followed by slow addition of neat sulfuryl chloride (343 |iL,

4.27 mmol). Stir for 1 h at 70 °C and concentrate in vacuo. Dilute the residue with water,
extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo to
afford a 4:1 mixture of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3>4,5-tetrahydro-
l//-benzo[rf]azepineand7,9-dichloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[]azepine as a white solid (1.07 g, 98%).
7-Chloro-6-dimethvlthiocarbamovloxv-3-(2v22-trifluoroacetvlV23A5-tetrahvdro-
l//-benzoMazepineand7,9-dichIoro-6-dimethylthiocarbamoyloxv-3-(2.2.2-
trifluoroacetvlV23,4,5-tetrahvdro-l/f-bcnzo[1azepine: To a mixture of 4:1 7-chloro-
6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[cQazepine and 7,9-
dichloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(0.513 g, 1.75 mmol) in anhydrous dioxane (10 mL) under nitrogen, add dimethyl
thiocarbamoyl chloride (0.432 g, 3.50 mmol), 4-dimethyIaminopyridine (21 mg, 0.18
mmol) and triethylamine (731 uL, 5.24 mmol) and heat under reflux overnight. Cool the
reaction mixture to ambient temperature and dilute with water, extract three times with
EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (17:1) to afford a mixture of 4:1 7-chloro-6-
dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[c/|azepine and 7,9-dichloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-li/-benzo[f/]azepine as a yellow oil (0.64 g, 95%)
7-Chloro-6-dimethylcarbamoylthio-3-(2^2-trifluoroacetyl)-23,4.5-tetrahYdro-l/r-
benzof1azepineand7,9-dichloro-6-dimethvlcarbamovlthio-3-(2JJ-trifluoroacetyO-
2,3,4,5-tetrahvdro-l//-benzo[ dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-
benzo[c/lazepineand7,9-dichloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-17/-benzo[£/]azepine (0.630 g, 1.66 mmol) in diphenyl ether (4.5 mL)
at 250 °C for 4 h under nitrogen. Cool to ambient temperature. Purify by
chromatography on silica gel eluting with hexane/EtOAc (7:3) to give a mixture of 4:1 7-
chloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lW-
benzo[rf]azepineand7,9-dichloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[c/]azepine as a yellow oil (0.54 g, 85%).

3-ferf-ButoxYcarbonvl-7-chloro-6-dimethvlcarbamoYlthio-23,4,5-tetrahvdro-l.Hr-
benzo[|azepineand 3-tert-butoxycarbonvI-7.9-dichloro-6-dimethvIcarbamovlthio-
2,3,4,5-tetrahvdro-l//-benzot|azepine: To the mixture of 4:1 7-chloro-6-
dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-benzo[|azepine
and 7,9-dichloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[]azepine (0.536 g, 1.47 mmol) in methanol (7 mL), add aqueous potassium
carbonate (0.812 g, 5.88 mmol in 1.5 mL of water). Stir for 5 h at ambient temperature,
add di-tert-butyl dicarbonate (418 mg, 1.91 mmol) and stir for an additional 30 min.
Dilute with EtOAc and water. Separate the layers and extract the aqueous layer three
times with EtOAc. Dry over anhydrous Na2SC>4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (7:3) to give a mixture of 4:1 3-
/ert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[ 2,3,4,5-tetrahydro-l//-benzo[]azepine as a white solid (0.52 g, 96%).
Preparation 174
7-Bromo-3-?er/-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-
benzo[rf]azepine

Use a method similar to the Preparation 172, using 7-bromo-6-hydroxy-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rfIazepine to give the title compound.
Preparation 175
3-fer/-Butoxycarbonyl-6-dimethylcarbamoylthio-7-methyl-2,3,4,5-tetrahydro-l//-
benzo[cOazepine


7-Bromo-6-methoxv-3-(2J2-trifluoroaeetviy23.4.5-tetrahvdro-l/r-
benzofrflazepine: Add potassium carbonate (10.214 g, 73.9 mmol) to a solution of 7-
bromo-6-hydroxy-3-(2,2,2-trifluoroacctyl)-2,3,4,5-tetrahydro-l//-benzo[(/|azepine (5.0 g,
14.8 mmol) in acetone (50 mL) and stir for 10 min. Add methyl iodide (4.2 g, 1.5 mL,
29.6 mmol) and stir the mixture overnight at room temperature. Remove the solvent in
vacua and partition the residue between water and DCM. Extract the aqueous phase twice
with DCM. Combine the organic extracts, dry over Na2SC>4, filter and concentrate in
vacua to obtain the desired intermediate as a solid (5.15 g, 99%). MS (ES+) m/r. 352
(M+H)+.
6-Methoxv-7-methvI-3-(2^ benzofrflazepine: Add potassium carbonate (5.65 g, 40.91 mmol),
tetrakis(triphenylphosphine)palladium (1.576 g, 1.363 mmol) and trimethylboroxine
(2.053 g, 2.3 mL, 16.35 mmol) to a solution of 7-bromo-6-methoxy-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (4.8 g, 13.63 mmol) in
dimethylformamide (40 mL) under nitrogen. Heat the mixture to 115°C for 6 h. Add
water and extract the aqueous phase twice with EtOAc. Combine the organic extracts,
dry over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (1:0 and 19:1) to obtain the desired intermediate as a solid
(3.23 g, 83%). GC-MS m/z 287 (NT).

6-Hydroxv-7-methYl-3-(2^,2-trinuoroacetvi)-23,4,5-tetrahvdro-lJff-
benzoftflazepine: Add borontribromide (21.6 mL, 1.0 M solution in DCM) to a solution
of6-methoxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[^]azepine
(3.1 g, 10.8 mmol) in DCM (200 mL) at 0°C under nitrogen. Warm to room temperature
and stir overnight. Dilute with DCM and wash with water. Dry the organic layer over
Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a solid (2.74 g,
93%). MS (ES+) m/z: 274 (M+H)+.
6-DimethYlthiocarbamovIoxv-7-methvl-3-f2^.2-trifluoroacetvl)-23.4,5-tetraliYdro-
1/7-benzofrflazepine: Dissolve 6-hydroxy-7-methyI-3-(2,2,2-trifluoroacetyl)-2,3>4,5-
tetrahydro-l/f-benzo[rfjazepine (1.0 g, 3.66 mmol) in acetone (50 mL). Add potassium
carbonate (1.517 g, 10.98 mmol) and dimethylthiocarbamoyl chloride (0.904 g, 7.32
mmol). Heat the mixture at reflux overnight. Remove the solvent in vacuo and partition
the residue between water and DCM. Dry the organic phase over Na2SO4, filter and
concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and
9:1) to obtain the desired intermediate as a solid (1.18 g, 90%). MS (ES+) m/z: 361
(M+H)+.
6-DimethYlcarbamoYlthio-7-methvl-3-(2,2J-triflnoroacetyn-23,4,5-tetrahvdro-lg-
benzofrflazepine: Dissolve 6-dimethylthiocarbamoyloxy-7-methyl-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[flT]azepine (1.15 g, 3.19 mmol) in diphenyl
ether (20 mL) and heat to 265°C for 3 h in a sealed tube. Cool the reaction to room
temperature. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1 and
7:3) to obtain the desired intermediate as a solid (1.10 g, 96%). MS (ES+) m/z: 361
(M+H)+.
3-fer/-Butoxvcarbonvl-6-dimethvlcarbamovlthio-7-methyl-23,4,S-tetrahvdro-l.g-
benzofrflazepine: Dissolve 6-dimethylcarbamoylthio-7-methyl-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l#-benzo[ solution of potassium carbonate (1.6 g, 11.6 mmol) in water (10 mL). Stir at room
temperature overnight. Remove the solvent and partition the residue between water and

DCM. Extract the aqueous phase twice with DCM. Combine the organic extracts, dry
over Na2SO4, filter and concentrate. Dissolve the residue (0.756 g, 2.86 mmol) in DCM
(50 mL). Add triethylamine (0.579 g, 0.8 mL, 2.0 equiv) and di-ter/-butyl dicarbonate
(0.624 g, 2.86 mmol) and stir at room temperature overnight. Dilute with DCM and wash
with water. Dry the organic phase over Na2SO4, filter and concentrate to obtain the title
compound as foam (1.038 g, 99%). MS (ES+) m/z: 264 (M+H-Boc)+.
Preparation 176
3-fc^Butoxycarbonyl-7-cyano-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-l//-
ru>r\"~rr\I /rl *a*wor%tr»*»

7-Cvano-6-dimethvlthiocarbamovloxv-3-(2J,2-trifluoroacetYl>-23.4,5-tetrahYdro-
l//-benzol|azepine: Add dimethylthiocarbamoyl chloride (197 mg, 1.58 mmol) to a
stirred solution of 7-cyano-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l#-
benzo[d]azepine (150 mg, 0.53 mmol), DMAP (6 mg, 0.05 mmol) and dry triethylamine
(300 \iL) in dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen and heat at 120 °C
for 6 h. Cool and continue stirring for 2 days at ambient temperature. Dilute with
EtOAc, wash with IN aqueous HC1, water, saturated aqueous N^CCh and brine. Dry
over MgSC"4 then concentrate in vacuo. Purify by chromatography on silica gel eluting
with EtOAc:heptane (0:1 to 3:10) to give the desired intermediate as a white solid (158
mg, 81%).
7-Cvano-6-dimethvlcarbamovlsulfanYl-3-f2.2^-trifluoroacetvl)-23.4,S-tetrahydro-
l//-benzoMazepine: Heat a round bottom flask containing a solution of 7-cyano-6-
dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (786 mg, 2.12 mmol) in diphenyl ether (21 mL) in a preheated oil bath at

230°C for 2 h. Cool and purify by chromatography on silica gel eluting with
EtOAc:heptane (0:1 to 1:1) to give the desired intermediate as a yellow foam (740 mg,
94%). 'H NMR (300 MHz, CDC13) 5 7.60-7.56 (d, 1H), 7.36-7.30 (d, 1H), 3.88-3.68 (m,
4H), 3.34-3.03 (m, 10H).
3-fert-Butoxvcarbonyl-7-cyano-6-dimethylcarbamoylsulfanvl-2.3A5-tetrahydro-l//-
benzof|azepine: Add potassium carbonate (4.13 g, 30 mmol) to a stirred solution of 7-
cyano-6-dimethyIcarbamoylsulfanyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[*/]azepine (740 mg, 2.0 mmol) in methanol (40 mL)/water (15 mL) and stir for 1.5
h. Add DCM (10 mL), di-/ert-butyl dicarbonate (480 mg, 2.2 mmol) and stir at ambient
temperature for 3 days. Concentrate in vacuo and dilute with DCM, wash with water and
extract with DCM. Combine the organic layers, wash with brine, dry over MgSC>4 and
concentrate in vacuo. Purify by chromatography on silica gel eluting with
EtOAc:heptane (0:1 to 1:1) to give the title compound as a colourless foam (370 mg,
50%). 'H NMR (300 MHz, CDC13) 8 7.52 (d, 78 Hz, 1H), 7.29 (d, J8 Hz, 1H), 3.69-
3.48 (m, 4H), 3.26-3.02 (m, 10H), 1.45 (s, 9H).
Preparation 177
(S)-3-/er/-Butoxycarbonyl-7-chloro-6-(5-oxo-tetrahydro-furan-2-ylmethylthio)-
2,3,4,5-tetrahydro-l#-benzo[*/]azepine

To a solution of 3-/er/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-benzo[c/]azepine (137 mg, 0.356 mmol) in methanol (2 mL) add potassium
hydroxide pellets (640 mg, 11.4 mmol) and heat for 3 h at 50 °C. Cool to ambient
temperature, add saturated aqueous NH4CI, extract three times with EtOAc, dry over
anhydrous Na2SO4, and concentrate in vacuo. Dissolve the crude thiophenol thus
obtained in dry DMF (2 mL), and add with stirring sodium hydride (18 mg, 0.713 mmol,

95% dispersion), followed by (.S>(+)-dihydro-5-(/>-tolylsulfonyloxymethyl)-2-(3tf)-
furanone (144 mg, 0.533 mmol). Continue stirring overnight at ambient temperature,
then dilute cautiously with EtOAc and cold saturated aqueous NH4CI. Extract three times
with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (7:3) to give the title compound
as a colorless oil.

Add with stirring hydroxylamine (50 % in water, 25.0 mL, 0.380 mol) to a
solution of acetonitrile (5.0 mL, 95.0 mmol) and ethanol (500 mL). Heat at 70 °C for
18 h. Concentrate in vacuo to provide crude Af-hydroxyacetamidine (7.0 g, 100 %).
Add slowly with stirring vinyl chloroacetate (2.1 mL) to iV-hydroxyacetamidine (J. Org.
Chem. 1971, 36, 1306-1307) (1.00 g, 13.5 mmol) and heat at 90 °C for 5 h. Cool to
ambient temperature, dilute with DCM, wash with aqueous IN aqueous NaOH, dry over
anhydrous Na2SC>4 and concentrate in vacuo to give the title compound (904 mg, 50%).
The compounds of Preparation 179-182 were prepared essentially as described in
Preparation 178.


Preparation 183
2-Bromomethyl-6-chloropyridine

Heat a mixture of 2-chloro-6-methylpyridine (5.46 g, 42.8 mmol), NBS (8.38 g,
47.08 mmol), and benzoyl peroxide (500 mg, 2.06 mmol) in carbon tetrachloride (80 mL)
for 20 h at 85 °C. Cool to ambient temperature, filter, and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/toluene (4:3) to provide the title
compound as a white solid (3.64 g, 41%).
Preparation 184
3-Bromo-2-bromomethyl-pyridine

Heat a mixture of 3-bromo-2-methylpyridine (J. Med. Chem. 1987, 30, 871-880)
(2.7 g, 15.8 mmol), NBS (3.10 g, 17.42 mmol), and benzoyl peroxide (190 mg, 0.78
mmol) in carbon tetrachloride (50 mL) overnight at 85 °C. Cool to ambient temperature,
filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with
toluene to provide the title compound as a white solid (1.81 g, 45%).
Preparation 185
2-Bromo-6-bromomethyl-pyridine

Use a method similar to the Preparation 184, using 2-bromo-6-methylpyridine, to
give the title compound.
Preparation 186
5-Bromo-2-bromomethylpyridine


2-HvdroxvmethvI-5-bromopyridine: Dissolve 2,5-dibromopyridine (10 g, 42 mmol) in
toluene (500 tnL) and cool to -78 °C. Add 2.5M n-butyllithium in hexane (20.3 mL, 50.6
mmol) and stir the mixture for 7 h at the same temperature. Add DMF (4.2 mL, 54.87
mmol) and stir for 1 h. Warm the solution to 0 °C and add sodium borohydride (3.2 g,
84.42 mmol). Stir the mixture at ambient temperature for 3 h. Dilute with EtOAc and
saturated aqueous NH4CI. Separate the layers and extract the aqueous layer three times
with EtOAc. Dry over anhydrous Na2SO4, filter and concentrate in vacuo.
Recrystallization from hexane/EtOAc (9:1) gives the desired intermediate as a white solid
(5.3 g, 66%).
5-Bromo-2-bromoniethvl-pyridine : Dissolve 2-hydroxymethyl-5-bromopyridine (5.21
g, 27.7 mmol) in 48% aqueous hydrobromic acid (20 mL). Heat the mixture at 150 °C for
2 h. Cool to ambient temperature and remove excess hydrobromic acid under vacuum.
Dilute with water, add cautiously saturated aqueous NaHCO3 and extract three times with
EtOAc. Dry over anhydrous NazSCU, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound
as pink oil (6.0 g, 87%) that crystallizes in the freezer.
Preparation 187
2-Chloromethyl-3-methylpyridine Hydrochloride

2-Hydroxvmethvl-3-methvlpyridine: Heat a mixture of 3-methylpicolinic acid (1.0 g,
7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol)
in acetone (35 mL) overnight under reflux. Filter, wash the residue with EtOAc, and
concentrate in vacuo. Pass through a short plug of silica gel eluting with hexane/EtOAc
(1:1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg,
57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL)

at 0 °C, add with stirring a solution of 1M lithium aluminum hydride in THF (5 mL, 5
mmol), and continue stirring for 30 min at 0 °C. Allow the mixture to warm to ambient
temperature and quench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60 °C
for 40 min, cool to ambient temperature, extract with EtOAc, dry over anhydrous Na2SC>4
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (4:3) to give the desired intermediate (90 mg, 18%).
2-Chloroniethvl-3-methvlpyridine hvdrochloride: To 2-hydroxymethyl-3-
methylpyridine (90 mg, 0.73 mmol) in dry DCM (10 mL) at ambient temperature, add
with stirring thionyl chloride (0.53 mL, 7.3 mmol). Continue stirring overnight,
concentrate in vacuo, and azeotrope three times with chloroform. Triturate the residue
with dry ether, filter, and dry under vacuum to obtain the title compound as a beige solid
(130 mg, 100%).
Preparation 188
2-Chloromethyl-6-methylpryidine

Add with stirring a solution of thionyl chloride (0.77 mL, 10.6 mmol) in dry DCM
(20 mL) to 2-hydroxymethyl-6-methylpyridine (1.0 g, 8.12 mmol) in dry DCM (20 mL)
at 0 °C. Continue stirring at 0 °C for 1.25 h. Quench with isopropanol and concentrate in
vacuo. Dissolve the residue in DCM, wash with saturated aqueous NaHCC>3, dry over
anhydrous Na2SO4, and concentrate in vacuo to give the title compound. MS (ES+) m/z
142 (M+H)+.
Preparation 189
5-Butyl-2-chloromethylpyridineHydrochloride

Use a method similar to the Preparation 187, using fusaric acid, to give the title
compound. MS (APCI+) m/z 184 (M+H)+.

Preparation 190
6-Bromomethylnicotinonitrile
Use a method similar to the Preparation 184, using 5-cyano-2-methylpyridine, to
give the title compound.
Preparation 191
5-Bromomethyl-pyridine-2-carbonitrile

Use a method similar to the Preparation 184, using 5-methyl-picolinonitrile (J.
Chem. Soc. 1962, 2637-2658), to give the title compound.
Preparation 192
2-Chloromethyl-3-trifluoromethylpyridine Hydrochloride

Use the chlorination method described in Preparation 187, using 2-
hydroxymethyl-3-trifluoromethylpyridine, to give the title compound. MS (APCI+) m/z
196 (M+H)+.
Preparation 193
2-Chloromethyl-3-methoxypyridine


2-HydroxvmethvI-3-methoxypYridine: Heat a mixture of 3-hydroxypicolinic acid (5.3
g, 38 mmol), potassium carbonate (15.8 g, 114 mmol), and iodomethane (9.6 mL, 153
mmol) in acetone (100 mL) and DMF (10 mL) overnight at 60°C. Cool the reaction
mixture to ambient temperature, pour into brine, extract three times with ethyl ether, dry
over anhydrous MgSO4 and concentrate in vacuo. Pass through a short plug of silica gel
eluting with ether to provide 3-methoxy-2-methoxycarbonylpyridine as a pale yellow
liquid (6.3 g, 100%). To a solution of 3-methoxy-2-methoxycarbonyl-pyridine (2.34 g,
14.0 mmol) in dry THF (25 mL) add slowly with stirring a solution of 1M lithium
aluminum hydride in THF (10 mL, 10 mmol) and continue stirring overnight at ambient
temperature. Quench cautiously with sodium sulfate decahydrate, filter under suction and
rinse the solids with additional THF. Concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (3:1) to provide the desired intermediate as a
white solid (350 mg, 18%).
2-Chloromethyl-3-methoxvpvridine: Use a method similar to the Preparation 188, using
2-hydroxymethyl-3-methoxypyridine, to give the title compound. MS (APCI+) mix 158
(M+H)+.
Preparation 194
2-Chloromethyl-6-methoxypyridine Hydrochloride

2-Hvdroxvmethvl-6-methoxypyridine: To 6-methoxy-pyridine-2-carbaldehyde (J. Org.
Chem. 1990, 55, 69-73) (11.0 g, 80.3 mmol) in wet THF (200 mL) add portion wise with
stirring sodium borohydride (3.0 g, 79mmol) and continue stirring for 1 h at ambient
temperature. Add brine, extract the reacton mixture twice with EtOAc, dry the organic
layer over anhydrous Na2SC>4 and concentrate in vacuo. Pass the residue through a small
plug of silica gel eluting with hexane/EtOAc (3:1) to provide the desired intermediate as a
clear liquid (9.0 g, 81%).

2-ChloromethvI-6-methoxvpyridine hydrochloride: Use the chlorination method
described in Preparation 187, using 2-hydroxymethyl-6-methoxypyridine, to give the title
compound as a pale yellow solid. MS (APCI+) m/z 158 (M+H)+.
Preparation 195
3-Bromomethyl-6-chloro-pyridazine

Use a method similar to the Preparation 184, using 3-chloro-6-methylpyridazine,
to give the title compound as a red-orange liquid that darkens on standing.
Preparation 196
(±)-2-( 1 -Chloroethyl)-3-cyanothiophene

2-Acetyl-3-cyanothiophene: Heat a stirred solution of 2-acetyl-3-bromothiophene (1.49
g, 7.29 mmol) {Chem. Pharm. Bull. 2000, 48, 1558-1566) in dry NMP (72 mL) for 10 h at
150 °C in the presence of copper cyanide (3.26 g, 36.5 mmol). Dilute the mixture with
water, extract three times with diethyl ether, dry over anhydrous Na2SO4 and concentrate
in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to
give the desired intermediate as a dark oil (1.1 g, 99%).
(d-)-2-(l-Hvdroxvethvl)-3-cvanothiophene: Use a method similar to the reduction
procedure described in Preparation 194, using 2-acetyl-3-cyanothiophene, to give the
desired intermediate as dark oil.
(±V2-q-Chloroethvl)-3-cvanothiophene: Use a method similar to the Preparation 188,
using (±)-2-(l-hydroxyethyl)-3-cyanothiophene, to give the title compound as dark oil.
Use the crude material without further purification.

Preparation 197
(±)-2-( 1 -Bromoethyl)-pyridine

To (±)-2-(l-hydroxyethyl)-pyridine (Bull. Chem. Soc. Jpn. 1990, 63, 461-465)
(10.0 g, 81.3 mmol) in DCM (120 mL) at 0° C, add with stirring triphenylphosphine
(22.39 g, 85.365 mmol) followed by NBS (15.2 g, 85.4 mmol) in portions. Warm the
reaction mixture to ambient temperature and continue stirring for 3 h. Concentrate in
vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to
give the title compound.
Preparation 198
(±)-2-( 1 -Chloroethyl)-6-methylpyridine Hydrochloride

(±)-2-(l-Hvdroxvethyl)-6-methvlpyridine: To 6-methylpyridine-2-carboxaldehyde
(2.0 g, 16.5 mmol) in dry THF (55 mL) at 0 °C under nitrogen, add a solution of 3M
methyl magnesium bromide in ether (6.0 mL, 18.0 mmol,) dropwise with stirring. After 1
h at 0°C, quench with saturated aqueous NH4CI, extract three times with EtOAc, dry over
anhydrous Na2SC>4 and concentrate in vacuo to give the desired intermediate (crude,
2.3 g).
(±)-2-(l-ChIoroethvl)-6-methvlpyridine hydrochloride: To the crude 2-(l-
hydroxyethyl)-6-methylpyridine (1.6 g, 11.7 mmol) in dry DCM (15 mL) add with
stirring thionyl chloride (2.0 mL, 27 mmol) and continue stirring overnight. Concentrate
in vacuo, azeotrope three times with dry chloroform and dry under high vacuum to
provide the title compound as a tan solid (1.9 g, 85%). MS (APCI+) m/z 156 (M+H)+.

Preparation 199
(7?J-Methanesulfonic acid 1 -(6-methyl-pyridin-2-yI)-ethyl ester

(±H-(6-Methvl-pvridin-2-vl)-ethanol: Use a method similar to the Preparation 198
(Step 1), using 6-methyl-2-pyridinecarboxaldehyde and methylmagnesium bromide, to
give the desired intermediate.
(J?j-l-(6-MethYl-pyridin-2-vl)-ethanol: Stir a mixture of l-(6-methyl-pyridin-2-yl)-
ethanol (2.9 g, 21 mmol), 4A molecular sieves powder (3 g), vinyl acetate (6 mL) and
lipase Candida Antarctica acrylic resin (0.87 g) in /-Pr2O (40 mL) at ambient temperature
overnight (J. Org. Chem. 1998, 63, 2481-2487; Synlett 1999,41-44). Remove the solid
residue by filtration. Evaporate the volatile substances and purify by chromatography
eluting with hexane/EtOAc (7:3 to 1:1) to give the faster eluting (J^-acetic acid l-(6-
methyl-pyridin-2-yl)-ethyl ester as colorless oil (1.9 g, 50%), and the slower eluting (S)-
alcohol as light yellow oil (1.258 g, 43%). Dissolve (fl>acetic acid l-(6-methyl-pyridin-
2-yl)-ethyl ester (1.72 g, 9.62 mmol) in methanol (50 mL) and add potassium carbonate
(5.3 g, 38.5 mmol) in water (10 mL). Stir the mixture at ambient temperature for 4 h.
Dilute with brine, extract three times with EtOAc, dry over anhydrous Na2SO4, filter
through a short pad of silica gel and concentrate in vacuo to give the desired intermediate
as a colorless oil (1.17 g, 89%).
W-Methanesulfonic acid l-(6-methvl-pyridin-2-yD-ethvl ester: To a stirred solution
of (/?>l-(6-methyl-pyridin-2-yl)-ethanol (175 mg, 1.28 mmol) and triethylamine (355 u,l,
2.56 mmol) in DCM (5 mL) at 0°C add methanesulfonyl chloride (148 \A, 1.92 mmol).
Stir at 0 °C for 30 min and quench the reaction mixture with saturated aqueous NaHCC>3
at the same temperature. Extract the mixture three times with EtOAc, dry over anhydrous
Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (8:2) to give the title compound as a colorless oil (274 mg, 100%).

Preparation 200
(±)-2-(l-Bromoethyl)-3-methyl-pyridine

(±)-l-(3-MethYl-pyridin-2-yD-ethanol: Dissolve JV.N-dimethylethanolamine (70.45
mmol) in hexane (90 mL) at 0°C, add 2.5M n-butyl lithium in hexane (140.9 mmol,) and
stir for 30 min at this temperature. Add a solution of 3-picoline (35.23 mmol) in hexane
(10 mL) and continue stirring at 0° C for 1 h. Cool the resulting mixture to -78° C, add
acetaldehyde (70.45 mmol) and continue stirring at -78° C for 1 h. Dilute with water,
warm to ambient temperature, extract three times with EtOAc, dry over anhydrous
Na2SO4, and concentrate in vacuo. Purify by chromatography eluting with hexane/EtOAc
(85:15) to give the desired intermediate as a light yellow oil.
(±)-2-(l-Bromoethyl>3-niethvl-pvridine: Use a method similar to the Preparation 197,
using l-(3-fluoro-pyridin-2-yl)-ethanol, to give the title compound.
Preparation 201
(±)-2-[ 1 -Methanesulfonyloxy-(2,2,2-trifluoroethyl)]pyridine

(±)-2-ri-HvdroxY-(2.2,2-trifluoroethv01-pvridine: To a stirred solution of 2-pyridine
carboxaldehyde (2.09 g, 19.5 mmol) and (trifluoromethyl)trimethylsilane (3.33 g, 23.4
mmol) in THF (30 mL) at 0°C add 1M tetrabutylammonium fluoride in THF (956 uJ,
0.956 mmol). Continue stirring for 30 min at 0° C and then at ambient temperature for 2
h. Add 1M aqueous HC1 (20 mL) and stir 2 h at ambient temperature. Dilute with
aqueous 1M aqueous NaOH to pH 8, extract the mixture three times with EtOAc, dry
over anhydrous Na2SC>4, and concentrate in vacuo. Purify by chromatography eluting
with hexane/EtOAc (8:2) to give the desired intermediate as a yellow oil (3.22 g, 93%).

(±)-2-U-Methanesulfonyloxv-(2,2,2-trifluoroethyl)1pvridine: Use a method similar to
the Preparation 199 (Step 3), using (±)-2-[l-hydroxy-(2,2,2-trifluoroethyl)]pyridine, to
give the title compound.
Preparation 202
(±)-2-(l-Bromopropyl)pyridine

(±)-l-Pvridin-2-yl-propan-l-ol: To a stirred solution of 2-pyridine carboxaldehyde (4.0
g, 37.34 mmol) in THF (50 mL) at 0° C, add 3M ethyl magnesium bromide in ether (18.7
mL, 56.0 mmol), continue stirring for 30 min at 0°C and then at ambient temperature for
2 h. Add water (200 mL), extract three times with EtOAc, dry over anhydrous Na2SO4,
filter through a short pad of silica gel and concentrate in vacuo to give the desired
intermediate as a yellow oil (3.39 g, 66%).
(±V2-(1-Bromopropyl)pyridine: Use a method similar to the Preparation 197, using 1-
pyridin-2-yl-propan-l-ol, to give the title compound.
Preparation 203
(±)-1 -Pyridazin-3-yl-ethanol

3-(l-Ethoxwinvnpyridazine: Heat pyridazine-3-chloride (WO 0107416) (2 g, 17.5
mmol) with tributyl-(l-ethoxyvinyl)tin (7.1 mL, 21.1 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.6 mmol) in DMF (18 mL) at
110°C for 13 h. Cool the mixture, dilute with ether (175 mL) and add a solution of
potassium fluoride (5.43 g, 94 mmol) in water (10 mL). After 1 h, filter the mixture
through Celite®, and wash the filtrate with brine. Dry the combined organic extracts over
Na2SC>4 and evaporate. Purify by chromatography on silica gel eluting with
EtOAc:hexane (0:1 to 6:4) to obtain the desired intermediate (1.7 g, 65%). HPLC tR=3.7

min (Zorbax Eclipse XBD-C8 4.6 x 150 mm 5 micron column, 1.5 mL/min of 90/10 to
10/90 0.1% TFA in water/acetonitrile over 10 min. Detector is at 230 and 254 nm.).
l-Pyridazin-3-yl-ethanone: Stir 3-(l-ethoxyvinyl)pyridazine (1.7 g, 11.3 mmol) in
acetone (6.3 mL) and 2.5N aqueous HC1 (3.1 mL) for 2 h at ambient temperature and
evaporate. Dissolve the residue in DCM and wash the organic layer with saturated
aqueous NaHCC>3, dry the organic layer over Na2SC>4 and evaporate to obtain the desired
intermediate (1.4 g, 99%). HPLC tR=1.9 min (Zorbax Eclipse XBD-C8 4.6 x 150 mm 5
micron column, 1.5 mL/min of 90/10 to 10/90 0.1% TFA in water/acetonitrile over 10
min. Detector is at 230 and 254 nm.).
(±M-Pyridazin-3-vl-ethanoI: To l-pyridazin-3-yl-ethanone (1.4 g, 11.2 mmol) in
methanol (112 mL) add sodium borohydride (0.85 g, 22.5 mmol) at 0 °C and stir for 1 h
at ambient temperature. Evaporate the mixture and purify by chromatography on silica
gel eluting with EtOAc:hexane (1:1 to 1:0) and methanol:EtOAc (0:1 to 1:9) to obtain the
title compound (1.3 g, 93%).
Preparation 204
(/?)-(-)-l-(2-Pyridinyl)ethanol methanesulfonate ester

(fl)-l-(Pyridin-2-yl)-ethaiiol: Stir a mixture of (±)-l-(pyridin-2-yl)-ethanol (21.2
mmol), 4A molecular sieves powder (3 g), vinyl acetate (6 mL) and lipase Candida
Antarctica acrylic resin (0.87 g) in /-Pr2O (40 mL) at ambient temperature overnight (J.
Org. Chem. 1998, 63, 2481-2487; Synlett 1999, 41-44). Remove the solid residue by
filtration. Evaporate the volatile substances and purify by chromatography eluting with
hexane/EtOAc (7:3 to 1:1) to give the faster eluting (/?)-acetic acid l-(pyridin-2-yl)-ethyl
ester as colorless oil (50%) and the slower eluting (S)-alcohol as light yellow oil (43%).
Dissolve (tf)-acetic acid 1 -(pyridin-2-yl)-ethyl ester (9.620 mmol) in methanol (50 mL)
and add potassium carbonate (38.48 mmol) in water (10 mL). Stir the mixture at ambient
temperature for 4 h. Dilute with brine, extract three times with EtOAc, dry over

anhydrous Na2SO,t, filter through a short pad of silica gel and concentrate in vacua to give
the desired intermediate as a colorless oil (89%).
(J?H-M-(2-Pvridinvl)ethanol methanesulfonatc ester: To a stirred solution of (i?)-l-
(pyridin-2-yl)-ethanol (1.28 mmol) and triethylamine (2.56 mmol) in DCM (5 mL) at 0°C
add methanesulfonyl chloride (1.92 mmol). Stir at 0°C for 30 min and quench the
reaction mixture with saturated aqueous NaHCC>3 at the same temperature. Extract three
times with EtOAc, dry over anhydrous Na2SC>4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to give the title compound
as a colorless oil (100 %). MS (APCI+) m/z 202 (M+H)+; [cx]D25= -73.5° (c 1, CHC13).
Preparation 205
(±)-1 -(4-FIuorophenyl)ethy 1 brom ide

Method A: Add carbon tetrabromide (646 mg, 1.95 mmol) to a solution of
triphenylphosphine (511 mg, 1.95 mmol) and (±)-4-fluoro-a-methylbenzyl alcohol (260
mg, 1.86 mol) in dry DMF (20 mL) at 0°C under nitrogen. Stir the reaction for 2 h to give
the title compound. No further purification required.
Method B: Add HBr (460 nL of 48% w/w in water, 4.28 mmol) to a solution of (±)-4-
fluoro-a-methylbenzyl alcohol (300 mg, 2.14 mmol) in dry DCM (10 mL) at ambient
temperature under an atmosphere of nitrogen. Stir for 2.5 h. Reduce volume in vacuo to
give the title compound. Dilute with DCM (1 mL) and use without further purification.
Preparation 206
(±)-2-( 1 -Bromoethyl)benzonitrile


Use a method similar to the Preparation 184, using 2-ethylbenzonitrile, to give the
title compound as a clear liquid.
Preparation 207
l-(4-Bromomethylphenyl)-3,3-dimethylbutan-l-one

f±V-33-Dimethyl-l-p-tolvlbutaii-l-ol: To a stirred solution of 4-methylbenzaldehyde
(1.51 g, 12.6 mmol) in THF (30 mL) at 0°C, add neopentyl magnesium chloride (33.0
mL, 16.34 mmol, 0.5-1M in ether) and continue stirring at 0 ° C for 1 h. Dilute with
saturated aqueous NH4CI, extract three times with EtOAc, dry over anhydrous Na2SO,t,
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (95:5) to give the desired intermediate as a colorless oil (2.15 g, 89%).
33-Dimethyl-l-p-tolyl-butan-l-one: To a stirred solution of (±)-3,3-dimethyl- 1-p-tolyl-
butan-1-ol (2.15 g, 11.3 mmol) in hexane (30 mL) add manganese dioxide (2.94 g, 33.8
mmol) and heat the mixture overnight at 65° C. Cool to ambient temperature, filter the
manganese salts, and concentrate in vacuo to give the desired intermediate as a colorless
oil (2.2 g, 100%).
l-(4-Bromomethvlnhenvl)-3,3-dimethvlbutan-l-one: Use a method similar to the
Preparation 184, using 3,3-dimethyl-l-p-tolylbutan-l-one, to give the title compound.
Preparation 208
1 -(4-Bromomethylphenoxy)-3,3 -dimethy lbutan-2-one

l-(4-Hvdroxymethvlphenoxy)-3y3-dimethvlbutan-2-one: Mix potassium carbonate
(2.764 g, 20 mmol), 4-hydroxy-benzyl alcohol (1.49 g, 12 mmol) in absolute ethanol (100

mL), add 1-bromopinacolone (1.791 g, 10 mmol) dropwise. Heat the mixture under
reflux for 12 h. Add water to dissolve the solid, and remove most of the ethanol in vacuo.
Extract the mixture with EtOAc three times. Combine the organic layers, wash with
brine, dry over Na2SC"4, filter and concentrate. Purify the residue by chromatography on
silica gel eluting with EtOAcrhexane (1:2) to provide the desired intermediate as a
colorless oil (1.08 g, 48%). MS (ES+) m/z: 205 (M+H-H20)+.
l-(4-Bromomethvlphenoxv>-3.3-dimethvlbutan-2-one: Add phosphorous tribromide
(1.45 g, 5.34 mmol) slowly to a solution of l-(4-hydroxymethyl-phenoxy)-3,3-
dimethylbutan-2-one (1.08 g, 4.85 mmol) in anhydrous THF under nitrogen at 0 °C. Stir
at 0 °C for 1 h and then raise to ambient temperature. Stir overnight. Dilute with EtOAc,
wash with saturated aqueous NaHCC>3, brine, dry over Na2SO4, filter and concentrate.
Purify the residue by chromatography on silica gel eluting with EtOAc:hexane (1:6) to
provide the title compound (1.152 g, 83%). MS (ES+) m/z: 205 (M-Br)+.
Preparation 209
l-(4-Bromomethyl-3-chlorophenoxy)-3,3-dimethylbutan-2-one

3-Chloro-4-hvdroxybenzyl alcohol: Add a solution of D1BAL-H in toluene (1.0 M, 35
mL) to a solution of methyl 3-chloro-4-hydroxybenzoate (1.9 g, 10 mmol) at 0 °C under
nitrogen. Stir the reaction at 0 °C and gradually warm to ambient temperature overnight.
Quench the reaction with slow addition of 0.1N aqueous HC1, add more acid to break the
gel-like solid to two clear layers. Separate the organic layer, and extract the aqueous
layer with EtOAc three times. Combine the organic layers, wash with brine, dry over
Na2SO4, filter and concentrate to give a white solid. MS (ES-) m/z 157 (M-H)
l-(4-BromomethvI-3-chIorophenoxv)-3J-dimethvl-butan-2-one: Use a method
similar to the Preparation 208 to convert 3-chloro-4-hydroxy-benzyl alcohol to the title
compound (1.144 g, 64% two steps). MS (ES+) m/z 319.0 (M+H)+.
Preparation 210
l-Bromomethyl-4-(2,2-dimethyl-propoxy)-benzene

l-(2,2-Dimethyl-propoxv>-4-methvl-benzene: To a solution of p-cresol (526 mg, 4.87
mmol) in THF (50 mL), add with stirring diisopropyl azodicarboxylate (2.16 mL, 10.7
mmol) followed by triphenylphosphine (306 mg, 11.7 mmol) and neopentyl alcohol (5.15
g, 58.4 mmol). Heat at 60 °C for 3 h, cool to ambient temperature and concentrate in
vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc to give the
desired intermediate as a colorless oil.
l-Bromomethvl-4-(2,2-dimethvl-propoxv>-benzene: Use a method similar to the
Preparation 184, using l-(2,2-dimethyl-propoxy)-4-methylbenzene, to give the title
compound.
Preparation 211
l-Bromomethyl-2-methanesulfonylbenzene

(2-Methanesulfonvlphenvl>methanol: To a stirred solution of 2-methanesulfonyl-
benzoic acid (2.7 g, 13.5 mmol) in dry THF (60 mL) at 0 °C, add a solution of borane in
THF (27.0 mL, 0.5 M, 13.5 mmol). Allow the mixture to warm to ambient temperature
and continue stirring for 2 days. Quench the excess borane by slow addition of methanol,
add brine, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in
vacua to provide the crude desired intermediate as a clear, thick oil (2.4 g, 97 %).

l-Bromomethvl-2-methanesuIfonvlbenzene: To a stirred solution of (2-
methanesulfonyl-phenyl)methanol (735 mg, 3.99 mmol) in dry DCM (2 mL) at 0 °C, add
a solution of 1M phosphorous tribromide in DCM (6.0 mL, 6.0 mmol) and continue
stirring for 1 h. Dilute with saturated aqueous NaHCC ether, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (12:1) to provide the title compound as a white
solid (950 mg, 97 %).
Preparation 212
l-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene

Methanesulfonic acid 333-trifluoro-2-methvl-2-trifluoromethvl-propvl ester: To
2,2-bis(trifloromethyl)propanol (4.34 g, 22.1 mmol) in DCM (100 mL) at 0 °C add with
stirring triethylamine (6.2 mL, 44 mmol) followed by methanesulfonyl chloride (2.6 mL,
33 mmol). After 15 min at 0°C dilute with water and extract three times with EtOAc.
Dry over anhydrous Na2SC"4 and concentrate in vacuo to give the crude desired
intermediate as a yellow oil (6.16 g, 100 %).
l-Methvl-4-(33J-trifluoro-2-niethvl-2-trifluoroniethvlpropvlthio)benzene: In a
sealed tube dissolve 4-methylbenzenethiol (4.13 g, 33.2 mmol) in DMF (20 mL) at
ambient temperature. Add portionwise with stirring sodium hydride (899 mg, 37.5
mmol) followed by tetrabutylammonium iodide (82 mg, 0.22 mmol) and a solution of
methanesulfonic acid 3,3,3-trifluoro-2-methyl-2-trifluoromethylpropyl ester (6.16 g, 22.5
mmol) in DMF (10 mL). Stir at 150°C overnight, cool the mixture to ambient
temperature and dilute cautiously with water. Extract three times with EtOAc, dry over
anhydrous Na2SC>4, and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane to give the desired intermediate as a yellow oil (4.5 g, 62 %).

l-Bromomethvl-4-r3,3^-trifluoro-2-methyI-2-trifluoromethvIpropYlthio)benzene:
Use a method similar to the Preparation 184, using l-methyl-4-(3,3,3-trifluoro-2-methyl-
2-trifluoromethylpropylthio)benzene, to give the title compound.
Preparation 213
l-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-l-sulfmyl)-
benzene

1-Methyl-4-(3.3,3-trifluort>-2-methvl-2-trifluoromethylpropane-l-sulfiDvlVbcnzene:
To l-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene(4.5 g, 14.9
mmol) in acetic acid (15 mL) at ambient temperature, add with stirring aqueous hydrogen
peroxide (15 mL, 30% in water) and stir for 1 h. Dilute the reaction with water, extract
three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify b>
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired
intermediate as a colorless oil (4.125 g, 88 %).
l-Bromomethvl-4-(33J-trifluoro-2-methvl-2-trifluoromethvlpropane-l-sulfinvl)-
benzene: To 1 -methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1 -sulfinyl)-
benzene (4.13 g, 13.0mmol) in carbon tetrachloride (50 mL) add NBS (2.31 g, 13.0
mmol), benzoyl peroxide (314 mg, 1.30 mmol) and stir overnight at reflux. Cool to
ambient temperature, dilute with water and extract three times with EtOAc. Dry over
anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (9:1) to give the title compound as colorless oil (2.3 g, 55 %).
Preparation 214
1 -Bromomethyl-4-(2,2-dimethylpropane-1 -sulfonyl)benzene


l-(2,2-Dimethvl-propane-l-sulfonvl)-4-methyl-benzene: In a sealed tube, dissolvep-
toluenesulfinic acid sodium salt (5.71 g, 32.1 mmol) in DMF (20 mL) and water (10 mL).
Add neo-pentyl bromide (6.3 mL, 48 mmol) and tetrabutylammonium iodide (592 mg,
1.60 mmol) and heat the mixture at 145 °C overnight. Cool the reaction to ambient
temperature, dilute with water and extract 3 times with EtOAc. Dry over anhydrous
Na2SO4 and concentrate in vacuo. Purity by chromatography on silica gel eluting with
hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (3.3 g, 45 %).
l-Bromomethvl-4-(2^-dimethvlpropane-l-sulfonyl)benzene: Use a method similar to
the Preparation 213 (Step 2), using l-(2,2-dimethylpropane-l-sulfonyl)-4-methyl-
benzene, to give the title compound.
Preparation 215
l-Bromomethyl-4-(3,33-trifluoro-2-methyl-2-trifluoromethylpropane-l-sulfonyl)-
benzene

l-MethvI-4-(33,3-trifluoro-2-methvl-2-trifluoromethylpropane-l-sulfonYl)benzene:
To l-methyl-4-(3,3,3-trifluoro-2-methy1-2-trifluoromethylpropylthio)benzene (3.47 g,
11.49 mmol) in trifluoroacetic acid (15 mL) at ambient temperature add with stirring
aqueous hydrogen peroxide (15 mL, 30% in water) and stir for 1 h. After removing
trifluoroacetic acid in vacuo, dilute with saturated aqueous NaHCO3. Extract three times
with EtOAc, dry over anhydrous Na2SO.t, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired
intermediate as a colorless oil (2.8 g, 74 %).
l-Bronioniethvl-4-(3,3.3-trifluoro-2-methvl-2-trifluoromethvlpropane-l-sulfonvn-
benzene: Use a method similar to the Preparation 213 (Step 2), using l-methyl-4-(3,3,3-
trifluoro-2-methyl-2-trifluoromethylpropane-l-sulfonyl)benzene, to give the title
compound.


Preparation 216
l-Bromomethyl-4-(4'-trifluoromethyl)-phenylsulfonylbenzene
l-Methyl-4-(4-trifluoromethyI)-phenylthio-benzene: Heat a mixture of 4-
methylbenzenethiol (7.67 g, 61.8 mmol), l-bromo-4-trifluoromethyl-benzene (4.63 g,
20.6 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (379 mg, 2.06 mmol), cesium
carbonate (20.1 g, 61.8 mmol) and CuCl (102 mg, 1.03 mmol) in NMP (30 mL) at 150°C
for 3 h. Cool the mixture to ambient temperature, dilute with water, extract three times
with EtOAc, dry the organic layer over anhydrous Na2SC>4, and concentrate in vacuo.
Recrystallize the residue from hexane/EtOAc to give the desired intermediate as a white
solid (3.87 g, 70%).
l-Bromomethvl-4-f4-trifluoromethyl)-phenvlsulfonvl-benzene: Use a method similar
to the Preparation 215, using l-methyl-4-(4-trifiuorornethyl)-phenylthiobenzene, to give
the title compound.

Use a method similar to the Preparation 214, using 2,4-difluorobenzyl bromide, to
give the title compound.

Preparation 218
l-Bromomethyl-4-cyclohexylmethanesulfonyl-benzene

Use a method similar to the Preparation 214, using cyclohexylmethyl bromide, to
give the title compound.
Preparation 219
Methyl 4-bromomethyl-2-fluorobenzoate

Methyl 2-fliioro-4-methyl-benzoate: Mix l-bromo-2-fluoro-4-methylbenzene (15 g,
79.4 mmol), palladium acetate (712 mg, 3.17 mmol), l,3-bis(diphenylphosphino)-propane
(2.94 g, 7.14 mmol), triethylamine (16.1 g, 159 mmol) in methanol (150 mL) and DMF
(100 mL). Degas the mixture under vacuo and pressurize to 65 psi with carbon
monoxide. Stir the reaction at 110°C for 2 days. Remove methanol in vacuo, dilute the
mixture with water, and extract three times with EtOAc. Dry over anhydrous Na2SC>4 and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
(9:1) to give the desired intermediate as a white solid (7.40 g, 55%).
Methyl 4-bromomethyl-2-fluoro-benzoate: Use a method similar to the Preparation
184, using methyl 2-fluoro-4-methylbenzoate, to give the title compound as a white solid.
Preparation 220
4-Chloromethyl-Ar-cyclohexylbenzamide


To 4-chloromethylbenzoyl chloride (1.03 g, 5.47 mmol) in DCM (20 mL) at 0°C,
add with stirring triethylamine (0.839 mL, 6.02 mmol) followed by cyclohexylamine
(0.688 mL, 6.02 mmol), and continue stirring for 15 min. Dilute the reaction mixture
with aqueous 1M hydrochloric acid, extract three times with EtOAc, wash with water and
saturated aqueous NaHCCb. Dry the combined organic extracts over anhydrous Na2SO4
and concentrate in vacuo to give the title compound as a white solid (1.31 g, 95%).


The compounds of Preparations 221-235 may be prepared essentially as described
in Preparation 220by using 4-chloromethylbenzoyl chloride and the appropriate amine.


Methanesulfonic acid 2-isopropoxvethyl ester: To a stirred solution of 2-
isopropoxyethanol (2.0 mL, 17.37 mmol) in DCM (100 mL) at ambient temperature add
methanesulfonyl chloride (1.48 mL, 18.08 mmol). Add triethylamine (2.70 mL, 19.37
mmol) slowly followed by DMAP (catalytic). Continue stirring overnight and
concentrate in vacuo. Add diethyl ether and filter. Wash the filtrate with aqueous IN

aqueous HC1, brine, and saturated aqueous NaHCOv Dry over anhydrous MgSO* and
concentrate in vacuo to give the desired intermediate (2.97 g, 94%).
2-(2-Iodoethoxv)propane: To a stirred solution of methanesulfonic acid 2-isopropoxy-
ethyl ester (2.95 g, 16.2 mmol) in acetone (200 mL) at ambient temperature add sodium
iodide (7.28 g, 19.4 mmol) and continue stirring overnight. Concentrate in vacuo, add
diethyl ether and filter, and concentrate in vacuo to give the title compound as a pale
yellow liquid (3.12 g, 90%).
Preparation 237
(i?)-Toluene-4-sulfonic Acid Tetrahydrofuran-3-yl Ester

To (/f)-tetrahydro-furan-3-ol (2.0 g, 22.7 mmol), triethylamine (3.8 mL, 27.3
mmol), DMAP (277 mg, 2.26 mmol), and silver oxide (5.26 g, 22.7 mmol) in dry DCM
(30 mL) at 0 °C under nitrogen, add portion wise with stirring p-toluenesulfonyl chloride
(4.76 g, 25.0 mmol). Warm to ambient temperature overnight, filter from silver salts, and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
(7:1) to give the title compound as a clear liquid (4.7 g, 85%).
Preparation 238
(5)-Toluene-4-sulfonic Acid Tetrahydrofuran-3-yl Ester

Use a method similar to the Preparation 237, using (S)-tetrahydro-furan-3-ol, to
give the title compound as a clear liquid.
Preparation 239
2-(2-BromoethyI)-pyridineHydrobromide


Use a method similar to the bromination procedure described in Preparation 186
(Step 2), using 2-pyridineethanol, to give the title compound. Recrystallize from 2-
propanol to give a light brown solid.
Preparation 240
5-(3-Bromopropyl)-3-ter/-butyl-[ 1,2,4]oxadiazole

4-Bromobutyric acid vinyl ester: To 4-bromobutyric acid (1.0 g, 6.0 mmol) in vinyl
acetate (54 mL) add with stirring palladium(II) acetate (188 mg, 0.84 mmol) and continue
stirring overnight at ambient temperature. Filter and concentrate in vacuo to provide the
crude desired intermediate.
5-(3-Bromopropyl)-3-fert-burvl-[l,2,41oxadiazole: Use a method similar to the
Preparation 178, using 4-bromobutyric acid vinyl ester, to give the title compound.
Preparation 241
1 -Bromomethyl-2-fluoro-4-phenoxybenzene

2-(4-Bromo-2-fluoro-benzyloxvMetrahydro-pyran: Mix under nitrogen atmosphere 4-
bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol),p-
toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL).
Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated
aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc

(1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+)
/n/z:312(M+Na)+.
2-(2-FIuoro-4-phenoxv-benzvloxv)-tetrahvdro-pvran: Mix under argon atmosphere 2-
(4-bromo-2-fluorobenzyloxy)-tetrahydropyran (2.9 g, 10 mmol), phenol (1.9 g, 20 mmol),
2,2,6,6-tetramethylheptane-3,5-dione (184.3 mg, 1.0 mmol), cesium carbonate (6.5 g, 20
mmol) and anhydrous NMP (20 mL). Degas the flask and fill with argon. Add copper(I)
chloride (495 mg, 5 mmol) quickly. Degas the flask three times then fill with argon.
Heat at 120 °C for 3 h. Cool to ambient temperature. Dilute with EtOAc and filter.
Concentrate in vacuo and purify by chromatography on silica gel to obtain the desired
intermediate (2.05 g, 68%). MS (ES+) m/z: 325 (M+Na)+.
(2-Fluoro-4-phenoxy-phenvl)-methanol: Mix under nitrogen atmosphere 2-(2-fluoro-4-
phenoxy-benzyloxy)-tetrahydro-pyran (2.05g, 6.8 mmol), methanol (60 mL) andp-
toluenesulfonic acid monohydrate (260 mg, 1.35 mmol). Stir at ambient temperature for
16 h. Dilute with EtOAc. Wash with saturated aqueous NaHCC layer, dry over Na2SC>4 and concentrate in vacuo to give the desired intermediate (1.41 g,
95%). MS (ES+) m/z: 201 (M-OH)+.
l-Bromomethyl-2-fluoro-4-phenoxv-benzene: Dissolve under nitrogen atmosphere (2-
fluoro-4-phenoxyphenyl)-methanol (1.41 g, 6.5 mmol) in anhydrous THF (60 mL). Cool
to 0 °C in an ice bath. Add phosphorous tribromide (2.11 g, 7.8 mmol). Stir at cold for 1
h, then remove the ice bath and stir at ambient temperature for 16 h. Quench the reaction
with saturated aqueous NaHCC>3. Extract aqueous phase three times with EtOAc.
Combine organic fractions, wash with brine, dry over Na2SC«4 and concentrate in vacuo.
Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1). Evaporate the
solvent to obtain the title compound (1.31 g, 72%).
Preparation 242
3-/er/-Butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-l//-
benzo[f/]azepine


S-tert-Butoxvcarbonvl-^f^carboxv-benzylthioVT-chtoro^vB^^tetrahydro-lJ?-
benzoltflazepine: To a solution of 3-/ert-butoxycarbonyl-7-chloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[]azepine (1.0 g, 2.6 mmol) in
methanol (15 mL) under nitrogen, add with stirring potassium hydroxide (4.5 g, 80.3
mmol) at ambient temperature. Heat at 55-60°C for 2 h, cool to ambient temperature, and
add methyl 4-bromomethylbenzoate (1.2 g, 5.2 mmol). TLC after 20 min shows
formation of product; however, after 4 h at ambient temperature both TLC and LC/MS
indicate complete hydrolysis of the ester and the carbamate. Dilute with saturated
aqueous NH4CI, extract three times with EtOAc, dry over anhydrous MgSC>4, and
concentrate in vacuo. Dissolve the crude material in THF (10 mL), treat with di-tert-
butyl-dicarbonate (2 equiv) and saturated aqueous NaHCC>3 (10 mL), and stir overnight.
Extract three times with EtOAc, dry over anhydrous MgSC>4 and concentrate in vacuo to
give the desired intermediate as an oil that was used without purification [2.32 g, 50%
purity with (Boc)2O]. MS (ES+) m/z 348 (M+H-Boc)+.
3-rgr/-ButoxvcarbonvI-7-chloro-6-(4-hYdroxvmethvl-benzvlthio)-23,4,S-tetrahvdro-
lg-benzofrflazepine: To a solution of 3-tert-butoxycarbonyl-6-(4-carboxybenzylthio)-7-
chloro-2,3,4,5-tetrahydro-l//-benzo[cf]azepine (1.85 g, 50% purity, 2.06 mmol) in
anhydrous THF (40 mL) under nitrogen, add with stirring 1M borane in THF (4.2 mL) at
0 °C. Warm to ambient temperature and stir 2-3 h. Quench by the careful addition of
water (3 mL), dilute with saturated aqueous NaHCCh, extract three times with ethyl ether,
dry over anhydrous MgSC>4, and concentrate in vacuo. Purify by chromatography on
silica gel eluting with hexane/EtOAc (5:1) to provide the title compound as a white solid
(485 mg, 54 %).

Preparation 243
3-/ert-Butoxycarbonyl-7-chloro-6-(4-methanesulfonylmethylbenzylthio)-2,3,4,5-
tetrahydro-1 //-benzof^Jazepine

3-/ert-ButoxvcarbonvI-7-chloro-6-r4-methanesulfonvIoxvmethvl-l)enzvlthio)-2^,4,5-
tetrahvdro-l//-benzo[fflazepine: To a stirred solution of 3-rerr-butoxycarbonyl-7-
chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[c(]azepine(170mg,
0.391 mmol) in anhydrous DCM under nitrogen, add methanesulfonyl chloride (33 ^L,
0.426 mmol) and triethylamine (61 uL, 0.44 mmol) and continue stirring for 2 h. Dilute
with water (5 mL) and extract three times with DCM. Wash the combined organic
extracts with brine, dry over anhydrous NajSCU, and concentrate in vacuo to obtain the
desired intermediate that was used without purification.
3-ferf-Butoxvcarbonvl-6-(4-bromomcthYl-henzylthio)-7-chloro-2J.4^-tetrahvdro-
l/T-benzoffflazepine: Dissolve the crude 3-/ert-butoxycarbonyl-7-chloro-6-(4-
methanesulfonyloxymethyl -benzylthio)-2,3,4,5-tetrahydro-l/7-benzo[rf]azepine in
anhydrous acetone (3 mL), treat with anhydrous lithium bromide (335 mg, 3.89 mmol)
and continue stirring overnight. Add water, extract the reaction mixture three times with
ethyl ether, wash with brine, dry over anhydrous MgSO-*, and concentrate in vacuo to
obtain the desired intermediate that was used without purification.
3-fer/-Butoxvcarbonvl-7-chloro-6-(4-methanesulfonvlmethvl-benzvlthio)-23,4,5-
tetrahvdro-l/T-benzo[ bromomethyl -benzylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine in anhydrous
DMF (1 mL) under nitrogen, add with stirring sodium methanesulfinate (400 mg, 3.9
mmol), and continue stirring for 30 min at ambient temperature followed by 2 h at 40 °C.
Add water, extract three times with EtOAc, wash with brine, dry over anhydrous MgSO4,
and concentrate in vacuo. Purify by chromatography on silica gel eluting with

hexane/EtOAc (3:1) to give a clear oil that solidifies on standing to a white solid (118 mg,
61%).
Preparation 244
6-(4-Bromo-3-fluorobenzylthio)-3-ferr-butoxycarbonyl-7-chIoro-2,3,4,5-tetrahydro-l^-
benzo[d]azepine

l-Bromo-4-bromomethvl-2-nuorobenzene: Use a method similar to the Preparation
184, using 4-bromo-3-fluorotoluene, to give the desired intermediate as a white solid.
6-(4-Bromo-3-fluorobenzvlthio)-3-fer/-butoxvcarbonvl-7-chloro-23.4,5-tetrahvdro-
l//-benzo[dlazepine: Use a method similar to the Preparation 177, using 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine and l-bromo-4-bromomethyl-2-fluorobenzene, to give the title
compound as a white solid.
Preparation 245
(±)-3-/err-Butoxycarbonyl-7-chloro-6-(l-methoxycarbonyl-l-phenyl-methyllthio)-
2,3,4,5-tetrahydro-l//-benzo[t/]azepine
c
(±)-3-/e/t-Butoxvcarbonvl-6-('l-carborv-l-phenYl-methvHthio)-7-chloro-23.4.5-
tetrahvdro-lj/-bcnzo[ dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (1.23 g, 3.2 mmol) in
methanol (20 mL) under nitrogen, add with stirring potassium hydroxide (5.36 g, 95.5
mmol) at ambient temperature. Heat at 55-60 °C for 2 h, cool to ambient temperature,

and add methyl a-bromophenylacetate (600 \xL, 3.81 mmol). After 30 min, dilute with
saturated aqueous NH4CI, extract three times with EtOAc, dry over anhydrous MgSO-j,
and concentrate in vacuo. Dissolve the crude material in THF (10 mL), treat with di-tert-
butyl-dicarbonate (2 equiv) and saturated aqueous NaHCO3 (10 mL), and stir overnight.
Extract three times with EtOAc, dry over anhydrous MgSC>4 and concentrate in vacuo to
give the desired intermediate as an oil that is used without purification (1.1 g, 77%).
(±)-3-fgr/-Butoxvcarbonvl-6-(l-methoxvcarbonvl-l-phenvl-methyIlthio>-7-chloro-
2,3,4,5-tetrahvdro-lff-benzo[|azepine: Treat a solution of 3-ter/-butoxycarbonyl-6-
(1 -carboxy-1 -phenyl-methylthio)-7-chloro-2,3,4,5-tetrahydrobenzo[rf]azepine (200 mg,
0.447 mmol) in anhydrous DMF (2 mL) with methyl iodide (317 mg, 2.237 mmol) and
potassium carbonate (310 mg, 2.237 mmol) for 1.5 h at ambient temperature. Add water
and extract the aqueous phase three times with EtOAc. Dry the organic phase over
MgSC>4 and concentrate to obtain the title compound that was used without purification.
Preparation 246
6-(3-Bromo-4-chloro-benz>lthio)-3-rert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine

2-Bromo-4-bromomethvl-l-chIoro-benzene: Use a method similar to the Preparation
184, using 3-bromo-4-chlorotoluene, to give the desired intermediate.
6-(3-Bromo-4-chloro-benzvIthio)-3-terr-butoxvcarbonvl-7-chloro-2,3,4,5-tetrahvdro-
1 /7-benzo[aTlazepine: Use a method similar to the Preparation 177, using 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-l//-
benzo[cGazepine and 2-bromo-4-bromomethyl-l-chloro-benzene, to give the title
compound.

Preparation 247
3-/er/-Butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydr(
1 //-benzo[rf]azepine

3-rgrr-Butoxvcarbonvl-7-chloro-6-(5-methoxvcarbonyl-pvridin-2-vlmethYlthio)-
2,3.4,5-tetrahydro-l/f-benzo[ bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[cf]azepine (2.13 g,
4.40 mmol), palladium acetate (35 mg, 0.156 mmol), 1,1'-
bis(diphenylphosphino)ferrocene (150 mg, 0.271 mmol) and triethylamine (1.30 mL) in
methanol (10 mL) and DMF (5 mL). Degas and then heat under a balloon filled with
carbon monoxide at 75 ° C for 10 h. Remove methanol in vacuo, and dilute the mixture
with water. Extract three times with EtOAc, dry over anhydrous Na2SO4, and
concentrated in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (7:1) to give the desired intermediate as a clear oil (1.86 g, 91%). MS
(APCI+) m/z 463 (M+H)+, 363 (M+H-Boc)+.
3-rgr tetrahydro-1 /7-benzo\d\azepine: Dissolve 3-rcr/-butoxycarbonyl-7-chloro-6-(5-
methoxycarbonyl-pyridin-2-ylmethylthio)-chloro-2,3,4,5-tetrahydro-l//-benzo[]azepine
(1.86 g, 4.03 mmol) in methanol (25 mL). Add 1M aqueous lithium hydroxide (12 mL)
and stir at ambient temperature overnight. Remove methanol in vacuo, and dilute the
mixture with cold 0.5M aqueous HC1 to pH 4. Add brine and extract three times with
EtOAc. Dry over anhydrous Na2SO4, and concentrate in vacuo to give the title compound
as an off-white solid (1.78 g, 95%). MS (APCI+) m/z 449 (M+H)+, 349 (M+H-Boc)+.

Preparation 248
6-(4-Bromo-thiophen-2-ylmethylthio)-3-ter/-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-
l//-benzo[cf]azepine

3-Bromo-S-bromomethyl-thiophene: Use the bromination procedure described in
Preparation 211 (Step 2), using (3-bromothiophen-2-yl)methanol (Synthesis 1983,1, 73-
75), to give the desired intermediate as a light brown liquid.
6-(4-Bromo-thiophen-2-vImethylthio)-3-fert-butoxvcarbi>nvl-7-chIoro-23,4,5-
tetrahydro-lif-benzo\d\azepine: Use a method similar to the Preparation 177, using 3-
ter^butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/7-
benzofrfjazepine and 3-bromo-5-bromomethyl-thiophene, to give the title compound as a
gum.
Example 315
7-Chloro-6-(2-isopropoxyethylthio)-2,3,4,5-tetrahydro-l//-benzo[ Hydrochloride

To a 4:1 mixture of 3-/crt-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro- l//-benzo[d]azepine and 3-ter/-butoxycarbonyl-7,9-dichloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (200 mg, 0.52 mmol) in
methanol (5 mL) under nitrogen, add potassium hydroxide (0.9 g, 16.1 mmol) at ambient
temperature. When the mixture becomes homogenous, heat at 55-60 °C for 2-3 h, until
TLC shows the disappearance of starting material. Cool to ambient temperature, add
aqueous saturated ammonium chloride, extract three times with diethyl ether, dry over
anhydrous MgSO4, and concentrate in vacuo. Dissolve the crude 3-tert-butoxycarbonyl-

7-chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[//]azepine in anhydrous THF (5 mL)
under nitrogen and add with stirring 1.0 M potassium r-butoxide in THF (1.0 mL) at
ambient temperature. After 10 min, add 2-(2-iodoethoxy)propane (223 mg, 1.04 mmol),
and allow the reaction to continue overnight. Dilute with aqueous saturated ammonium
chloride, extract the mixture three times with diethyl ether, dry over anhydrous MgSO4,
and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (12:1) to provide 3-tert-butoxycarbonyl-7-chloro-6-(2-isopropoxy-
ethylthio)-2,3,4,5-tetrahydro-l/f-benzo[*/]azepine as a clear oil (127 mg, 63 %). Use a
method similar to the General Procedure 1-4 to give the title compound as a white solid.
MS (ES+) m/z: 300 (M+H)+.
Example 316
(±)-7-Chloro-6-(l-pyridin-2-yl-ethyIthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine
Hydrochloride

Use a method similar to the General Procedure 7, using 3-terf-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[//]azepine and (±)-2-(l-
bromoethyl)-pyridine to give, after deprotection by a method similar to the General
Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 319 (M+H)+.
Example 317
(-)-7-Chloro-6-(l-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-li/-benzo[J]azepine
Succinate


Separate the enantiomers of (±)-7-chloro-6-(l-pyridin-2-yl-ethylthio)-2,3,4,5-
tetrahydro-l//-benzo[i/lazepine by chiral normal phase chromatography (Chiralpak AD
8x30 cm column, eluting with 0.2% DMEA in methanol). Take the second eluting
isomer and purity by chromatography on silica gel eluting with DCM/2M ammonia in
methanol (100:1 to 80:20).
Use the General Procedure 2-1 to give the title compound as a white solid (4.27 g,
33%). MS (ES+) m/r. 319 (M+H)+; ee = 99.4%; [a]20D -179° (c 0.5, CH3OH).
Example 318
(-)-7-Chloro-6-(l-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-l//-benzo[£(]azepine
Hydrochloride

Use a method similar to the General Procedure 7, except that the alkylation is
conducted at 0° C, to react 3-terf-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-l//-benzo[af]azepine with (/?)-(-)-1-(2-pyridinyl)ethanol
methanesulfonate ester. Use a method similar to the General Procedure 1-4 to give the
title compound as a white solid. MS (APCI+) m/r. 319 (M+H)+; ee = 98.6% [Chiral
HPLC: Chiralpak AD-H 0.46x15 cm column, eluting with 15:85 ethanol/heptane].
Example 319
(±)-7-Chloro-6-[l-(6-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride


Use a method similar to the Example 315, using 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[J]azepineand (±)-2-(l-
chloroethyl)-6-methylpyridine hydrochloride to give, after deprotection by a method
similar to the General Procedure 1 -4, the title compound as a tan solid. MS (ES+) m/z:
333 (M+H)+.
Example 320
7-Chloro-6-[l-(6-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride, Isomer 1

Use a method similar to the Preparation 177, except that the alkylation is
conducted at 0° C, to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-l//-benzo|aT|azepine with (J^-methanesulfonic acid l-(6-methyl-
pyridin-2-yl)-ethyl ester. Use a method similar to the General Procedure 1-5, basic
workup, and a method similar to the General Procedure 2-2 to give the title compound as
a white solid. MS (APCI+) m/z: 333 (M+H)+; ee >97%, tR = 6.53 min. (Chiral HPLC:
Chiralpak OJ 120A 4.6x250 mm, 45 °C; eluent: 20% isopropanol with 0.05%
triethylamine in SFC, flow rate 2 mL/min, UV detector at 234 nm).
Example 321
(±)-7-Chloro-6-[l-(3-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[cf]azepine Hydrochloride


Use a method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/]azepine with (±)-2-(l-
bromoethyl)-3-methyl-pyridine. Use a method similar to the General Procedure 1-5, basic
workup, and a method similar to the General Procedure 2-2 to give the title compound as
a white solid. MS (APCI+) m/r. 333 (M+H)+.
Example 322
(-)-7-Chloro-6-[l-(3-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride

Separate the enantiomers of (±)-7-chloro-[l-(3-methyl-pyridin-2-yl)-ethylthio]-
2,3,4,5-tetrahydro-l/f-benzo[ (Chiralpak AD 8x30 cm column, eluting with 85:15 heptane:0.2% DMEA in ethanol).
Take the second eluting isomer and purify by SCX column chromatography.
Use the General Procedure 2-2 to give the title compound as a white solid (60 mg,
43%). MS (ES+) m/r 333 (M+H)+; [a]20D -232° (c 0.5, CH3OH).
Example 323
(±)_7 benzoftflazepine Hydrochloride


Use a method similar to the Preparation 177 to react 3-/e^-butoxycarbonyI-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l^-benzo[rflazepinewith(±)-2-[l-
methanesulfonyloxy-(2,2,2-trifluoroethyl)]-pyridine. Use a method similar to the General
Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give
the title compound as a white solid. MS (APCI+) m/z: 373 (M+H)+.
Example 324
(±)-7-Chloro-6-(l-pyridin-2-yl-propylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine
Hydrochloride

Use method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[f/Jazepine with(±)-2-(l-
bromopropyl)pyridine. Use a method similar to the General Procedure 1-5, basic workup,
and a method similar to the General Procedure 2-2 to give the title compound as a white
solid. MS (APCI+) m/z: 333 (M+H)+.
Example 325
(±)-7-Chloro-6-[l-(pyridazin-3-yl)-ethylthio]-2,3,4,5-tetrahydro-l/f-benzo[]azepine
Oxalate

Dissolve (±)-l-pyridazin-3-yl-ethanol (38 mg, 0.31 mmol) in thionyl chloride
(0.14 mL) at 0°C and stir for 1 h at ambient temperature. Evaporate the mixture, add
toluene and evaporate again. Treat this residue with the thiolate prepared from 7-chloro-
6-dimethyIcarbamoylthio-2,3,4,5-tetrahydro- 177-benzo[rf]azepine-3-carboxylic acid tert-
butyl ether (0.1 g, 0.25 mmol) according to the General Procedure 7 in the presence of
potassium carbonate (0.3 g, 2.25 mmol) in DMF (3 mL) at 80°C for 16 h.

Use a method similar to the General Procedure 1-5, basic work-up, and a method
similar to the General Procedure 2-5 to give the title compound (38 mg, 37%). HRMS
calcd for C16H,9C1N3S 320.0988, found 320.0970.
Example 326
(+)-7-Chloro-6-[l-(pyridazin-3-yl)-ethylthio]-2,3,4,5-tetrahydro-l/f-benzo[|azepine
Oxalate

Dissolve (±)-l-pyridazin-3-yl-ethanol (0.29 g, 2.35 mmol) in thionyl chloride (1.0
mL) at 0°C and stir for 1 h at ambient temperature. Evaporate the mixture, add toluene
and evaporate again. Treat this residue with the thiolate prepared from 7-chloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro- l/7-benzo[rf]azepine-3-carboxylic acid tert-
butyl ether (0.72 g, 1.88 mmol) according to the General Procedure 7 in the presence of
potassium carbonate (2.60 g, 18.8 mmol) and tetrabutylammonium iodide (7 mg, 0.02
mmol) in DMF (20 mL) at 80 °C for 28 h. Separate the enantiomers by preparative
HPLC (Waters Symmetry C18 4.6 x 150 mm 3.5 micron column, 1 mL/min of 90:10 to
50:50:0.1% TFA in water:ACN over 25 min. Detector is at 254 nm) to obtain 3-tert-
butoxycarbonyl-7-chloro-6-[l-(pyridazin-3-yl)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzofeflazepine, isomer 1.
Use a method similar to the General Procedure 1-5, basic work-up, and a method
similar to the General Procedure 2-5 to give the title compound (56 mg, 7%). HPLC tR =
3.0 min (Chiralpak AD-H 4.6x150 mm, 3 micron column, 1.0 mL/min of 99.8:0.2
methanol/dimethyethylamine isocratic; detector at 225 nm); HRMS calc'd for
C|6Hi9ClN3S 320.0988, found 320.1001. [a]20D +160° (c 0.5, CH3OH).

Example 327
7-Chloro-6-(pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-lW-benzo[J]azepine
Hydrochloride

React 3-chloromethyl-pyridazine (prepared as described in WO 99/54333, WO
98/49166) (1.8 g, 11.0 mmol) with 3-tert-butoxycarbonyl-7-chloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[ according to the General Procedure 7 in the presence of tetrabutylammonium iodide (0.1
g, 0.27 mmol) at ambient temperature for 3 h.
Use a method similar to the General Procedure 1-4 to give the title compound as a
tan powder (1.9 g, 98 %): HRMS calcd for Ci5Hi6ClN3S 306.0832, found 306.0829.
Example 328
7-Chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-li/-benzo[c/]azepine
Hydrochloride

Use a method similar to the Preparation 177, using 3-ferT-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- l//-benzo[£/]azepine and 3-
bromomethyl-6-chloropyridazine to give 3-fer/-butoxycarbonyl-7-chloro-6-(6-chloro-
pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine. Use a method similar
to the General Procedure 1-4 to give the title compound as an off-white powder. MS
(APCI+) m/z: 340 (M+H)+.

Example 329
7-Chloro-6-[6-(2,2-dimethylpropoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-li/-
benzo[
To a stirred solution of neopentyl alcohol (105 mg, 1.19 mmol) in THF (5 mL) at
ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol) and continue stirring
for 3 h at ambient temperature. Add a solution of 3-terr-butoxycarbonyl-7-chloro-6-(6-
chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[ mmol) in THF (1 mL) and continue stirring overnight at ambient temperature and then at
60°C for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry
over anhydrous Na2SC>4, and concentrate in vacua. Purify by chromatography on silica
gel eluting with hexane/EtOAc (6:1) to give 3-terf-butoxycarbonyl-7-chloro-6-[6-(2,2-
dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1 //-benzo[//]azepine as a
clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)+, 392 (M+H-Boc)+. Use a method
similar to the General Procedure 1-4 to give the title compound as a white powder. MS
(APCI+) m/z: 392 (M+H)+, m/z: 322 (M+H-C5Hn)+.
Example 330
7-Chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-lH-benzo[d]azepine
Hydrochloride



To a 4:1 mixture of 3-te/-/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-l//-benzo[f/]azepine and3-terf-butoxycarbonyl-7,9-dich!oro-6-
dimethylcarbamoyIthio-2,3,4,5-tetrahydro-benzo[c/]azepine (108 mg, 0.281 mmol) in
methanol (3 ml), add potassium hydroxide pellets (504 mg, 9.0 mmol) and heat the
mixture 2 h at 50 °C. Cool the reaction to ambient temperature, add 2-
chloromethylthiophene (186 ^L, 1.406 mmol), and continue stirring for 30 min. Dilute
with EtOAc and water. Separate the layers and extract the aqueous layer three times with
EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (19:1) to give 3-rerf-
butoxycarbonyl-7-chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-benzo[t/]azepine
as a colorless oil (36 mg, 31%).
Use a method similar to the General Procedure 1-5, using 3-fert-butoxycarbonyl-
7-chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-benzo[£/]azepine to give, after
basic workup and a method similar to the General Procedure 2-2, the title compound as a
white solid. MS (ES+) m/z: 310 (M+H)+.
Example 331
(±)-7-Chloro-6-(3-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-W-
benzo[rfjazepine Trifluoroacetate

Use a method similar to the Preparation 177, using 3-/erf-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepineand(±)-2-(l-
chloroethyl)-3-cyanothiophene to give, after deprotection using a method similar to the
General Procedure 1-5, the title compound as a white solid. MS (APCI+) m/z: 349
(M+H)+.

Example 332
7-Chloro-6-(5-methylisoxazol-3-ylmethylthio)-2,3,4,5-tetrahydro-lfl-benzo[rfjazepine
Hydrochloride

To a 4:1 mixture of 3-ter/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-l//-benzo[]azepineand3-terf-butoxycarbonyl-7,9-dichloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rflazepine (200 mg, 0.521 mmol) in
methanol (3.3 mL) under nitrogen add potassium hydroxide (0.9 g, 16.1 mmol) at
ambient temperature. When the mixture becomes homogenous, heat at 55-60°C for 2-3 h,
until TLC shows the disappearance of starting material. Cool to ambient temperature,
add 3-(chloromethyl)-5-methylisoxazole (82 mg, 0.62 mmol) and continue stirring for 30
min. Add aqueous saturated ammonium chloride, extract the mixture three times with
diethyl ether, dry over anhydrous MgSC>4, and concentrate in vacuo. Treat a solution of
the crude material so obtained in DCM (2 mL) with 2M hydrogen chloride in ether
(excess) and continue stirring until TLC shows consumption of the starting material.
Concentrate in vacuo, purify by preparative TLC eluting with 19:1 DCM/saturated
ammonia in methanol, and convert to the hydrochloride by following a method similar to
the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z:
309 (M+H)+.
Example 333
7,9-Dichloro-6-(5-methylisoxazolO-ylmethylthio)-2,3,4,5-tetrahydro-l/7-
benzo[c(|azepine Hydrochloride


Obtain the free base of the title compound as a minor product from Example 332,
after preparative TLC eluting with 19:1 DCM/saturated ammonia in methanol. Use a
method similar to the General Procedure 2-2 to give the title compound as a white solid.
MS (APCI+) m/z: 343 (M+H)+.
Example 334
7-Chloro-6-(2-methy lthiazol-4-ylmethylthio)-2,3,4,5-tetrahydro-1 #-benzo[rf]azepine
Hydrochloride

Use a method similar to the Example 332, using 3-fer/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/lazepineand4-chloromethyl-2-
methylthiazole hydrochloride to give, after deprotection by the General Procedure 1-4,
the title compound as a white solid. MS (APCI+) m/z: 325 (M+H)+.
Example 335
6-(4-Bromothiophen-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

Use a method similar to the General Procedure 1-4, using 6-(4-bromothiophen-2-
ylmethylthio)-3-rerr-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[f/lazepineto
give the title compound as a white solid. MS (APCI+) m/z: 390 (M+H)+.
Example 336
7-Chloro-6-(4-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-lif-benzo[i/]azepine
Hydrochloride



Degas a stirred solution of 6-(4-bromothiophen-2-ylmethylthio)-3-ter/-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[]azepine (183 mg, 0.37 mmol),
zinc cyanide (50 mg, 0.42 mmol) and tetrakistriphenylphosphine paUadium(O) (30 mg,
0.026 mmol) in dry DMF. Purge with dry nitrogen, and heat at 120°C for 6 h. Dilute
with water, extract three times with EtOAc, dry over anhydrous MgSC>4 and concentrate
in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to
give 3-tert-butoxycarbonyl-7-chloro-6-(4-cyanothiophen-2-ylmethylthio)-2,3,4,5-
tetrahydro-l//-benzo[|azepine as an oil (85 mg, 52%). MS (APCI+) m/z: 335 (M+H-
Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a
white solid. MS (APCI+) m/z: 335 (M+H)+.
Example 337
7-Chloro-6-([l,2,4]-oxadiazol-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[*/]azepine
Hydrochloride

Use a method similar to the Preparation 177, using 3-terr-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[ chloromethyl-l,2,4-oxadiazole to give, after deprotection using a method similar to the
General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z 296 (M+H)+.
Examples 338-343 may be prepared essentially as described in Example 337 using
3-fer/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine and the appropriately substituted 5-chloromethyl-l,2,4-oxadiazole or 4-
chloromethyl-thiazole. MS (ES+) data are included in the Table below.



Example 344
7-ChIoro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine
Hydrochloride

Using a method similar to the General Procedure 7, react 3-tert-butoxycarbonyl-7-
chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (8 g, 20.8
mmol) with 2-picolyl chloride hydrochloride (3.41 g, 20.8 mmol). Dilute the reaction
mixture with diethyl ether and filter the precipitate. Concentrate the filtrate in vacuo,
dissolve the residue in diethyl ether (100 mL) and add IN aqueous HC1 (100 mL). Stir
the mixture for 16 h at ambient temperature. Separate, wash the aqueous layer with
diethyl ether, adjust the pH of the aqueous layer to 12 with sodium hydroxide and extract
with diethyl ether. Dry over Na2SO4 and concentrate in vacuo to give the free base of the
title compound. Use the General Procedure 2-2 to give the title compound as a white solid
(4.91 g, 78%). MS (ES+) m/z: 305 (M+H)+.
Example 345
7-Chloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[£/]azepine Succinate

Dissolve 3-ter/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[oT|azepine (1 equiv.) in methanol (0.1-0.4 M) and add potassium
hydroxide (8-20 equiv.). Stir at 60°C for 4-24 h. Cool the reaction mixture in an ice bath,
add picolyl chloride hydrochloride (1-3 equiv.) and stir the mixture at ambient
temperature for 16-24 h. Add a volume of toluene approximately equal to the volume of

the reaction mixture and concentrate the resulting mixture to approximately Vi the
resulting total volume and repeat this process once more. Add water until all solids
dissolve and separate the layers. Dry the organic layer over Na2SC>4 and filter. Heat the
solution (containing about 0.25-0.40 M of free base of the title compound) to 50-75°C
and then optionally seed with previously formed crystals of the title compound. Add
succinic acid (1-1.3 equivalents) in isopropyl alcohol (0.25-0.40M solution) to the
solution over 5-45 min. Cool the solution to 20-25°C over 1-3 h and filter, rinsing with a
solution of toluene/isopropyl alcohol (1:1). Dry the resulting solid under vacuum at
50-70°C/5 Torr to give the title compound as a white solid, mp 159-160 CC. Anal. Calc'd
for C20H23CIN2O4S: C, 56.80; H, 5.48; N, 6.62. Found: C, 56.56; H, 5.41; N, 6.57.
Example 346
7,9-Dichloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-rjenzo[//|azepine
Hydrochloride

Obtain as minor product from the reaction of the 4:1 mixture of 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li7-
benzo[rf|azepine and 3-ter/-butoxycarbonyl-7,9-dichloro-6-dirnethylcarbamoylthio-
2,3,4,5-tetrahydro-benzo[*/|azepine with 2-bromomethylpyridine hydrobromide, using a
method similar to the General Procedure 7. Treat a solution of the crude mixture in DCM
with 4M hydrogen chloride in dioxane (excess) overnight. Concentrate in vacuo and
purify by preparative TLC eluting with 19:1 DCM/saturated ammonia in methanol. Use a
method similar to the General Procedure 2-2 to give the title compound as an off-white
solid. MS (APCI+) m/z: 339 (M+H)+.
Example 347
7-Chloro-6-(2-fluorobenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Hydrochloride


To a mixture of 3-rm-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[rf]azepineand 3-tert-butoxycarbonyl-7,9-dichloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[rf]azepine (102 mg, 0.267 mmol) in
methanol (2 ml), add potassium hydroxide pellets (450 mg, 8.02 mmol) and heat the
mixture 3 h at 60 °C. Cool to ambient temperature, add aqueous saturated ammonium
chloride solution, extract three times with EtOAc, dry over anhydrous Na2SO4, and
concentrate in vacuo. Dissolve the crude thiophenol thus obtained in dry DCM (2 mL)
under nitrogen, and add DBU (80 QL, 0.54 mmol) and 2-fluorobenzyl bromide (65 DL,
0.54 mmol) with stirring. Stir overnight at ambient temperature, dilute with water, extract
three times with EtOAc, dry over anhydrous Na2SC>4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-/ert-
butoxycarbonyl-7-chloro-6-(2-fluorobenzylthio)-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine
as a yellow oil (31 mg, 25%). Use a method similar to the General Procedure 1-4 to give
the title compound as a white solid. MS (ES+) m/z: 322 (M+H)+.
Example 348
7-Chloro-6-(pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l^T-benzo[t/]azepine
Hydrochloride

Use a method similar to the Example 347, using 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l#-benzo[|azepineand3-
(bromomethyl)pyridine hydrobromide to give, after deprotection by a method similar to
the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 305
(M+H)+.

Example 349
7-Chloro-6-(5-fluoropyridin-2-ylmethylthio)-2,3,4,54etrahydro-l//-benzo[d]azepine
Succinate

Dissolve 3-rcr/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[ mmol) in methanol (10 mL) and heat the solution to reflux for 2 h. Cool the reaction
mixture to ambient temperature and remove the solvent in vacuo. Slurry the residue with
EtOAc (50 ml), and wash the slurry with a saturated NH4CI. Collect and dry the organic
phase over Na2SO4, remove the solvent under reduced pressure to obtain the intermediate
thiophenol as an oil. Dissolve the oil in DMSO (10 ml), add triethylamine (l.l ml, 8.2
mmol) and methanesulfonic acid 5-fluoro-pyridin-2-ylmethyl ester (500mg, 2.4 mmol).
Heat the reaction mixture to 60 °C for 1 h. Monitor the reaction by HPLC and TLC.
Cool the reaction to ambient temperature, add 1:1 hexane/EtOAc (80 ml) and wash the
organic layer with a 5% NaCl (3 X 30 ml). Collect the organic layer, concentrate, and
purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 ) to obtain
3-/erNbutoxycarbonyl-7-chloro-6-(5-fluoro-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-
l#-benzo[rf]azepine (519 mg, 89%). MS (ES+) m/r. 423 (M+H)+.
Use the General Procedure 1-4 to deprotect 3-ter/-butoxycarbonyl-7-chloro-6-(5-
fluoro-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (510 mg, 1.2
mmol). Purify by SCX chromatography followed by chromatography on silica gel
eluting with DCM/2M ammonia in methanol (99:1 to 90:10). Use the General Procedure
2-1 to give the title compound (370 mg, 70%). MS (ES+) m/r. 323 (M+H)+.

Example 350
7-Chloro-6-(6-chloropyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Hydrochloride

Use a method similar to the Preparation 177, using 3-ferf-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-benzo[rf]azepineand2-
bromomethyl-6-chloropyridine hydrochloride to give, after deprotection by a method
similar to the General Procedure 1-4, the title compound as an off-white solid. MS
(APCI+) m/z: 339 (M+H)+.
Examples 351-360 may be prepared essentially as described in Example 350 b
using 3-rcr/-butoxycarbonyl-7-chloro-6-dimethyIcarbamoylthio-2,3,4,5-tetrahydro-lfl
benzo[c(]azepine and the appropriately substituted chloromethylpyridine,
bromomethylpyridine or chloromethylquinoline. MS (ES+) data are included in the T
below.




Example 361
7-Chloro-6-(3-methoxypyridin-2-yImethylthio)-2,3,4,5-tetrahydro-17/-benzo[c/]azepine
Hydrochloride



Use a method similar to the Example 315, using 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[t/]azepineand 2-chloromethyl-3-
methoxypyridine to give, after deprotection by a method similar to the General Procedure
1-4, the title compound as a white solid (71 mg). MS (APCI+) m/z: 335 (M+H)+.
Example 362
7-Chloro-6-(6-methoxypyridin-2-ylmethylthio)-2,3,4,5-terrahydro-li/-benzo[rf]azepine
Hydrochloride

Use a method similar to the Example 330, using 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[f/Jazepine and 2-chloromethyl-6-
methoxypyridine hydrochloride to give, after deprotection by a method similar to the
General Procedure 1-4, the title compound as a white solid (120 mg). MS (APCI+) m/z:
335 (M+H)+.
Example 363
6-(5-Butylpyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-li/-benzo[fiT]azepine
Hydrochloride


Use a method similar to the Example 315, using 3-terf-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- l//-benzo[d]azepine and 5-butyl-2-
chloromethylpyridine hydrochloride to give the title compound as a white solid. MS
(APCI+) m/z: 330 (M+H)+.
Example 364
7-Chloro-6-[5-(3-methylbutyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-lfl-
benzo[]azepine Hydrochloride

To 6-(5-bromo-pyridin-2-ylmethylthio)-3-ferf-butoxycarbonyl-7-chloro-2,3,4,5-
tetrahydro-l//-benzo[J]azepine (219 mg, 0.452 mmol) and
dichloro[ 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct
(18 mg, 0.022 mmol) under dry nitrogen add with stirring a solution of 0.5M
3-methylbutylzinc bromide in THF (4.6 mL, 2.3 mmol). Degas, purge with dry nitrogen,
and stir overnight at ambient temperature. Dilute with EtOAc, wash with water, dry over
anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (5:1) to give 3-/erf-butoxycarbonyl-7-chloro-6-[5-(3-methyl-
butyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-lfl-benzo[cf]azepine as an oil (160 mg,
75%). MS (APCI+) m/z: 475 (M+H)+. Use a method similar to the General Procedure 1-4
to give the title compound as a tan solid. MS (APCI+) m/z: 375 (M+H)+.

Example 365
7-Chloro-6-[5-(2,2-dimethylpropyI)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine Hydrochloride

To a stirred solution of 1.0 M neopentyl magnesium chloride in diethyl ether (50
mL, 50 mmol) at -78 °C under nitrogen, add via syringe a solution of 0.5 M zinc chloride
in THF (100 mL, 50 mmol). Warm gradually to ambient temperature and transfer via
syringe of this solution (25 mL, -8.33 mmol) to a stirred solution of 3-tert-
butoxycarbonyl-6-(5-bromo-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l/f-
benzo[|azepine (300 mg, 0.62 mmol) in THF (2 mL) at ambient temperature. Add
dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (50
mg, 0.061 mmol) and heat at 65°C for 6 h. Cool to ambient temperature, dilute with
EtOAc, wash with water, dry over anhydrous MgSC>4 and concentrate in vacuo. Purify by
chromatography onr silica gel eluting with hexane/EtOAc (6:1) to give 3-terf-
butoxycarbonyl-7-chloro-6-[5-(2,2-dimethyl-propyl)-pyridin-2-ylmethylthio]-2,3,4,5-
tetrahydro-l#-benzo[c/]azepine as an oil (69 mg, 24%). MS (APCI+) m/z: 501 (M+H)+.
Use a method similar to the General Procedure 1-4 to give the title compound as a white
powder. MS (APCI+) m/z: 375 (M+H)+.
Example 366
7-Chloro-6-(5-cyclohexylpyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[cf]azepine
Hydrochloride


To a mixture of 6-(5-bromopyridin-2-ylmethylthio)-3-ferf-butoxycarbonyl-7-
chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (146 mg, 0.30 mmol) and dichloro[l,l'-
bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (12 mg, 0.015
mmol) under dry nitrogen add with stirring a solution of 0.5 M cyclohexylzinc bromide in
THF (3.0 mL, 1.5 mmol). Degas, purge with dry nitrogen, and stir overnight at 60 °C.
Cool to ambient temperature, dilute with EtOAc, wash with water, dry over anhydrous
MgSC>4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(5-cyclohexyl-pyridin-2-
ylmethylthio)-2,3,4,5-tetrahydro-l//:-benzo[fif]azepine as an oil (46 mg, 32%). MS
(APC1+) m/z: 487 (M+H)+. Use a method similar to the General Procedure 1-4 to give the
title compound as a white solid. MS (APCI+) m/z: 387 (M+H)+.
Example 367
7-Chloro-6-(5-cyclopentylpyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-lfl-
benzo[rf]azepine Succinate

Use a method similar to the Example 366 to react 6-(5-bromo-pyridin-2-
ylmethylthio)-3-rerf-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[£/]azepine
with a solution of cyclopentylzinc bromide in THF. Use a method similar to the General
Procedure 1-4, basic workup, and a method similar to the General Procedure 2-1 to give
the title compound as a tan solid. MS (APCI+) m/z: 373 (M+H)+.

Example 368
7-Chloro-6-(5-cyclohexylmemylpyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l/7-
benzo[rf]azepine Hydrochloride

Use a method similar to the Example 366 to react 6-(5-bromo-pyridin-2-
ylmethylthio)-3-ter/-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l^-benzo[t/]azepine
with cyclohexylmethylzinc bromide. Use a method similar to the General Procedure 1-5,
basic workup, and a method similar to the General Procedure 2-2 to give the title
compound as a white solid. MS (APCI+) m/z: 401 (M+H)+.
Example 369
7-Chloro-6-(3,4,5,6-tetrahydro-2//-[l,3']bipyridinyl-6'-ylmethylthio)-2,3,4,5-tetrahydro-
l//-benzo[]azepine Hydrochloride

In a sealed tube, add tris(dibenzylideneacetone)dipalladium(0) (3.44 rng, 0.00376
mmol) and 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (4.98 mg, 0.00752 mmol) to a
mixture of 6-(5-bromopyridin-2-ylmethylthio)-3-/ert-butoxycarbonyl-7-chloro-2,3,4,5-
tetrahydro-l#-benzo[]azepine (242 mg, 0.501 mmol), sodium tert-butoxide (96 mg, 1.0
mmol), 18-crown-6 (13 mg, 0.050 mmol) and piperidine (496 |^L, 5.01 mmol) in toluene
(3 mL). Flush the mixture with nitrogen and heat overnight. Cool to ambient
temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous

Na2SC>4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1) to give 3-ferf-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2#-
[l,3']bipyridinyl-6'-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[dT]azepine as a yellow oil
(179mg,73%).
Use a method similar to the General Procedure 1-5, using 3-/ert-butoxycarbonyl-
7-chloro-6-(3,4,5,6-tetrahydro-2//-[l,3']bipyridinyl-6'-ylmethylthio)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine to give, after basic workup and a method similar to the General
Procedure 2-2, the title compound as a yellow solid. MS (ES+) m/z: 388 (M+H)+.
Example 370
7-Chloro-6-(5-pyirolidin-l-yI-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-li/-
benzo[t/)azepine Hydrochloride

Use a method similar to the Example 369, using 6-(5-bromopyridin-2-
ylmethylthio)-3-terf-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lJc/-benzo[rf]azepineanc
pyrrolidine to give the title compound as a pale yellow solid. MS (ES+) m/z: 374
(M+H)+.
Example 371
6-(5 - Azepan-1 -yl-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5 -tetrahydro-1H-
benzo[rf]azepine Hydrochloride


Use a method similar to the Example 369, using 6-(5-bromopyridin-2-
ylmethylthio)-3-/e/-r-butoxycarbonyl-7-chIoro-2,3,4,5-tetrahydro-l//-benzo[]azepineand
homopiperidine to give the title compound as a yellow solid. MS (ES+) m/z 402 (M+H)+.
Example 372
7-Chloro-6-(3,4,5,6-tetrahydro-2//-[l,2']bipyridinyl-5'-ylmethylthio)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine Hydrochloride

Use a method similar to the Example 369, using 3-terf-butoxycarbonyl-7-chloro-
6-(6-chloropyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[J|azepineand
piperidine, to give the title compound as a white solid. MS (ES+) m/z: 388 (M+H)+.
Example 373
7-Chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-l^-
benzo[rf]azepine Hydrochloride


Dissolve 3-terr-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-
2,3,4,5-tetrahydro-l//-benzo[]azepine (1.0 g, 2.07 mmol), tetrakistriphenylphosphine
palladium(O) (120 mg, 0.104 mmol), cuprous iodide (20 mg, 0.105 mmol), triethylamine
(2.60 mL) and l-ethynyl-4-fluorobenzene (500 mg, 4.16 mmol) in DMF (8 mL). Degas
the mixture, purge with nitrogen, and heat at 65 ° C for 3 days. Dilute the mixture with
water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in
vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (50:1) to give
3-?er/-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-
2,3,4,5-tetrahydro-li/-benzo[]azepine as a tan foam (1.02 g, 95%). MS (APCI+) mJr.
523 (M+H)+, 423 (M+H-Boc)+. Use a method similar to the General Procedure 1-4 to
give the title compound as a tan powder. MS (APCI+) m/z: 423 (M+H)+.
Example 374
(Z)-7-Chloro-6-{5-[2-(4-fluorophenyI)vinyl]-pyridin-2-ylmethylthio}-2,3,4,5-tetrahydro-
l//-benzo[]azepine Hydrochloride

Dissolve 3-/ert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-
ylmethylthio]-2,3,4,5-tetrahydro-l//-benzo[rflazepine (l.o g, 1.9 mmol), Lindlar catalyst
(240 mg), and quinoline (0.8 mL) in methanol (30 mL). Degas, purge with nitrogen, and
stir under a balloon of hydrogen for 36 h. Filter the mixture and wash the catalyst with

additional methanol. Concentrate the filtrate in vacuo. Purify by chromatography on
silica gel eluting with hexane/EtOAc (8:1) to give (Z)-3-ter/-butoxycarbonyl-7-chloro-6-
{5-[2-(4-fluoro-phenyl)-vinyl]-pyridin-2-yImethylthio}-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine as a clear oil (630 mg, 63%). MS (APCI+) m/z: 525 (M+H)+, 425
(M+H-Boc)+. Use a method similar to the General Procedure 1-4 to give the title
compound as a pale yellow solid. MS (APCI+) m/z: 425 (M+H)+.
Example 375
7-Chloro-6-[5-(2-fluoro-4-trifluoromethylbenzylcarbamoyl)-pyridin-2-ylmethylthio]-
2,3,4,5-tetrahydro-l//-benzo[|azepine Succinate

Dissolve 3-/ert-butoxycarbonyl-6-(5-carboxypyridin-2-ylmethylthio)-7-chloro-
2,3,4,5-tetrahydro-lfl-benzo[c/lazepine (300 mg, 0.67 mmol) in DMF (5.0 mL). Treat
successively with HATU (305 mg, 0.802 mmol), ATAT-diisopropylethylamine (140 uL,
0.804 mmol) and 2-fluoro-4-(trifluoromethyl)benzylamine (260 mg, 1.34 mmol). Stir
overnight at 40° C. Dilute the mixture with water, extract three times with EtOAc, dry
over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica
gel eluting with hexane/EtOAc (3:1) to give 3-/err-butoxycarbonyl-7-chloro-6-[5-(2-
fluoro-4-trifluoromethyl-benzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine as a foam (409 g, 98%). Use a method similar to the General
Procedure 1-4 to give, after basic work-up and a method similar to the General Procedure
2-1, the title compound as an off-white solid. MS (APCI+) m/z: 524 (M+H)+.

Example 376
7-Chloro-6-[5-(2,2-dimethylpropylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-
tetrahydro-1 H-benzo[t/]azepine Succinate

Use a method similar to the Example 375, using 3-/ert-butoxycarbonyl-6-(5-
carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[£/]azepineand
neopentylamine, to give the title compound as an off-white solid. MS (APCI+) m/z: 418
(M+H)+.
Example 377
7-Chloro-6-[5-(4-fluoro-benzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-
l#-benzo[rf|azepine Succinate

Use a method similar to the Example 375, using 3-/ert-butoxycarbonyl-6-(5-
carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro- l//-benzo[c/Jazepine and 4-
fluorobenzylamine, to give the title compound as an off-white solid. MS (APCI+) m/z:
456 (M+H)+.
Example 378
7-Chloro-6-[5-(cyclohexylmethylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-
l//-benzo[cf]azepine Hydrochloride


Use a method similar to the Example 375, using 3-te/-/-butoxycarbonyl-6-(5-carboxy-
pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine and
aminomethylcyclohexane to give, after deprotection by the General Procedure 1 -4, the
title compound as a white solid. MS (APCI+) m/r. 444 (M+H)+.
Example 379
6-(5-/ert-Butylcarbamoyl-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l/f-
benzo[rfjazepine Hydrochloride

Use a method similar to the Example 375, using 3-tert-butoxycarbonyl-6-(5-
carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine and
/ert-butylamine to give, after deprotection by the General Procedure 1-4, the title
compound as an off-white solid. MS (APCI+) m/r. 404 (M+H)+.
Example 380
7-Chloro-6-(4-trifluoromethoxybenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride


To a 4:1 mixture of 3-ferr-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro- l//-benzo[rf]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/Jazepine (102 mg, 0.27 mmol) in
methanol (1.7 mL) under nitrogen, add potassium hydroxide (0.9 g, 16.1 mmol) at
ambient temperature. When the mixture becomes homogenous, heat at 55-60 °C for
2-3 h, until TLC shows the disappearance of starting material. Cool to ambient
temperature, add aqueous saturated ammonium chloride solution, extract three times with
diethyl ether, dry over anhydrous MgSC>4, and concentrate in vacuo. Dissolve the crude
3-terf-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[]azepinein
anhydrous DCM (2 mL) under nitrogen. Add with stirring DBU (80 |aL, 0.532 mmol)
and 4-(trifluoromethoxy)benzyl bromide (77 pL, 0.53 mmol) at ambient temperature and
allow the reaction to continue overnight. Dilute with aqueous saturated ammonium
chloride solution, extract three times with diethyl ether, dry over anhydrous MgSCH, and
concentrate in vacuo. Treat a solution of the crude 3-tert-butoxycarbonyl-7-chloro-6-(4-
trifluoromethoxy-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[c/lazepine in DCM (2 mL)
with 2M hydrogen chloride in ether (excess) and continue stirring until TLC shows
consumption of starting material. Concentrate in vacuo and triturate the obtained solid
with ether/pentane (10:90). Purify by preparative TLC eluting with 19:1 DCM/saturated
ammonia in methanol and convert to the hydrochloride by following a method similar to
the General Procedure 2-2 to give the title compound as a white solid (48 mg, 43%). MS
(APCI+) m/r. 388 (M+H)+.
Examples 381-383 may be prepared essentially as described in Example 380 by
using 3-/ert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[tf|azepine and the appropriately substituted benzyl bromide. Example 382 may be
purified after deprotection by preparative reverse phase HPLC [Column: YMC ODS-AQ

120A 20x250mm [S10-20^m], eluent: gradient from 95:5 to 5:95 A/B, flow rate: 15
mL/min; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05%
TFA, 1% isopropanol]. MS (ES+) data are included in the Table below.

Example 384
7-Chloro-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[^azepineTrifluoroacetate

Use a method similar to the Example 380 to react 3-terf-butoxylcarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1 //-benzo[c(]-azepine with 4-
fluorobenzyl bromide. Purify by preparative reverse phase HPLC [Column: YMC ODS-
AQ 120A 20 x 250mm [S10-20um], eluent: gradient from 95:5 to 5:95 A/B, flow rate: 15
mL/min; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05%
TFA, 1% isopropanol] to give the title compound as a white solid. MS (ES+) m/z: 322
(M+H)+.

Examples 385-386 may be prepared essentially as described in Example 384 by
using 3-terr-butoxycarbonyI-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[oT)azepine and the appropriately substituted benzyl bromide. MS (ES+) data are
included in the Table below.

Example 387
7-Chloro-6-(3,4-dichlorobenzylthio)-2,3,4,5-tetrahydro-l//-benzo[d]azepine
Trifluoroacetate

To a 4:1 mixture of 3-/ert-butoxycarbonyl-7-chloro-6-dirnethylcarbamoylthio-
2,3,4,5-tetrahydro-l//-benzo[^azepineand3-te^butoxycarbonyl-7,9-dichloro-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/7-benzo|>/]azepine (200 mg, 0.521 mmol) in
methanol (3.3 mL) under nitrogen add potassium hydroxide (0.9 g, 16.07 mmol) at
ambient temperature. When the mixture becomes homogenous, heat at 55-60°C for 2-3 h,
until TLC shows the disappearance of starting material. Cool to ambient temperature,

add aqueous saturated ammonium chloride solution, extract three times with diethyl ether,
dry over anhydrous MgSO4, and concentrate in vacuo. Dissolve the crude 3-tert-
butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[rf]azepinein
anhydrous DCM (5 mL) under nitrogen. Add PS-DIEA (Argonaut, 3.83 mmol/g, 410
mg, 1.57 mmol) and 3,4-dichlorobenzyl bromide (100 uL, 0.586 mmoi) at ambient
temperature and allow the reaction to continue overnight. Filter the reaction mixture from
the resin and rinse with DCM (2 mL), methanol (2 mL), DCM (2 mL), and methanol
(2 mL). Concentrate in vacuo. Treat a solution of the crude 3-rer/-butoxycarbonyl-7-
chloro-6-(3,4-dichloro-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[|azepineinDCM
(2 mL) with a 2M hydrogen chloride in ether (excess) and continue stirring until TLC
shows consumption of starting material. Concentrate in vacuo and triturate the obtained
solid with ethenpentane (10:90). Purify by preparative reverse phase HPLC (Column:
Xterra Prep RP18 19x250mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent
B: acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min) to give the title
compound as a white solid (97 mg, 38%). MS (APCI+) m/z: 374 (M+H)+.
Examples 388-393 may be prepared essentially as described in Example 387 by
using 3-/err-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-17/-
benzo[rf]azepine and the appropriately substituted benzyl bromide. MS (ES+) data are
included in the Table below.




Example 394
7,9-Dichloro-6-(3-fluorobenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Trifluoroacetate




Obtain as minor product from the reaction of the 4:1 mixture of3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-
benzo[i/|azepineand3-fert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-benzo[rf]azepine with 3-fluorobenzyl bromide, using a method similar
to the Example 387. Deprotect and isolate the title compound as a white solid after
preparative reverse phase HPLC. MS (ES+) m/z: 356 (M+H)+.

Example 395
7,9-Dichloro-6-(3,4,5-trifluorobenzylthio)-2,3,4,5-tetrahydro-li/-benzo[rf]azepine
Trifluoroacetate

Obtain as minor product from the reaction of the 4:1 mixture of 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/T-
benzo[ 2,3,4,5-tetrahydro-benzo[rf)azepine with 3,4,5-trifluorobenzyl bromide, using a method
similar to the Example 387. Deprotect and isolate the title compound as a white solid
after preparative reverse phase HPLC. MS (APCI+) m/z: 392 (M+H)+.
Example 396
7-ChIoro-6-(2-nitro-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine Hydrochloride

Use a method similar to the Example 387, using 3-/ert-butoxylcarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lJ7-benzo[]-azepineand2-nitrobenzyl
bromide to give, after chromatography eluting with hexane/EtOAc (10:1) and
deprotection by the General Procedure 1-4, the title compound as an off-white powder.
MS (APCI+) m/z: 349 (M+H)+.
Examples 397-399 may be prepared essentially as described in Example 396 by
using 3-fer/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-

benzo[rf]azepine and the appropriately substituted benzyl bromide. MS (ES+) data are
included in the Table below.

Example 400
7,9-Dichloro-6-(3,5-Z»w-trifluoromethylbenzylthio)-2,3,4,5-tetrahydro-l//-
benzofcflazepine Hydrochloride (2148393)

Obtain as minor product from the reaction of the 4:1 mixture of 3-terf-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine and 3-ter/-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-benzo[f/]azepine with 3,5-bis-trifluoromethylbenzyl bromide, using a
method similar to the Example 396. Deprotect the crude mixture and purify by
preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm; solvent A: 10
mM aqueous ammonium carbonate; solvent B: acetonitrile; 30-100% B over 20 minutes;

flow rate 25 mL/min). Use a method similar to the General Procedure 2-2 to give the title
compound as a white solid. MS (APCI+) m/z: 474 (M+H)+.
Example 401
7-Chloro-6-(2,6-difluorobenzylthio-)2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Hydrochloride

Use a method similar to the Example 330, using 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l#-benzo[^azepineand2,6-difluorobenzyl
bromide to give, after deprotection by the General Procedure 1-4, the title compound.
Example 402
7-Chloro-6-(2-trifluoromethylbenzylthio)-2,3,4,5-tetrahydro-U7-benzo[]azepine
Hydrochloride

Use a method similar to the Example 347 to react 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[d]azepine with 2-
trifluoromethylbenzyl bromide. Use a method similar to the General Procedure 1-4 to
give the title compound as a waxy tan solid. MS (APCI+) m/z: 372 (M+H)+.
Example 403
7-Chloro-6-(4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-benzo[i/]azepine
Hydrochloride


Use a method similar to the Preparation 177, using 3-/erf-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[ (bromomethyl)benzoate to give, after deprotection by the General Procedure 1-4, the title
compound as a white solid. MS (ES+) m/z: 362 (M+H)+.
Example 404
7-Chloro-6-(3-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

Use a method similar to the Example 347 to react 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-benzo[rf|azepine with methyl 3-
(bromomethyl)benzoate. Use a method similar to the General Procedure 1-5, basic
workup, and a method similar to the General Procedure 2-2 to give the title compound.
MS (APCI+) m/z: 362 (M+H)+.
Example 405
7-Chloro-6-(2-methoxycarbonylbenzyIthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride


Use a method similar to the Example 347, using the 4:1 mixture of 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[J]azepineand3-/err-butoxycarbonyl-7>9-dichloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-benzo[c/]azepine with methyl 2-(bromomethyl)benzoate. Use a method
similar to the General Procedure 1-4 and purify by preparative reverse phase HPLC
(Column: Xterra Prep RP18 19x250mm; solvent A: 10 mM aqueous ammonium
carbonate, solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min).
Use a method similar to the General Procedure 2-2, to give the title compound as a white
solid. MS (ES+) m/z: 362 (M+H)+.
Example 406
7,9-Dichloro-6-(2-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-l^-benzo[rf]azepine
Hydrochloride

Obtain the free base of the title compound as a minor product from Example 405,
after preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm; solvent A:
10 mM aqueous ammonium carbonate; solvent B: acetonitrile; 30-100% B over 20
minutes; flow rate 25 mL/min). Use a method similar to the General Procedure 2-2 to
give the title compound as a white solid. MS (ES+) m/z: 396 (M+H)+.
Example 407
6-(4-Benzoylbenzylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Hydrochloride


Use a method similar to the Example 380 to react 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/]azepine with 4-
(bromomethyl)benzophenone. Purify by preparative reverse phase HPLC (Column:
Xterra Prep RP18 19x250mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent
B: acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min). Use a method similar
to the General Procedure 2-2 to give the title compound as a white solid. MS (ES+) m/z:
408 (M+H)+.
Example 408
7-Chloro-6-[4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[]azepine Succinate

Use a method similar to the General Procedure 7, using 3-ter/-butoxycarbonyl-7-
chloro-6-dimemylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[*/lazepine (577 mg, 1.5
mmol) and l-(4-bromomethylphenoxy)-3,3-dimethylbutan-2-one (556 mg, 1.95 mmol) to
give, after chromatography on silica gel eluting with EtOAc/hexane (1:5), 3-tert-
butoxycarbonyl-7-chloro-6-[4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-
tetrahydro-l//-benzo[rfjazepine as a colorless oil (669 mg, 86%). MS (ES+) m/z: 518
(M+H)+.
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-[4-(3,3-dimethyI-2-oxo-butoxy)-benzylthio]-2,3,4)5-
tetrahydro-l//-benzo[c/)azepine (669 mg, 1.29 mmol). Purify by chromatography on
silica gel eluting with DCM/2M ammonia in methanol (92:8) to give the free base of the
title compound as a colorless oil (349 mg, 64%). MS (ES+) m/z: 418 (M+H)+. Use a
method similar to the General Procedure 2-1 to give the title compound.

Example 409
7-Chloro-6-[3-chIoro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Use a method similar to the Example 408, using 3-terf-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[ 3-chlorophenoxy)-3,3-dimethylbutan-2-one to give the title compound. MS (ES+) m/z:
452 (M+H)+.
Example 410
7-Chloro-6-(4-methanesulfonylmethyl-benzylthio)-2,3,4,5-tetrahydro-l//-
benzo[c/)azepine Hydrochloride

Use a method similar to the General Procedure 1-4, using 3-^rr-butoxycarbonyl-
7-chloro-6-(4-methanesulfonylmethyl-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine
to give the title compound as a white solid. MS (ES+) m/z: 396 (M+H)+.
Example 411
7-Chloro-6-(5-chloro-thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[|azepine
Hydrochloride



Use a method similar to the Example 387, using 3-teA-/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- l//-benzo[]azepine and 2-chloro-5-
(chloromethyl)thiophene to give, after hydrochloride formation by the General Procedure
2-2, the title compound as a brown solid. MS (APCI+) m/z: 344 (M+H)+.
Example 412
7-Chloro-6-(pyridin-4-yImethylthio)-2,3,4,5-tetrahydro-17/-benzo[c/]azepine
Hydrochloride

NH (HCI)X
Use a method similar to the Example 387, using 3-/er/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- l//-benzo[c(|azepine and 4-
bromomethylpyridine hydrobromide to give, after hydrochloride formation by the
General Procedure 2-2, the title compound as a white solid. MS (APCI+) m/z: 305
(M+H)+.
Example 413
7-Chloro-6-(6-methyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l/f-benzo[fi(]azepine
Hydrochloride



Use a method similar to the Example 387, using 3-/e/-f-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rfjazepineand2-chloromethyl-6-
methylpryidine to give, after chromatography on silica gel eluting with hexane/EtOAc
(4:1) and deprotection by the General Procedure 1-4, the title compound as a white solid.
MS (ES+) m/z: 319 (M+H)+.
Example 414
7-Chloro-6-[3-fluoro-4-(3-methylbutyl)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[



To6-(4-bromo-3-fluorobenzylthio)-3-/err-butoxycarbonyl-7-chloro-2,3,4,5-
tetrahydro-l//-benzo[d]azepine (0.210 mg, 0.42 mmol) and dichloro[l,l'-
bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (17 mg, 0.021
mmol) add 0.5 M 3-methyIbutylzinc bromide in THF (4.2 mL, 2.10 mmol). Degas, purge
with dry nitrogen, and stir overnight at 80 °C. Cool to ambient temperature, dilute with
EtOAc, wash with water, dry over anhydrous MgSCU and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-feT-N
butoxycarbonyl-7-chloro-6-[3-fluoro-4-(3-methylbutyl)-benzylthio]-2,3,4,5-tetrahydro-
l/f-benzo[]azepine as a yellow oil (85 mg, 42%). Use a method similar to the General
Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 392 (M+H)+.
Example 415
7-Chloro-6-(4-cyclohexylmethyl-3-fluorobenzylthio)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate




Use a method similar to the Example 414 to react 6-(4-bromo-3-
fluorobenzylthio)-3-rert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[d]azepine
with (cyclohexyl)methylzinc bromide. Use a method similar to the General Procedure 1-
4, basic work-up, and a method similar to the General Procedure 2-1, to give the title
compound as a white solid. MS (ES+) mJz: 418 (M+H)+.
Example 416
7-Chloro-6-(4-cyclohexyl-3-fluorobenzylthio)-2,3,4,5-tetrahydro-l/f-benzo[£/]azepine
Hydrochloride

Use a method similar to the Example 414, using 6-(4-bromo-3-fluorobenzylthio)-
3-/er^butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[]azepineand
cyclohexylzinc bromide. Use a method similar to the General Procedure 1-4, basic work-
up, and a method similar to the General Procedure 2-1, to give the title compound as a
white solid. MS (ES+) m/z: 404 (M+H)+.
Example 417
7-Chloro-6-(2,5'-difluoro-2'-methoxybiphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine Hydrochloride



Degas a stirred mixture of 6-(4-bromo-3-fluorobenzylthio)-3-ter/-butoxycarbonyl-
7-chloro-2,3,4,5-tetrahydro-l//'-benzo[£/]azepine (212 mg, 0.424 mmol), 5-fluoro-2-
methoxybenzene boronic acid (108 mg, 0.636 mmol), potassium carbonate (292 mg, 2.12
mmol), triphenylphosphine (11 mg, 0.0424 mmol) and bis(triphenylphosphine)-
palladium(II) chloride (15 mg, 0.0212 mmol) in dioxane (3 mL) and water (1 mL). Purge
with dry nitrogen and heat at 100°C for 5 h. Cool to ambient temperature, add water,
extract three times with EtOAc, dry over anhydrous Na2SC>4 and concentrate in vacuo.
Purify by chromatography on silica gel eluting with hexane/ EtOAc (9:1) to give 3-tert-
butoxycarbonyl-7-chloro-6-(2,5'-difluoro-2'-methoxy-biphenyl-4-ylmethyhhio)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine as yellow oil (216 mg, 93%). Use a method similar to the
General Procedure 1 -4 to give the title compound as a yellow foam. MS (ES+) mJz: 446
(M+H)+.
Example 418
7-Chloro-6-(2'-chloro-2-fluorobiphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[rf|azepine Hydrochloride




Use a method similar to the Example 417, using 2-chlorophenylboronic acid to
give, after deprotection by the General Procedure 1-4, the title compound as a white solid.
MS (ES+) m/z: 432 (M+H)+.

Example 419
7-Chloro-6-(3-fluoro-4-piperidin-l-yl-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[*/]azepine
Hydrochloride

NH (HCI),
In a sealed tube, add tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol)
and 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (19 mg, 0.029 mmol) to a mixture of 6-
(4-bromo-3-fluorobenzylthio)-3-ter^butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[d]azepine (957 mg, 1.91 mmol), sodium terf-butoxide (367 mg, 3.83 mmol), 18-
crown-6 (50 mg, 0.191 mmol) and piperidine (944 \il, 9.57 mmol) in toluene (10 mL).
Flush the mixture with nitrogen and heat overnight. Cool to ambient temperature, dilute
with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and
concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc
(9:1) to give 3-/ert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-piperidin-l-yl-benzylthio)-
2,3,4,5-tetrahydro-li/-benzo[rf]azepine as a yellow oil (511 mg, 33%). Use a method
similar to the General Procedure 1-4 to give the title compound as a white solid. MS
(ES+) m/z: 405 (M+H)+.
Example 420
7-Chloro-6-(3-fluoro-4-pyrrolidin-l-yl-benzylthio)-2,3,4,5-tetrahydro-l/T-
benzo[rf]azepine Hydrochloride
o



Use a method similar to the Example 419 to react 6-(4-bromo-3-
fluorobenzylthio)-3-/er/-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[d]azepine
with pyrrolidine. Use a method similar to the General Procedure 1-4 to give the title
compound as a white solid. MS (ES+) m/z: 391 (M+H)+.
Example 421
6-(4-Azepan-l-yl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-l/f-benzo[c/]azepine
Hydrochloride




Use a method similar to the Example 419 to react 6-(4-bromo-3-
fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-li?-benzo[d]azepine
with homopiperidine. Use a method similar to the General Procedure 1-4 to give the title
compound as a white solid. MS (ES+) m/z: 419 (M+H)+.
Example 422
7-Chloro-6-(4-chloro-3-pyrrolidin-l-yl-benzylthio)-2,3,4,5-tetrahydro-l/f-
benzo[]azepine hydrochloride
UONH (HGI)*
Use a method similar to the Example 419, using 6-(3-bromo-4-chloro-benzylthio)-
3-/ert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lfl-benzo[^lazepine and pyrrolidine to
give, after deprotection using a method similar to the General Procedure 1-4, the title
compound as a white solid. MS (ES+) m/z: 407 (M+H)+.

Example 423
7-Chloro-6-(4-cyclohexylmethoxybenzylthio)-3-fer/-butoxycarbonyl- -2,3,4,5-tetrahydro-
l//-benzo[]azepine Hydrochloride

Use a method similar to the Preparation 177, using 3-terf-butoxycarbonyl-7-
chloro-6-dimemylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[ (chloromethyl)phenyl acetate to give 6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-
chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a white solid.
To 6-(4-acetoxybenzylthio)-3-ter/-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-
l//-benzo[*/]azepine (532 mg, 1.15 mmol) in methanol (8 mL) at ambient temperature
add with stirring a solution of potassium carbonate (796 mg, 5.77 mmol) in water (4 mL)
and stir the mixture for 2 h. Dilute with water, extract three times with EtOAc, dry over
anhydrous Na2SO4, and concentrate in vacuo. To a portion of the crude phenol thus
obtained (204 mg, 0.487 mmol) in THF (5 mL), add with stirring diisopropyl
azodicarboxylate (216 |d, 1.71 mmol) followed by triphenylphosphine (306 mg, 1.17
mmol) and cyclohexylmethanol (619 mg, 5.42 mmol). Heat at 60°C for 3 h, cool to
ambient temperature and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (9:1) to give 3-terf-butoxycarbonyl-7-chloro-6-(4-
cyclohexylmethoxy-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine as a colorless oil
(176 mg, 70%). Use a method similar to the General Procedure 1-4 to give the title
compound as a white solid. MS (ES+) m/z: 416 (M+H)+.
Example 424
7-Chloro-6-(4-cycloheptyloxybenzylthio)-2,3,4,5-tetrahydro-l/f-benzo[d]azepine
Hydrochloride


Use a method similar to the Example 423 to react 6-(4-acetoxybenzyIthio)-3-terr-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[]azepine with cycloheptanol. Use
a method similar to the General Procedure 1-4 to give the title compound as a white solid.
MS (ES+) m/z: 416 (M+H)+.
Example 425
7-Chloro-6-[4-(2,2-dimethylpropoxy)-benzylthio]-2,3,4,5-tetrahydro-l/:/-benzo[rf)azepine
Hydrochloride

Use a method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-benzo[rf|azepine and 1 -
bromomethyl-4-(2,2-dimethylpropoxy)-benzene. Use a method similar to the General
Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 390 (M+H)+.
Example 426
7-Chloro-6-(2-methanesulfonylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[J]azepine
Hydrochloride


Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf|azepine and 1-
bromornethyl-2-methanesulfonyl-benzene to give, after deprotection by the General
Procedure 1-4, the title compound and as a white solid. MS (APCI+) m/z: 382 (M+H)+.
Example 427
7-Chloro-6-(4-methanesulfonylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Hydrochloride

Use a method similar to the Example 380, using 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-benzo[«/]azepine and 4-
methylsulfonylbenzyl bromide to give, after hydrochloride formation by the General
Procedure 2-2, the title compound as a white solid. MS (ES+) m/z: 382 (M+H)+.
Example 428
7-Chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-l-sulfinyl)-
benzylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Hydrochloride


ro3-/err-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-
i//-benzo[]azepine (723 mg, 1.88 mmol) in methanol (10 mL) add potassium hydroxide
pellets (3.34 g, 60.2 mmol) and stir mixture at 50°C for 2 h. Cool to ambient
temperature, add aqueous saturated ammonium chloride, extract three times with EtOAc,
dry over anhydrous Na2SO4, and concentrate in vacuo to give the crude 3-tert-
butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[*f]azepine. Dissolve
the compound in DMF (5 mL), add cesium carbonate (920 mg, 2.82 mmol) and 1-
bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-l-sulfinyl)-benzene
(824 mg, 2.071 mmol) and stir 2 h at ambient temperature. Dilute with water, extract
three times with EtOAc, dry over anhydrous Na2SC>4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-
butoxycarbonyl-7-chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-l-
sulfinyl)-benzylthio]-2,3,4,5-tetrahydro-l//-benzo[(iJazepine as a yellow oil (986 mg,
83%). Use a method similar to the General Procedure 1-4 to give the title compound as a
white foam. MS (ES+) m/z: 530 (M+H)+.
Examples 429-432 may be prepared essentially as described in Example 428 by
using 3-re7"/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[//]azepine with the appropriately substituted benzyl bromide. MS (ES+) data are
included in the Table below.








Example 433
7-Chloro-6-[4-(2,4-difluoro-phenylmethanesulfonyl)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[]azepine Succinate

Use a method similar to the Example 428 to react 3-terf-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine with l-(4-
bromomethyl-benzenesulfonylmethyl>2,4-difluoro-benzene. Use a method similar to the
General Procedure 1-4, basic work-up, and a method similar to the General Procedure 2-
1, to give the title compound as a white solid. MS (ES+) m/z: 494 (M+H)+.
Example 434
7-Chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)-benzylthio]-2,3,4,5-
tetrahydro-l#-benzo[djazepine Succinate


Use a method similar to the Example 428 to react 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lJ7-benzo[]azepine with l-bromomethyl-4-
(3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propylthio)-benzene. Use a method similar to
the General Procedure 1-5, basic workup, and a method similar to the General Procedure
2-1, to give the title compound as a white solid. MS (APCf) m/z: 514 (M+H)+.
Example 435
7-Chloro-6-[4-(3,3-dimethylbutyryl)-benzylthio]-l,2,4,5-tetrahydro-benzo[|azepine
Hydrochloride

Use a method similar to the Example 428 to react 3-terr-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- l//-benzo[t/]azepine with
l-(4-bromomethylphenyl)-3,3-dimethylbutan-l-one. Use a method similar to the General
Procedure 1-4, basic workup, and a method similar fo the General Procedure 2-2 to give
the title compound as a white solid. MS (APCI+) m/z: 402 (M+H)+.
Example 436
(±)-7-Chloro-6-[l-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-l//-benzo[t/lazepine
Hydrochloride




Use a method similar to the Preparation 177, using 3-ter/-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylmio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine and (±)-2-(l-
bromoethyl)benzonitrile to give, after deprotection by the General Procedure 1-4, the title
compound as a white solid. MS (APCI+) m/z: 343 (M+H)+.
Example 437
(-)-7-Chloro-6-[l-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Hydrochloride




Dissolve (±)-7-chloro-6-[l-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[af|azepine succinate (326 mg, 1.0 mmol) in DCM (5 mL) and pyridine (0.4 mL, 5
mmol). Add di-tert-butyl-dicarbonate (270 mg, 1.2 mmol) and stir the mixture for 16 h at
ambient temperature. Wash the mixture with 5N aqueous NaOH and saturated aqueous
NaHCO3 successively. Collect the organic layer and concentrate in vacuo. Purify the
residue by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain (±)-3-
rerr-butoxycarbonyl-7-chloro-6-[l-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (393 mg, 93%). Separate the enantiomers of (±) 3-tert-butoxycarbonyl-
7-chloro-6-[l-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-l^-benzo[ chiral normal phase chromatography (Chiralpak AD 8x30 cm column, eluting with
heptane/isopropylamine, 95:5).
Take the second eluting isomer and deprotect using the General Procedure 1-5.
Purify with SCX chromatography. Use a method similar to the General Procedure 2-2 to

obtain the title compound (125 mg, 37%). MS (ES+) m/z: 343 (M+H)+. [a]20D -112°
(c 0.5, CH3OH).
Examples 438 and 439
6-[4-(2-Butyl-2//-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride and 6-[4-(l-Butyl-l//-pyrazol-3-yl)-benzylthio]-7-
chloro-2,3»4,5-tetrahydro-l//1benzo[cf]azepine Hydrochloride




4-Acetylbenzyl bromide: Use a method similar to the Preparation 184, using
4-methylacetophenone, to give the desired intermediate as a white solid.
6-(4-Acetylbenzylthio)-3-fe/t-butoxvcarbonvI-7-chloro-2,34,5-tetrahvdro-lg-
benzofrflazepine; Use a method similar to the Example 380, using 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine and 4-acetylbenzyl bromide to give, after chromatography eluting with
hexane/EtOAc (15:1), the desired intermediate as a white solid. MS (APCI+) m/z 346
(M+H-Boc)+.
3-fert-Butoxvcarbonvl-7-chIoro-6-f4-(3-dimethvlaminoacrvlovn-benzvithiol-2»3.4.5-
tetrahvdro-l//-benzo[|azepine: Heat a solution of 6-(4-acetylbenzylthio)-3-terr-
butoxycarbonyl-7-chloro-2,3,4,5-tettahydro-l//-benzo[d]azepine (1.0 g, 2.2 mmol) in

toluene (10 mL) at 110 °C overnight in the presence of terf-butoxy-bis(dimethylamino)-
methane (1.0 mL, 4.84 mmol). Concentrate in vacuo to provide the desired intermediate
as a dark oil (1.2 g, 100%). MS (APCI+) m/z 40] (M+H-Boc)+.
6-r4-(l-Butvl-lg-PVrazol-3-vn-benzvlthiol-7-chloro-23.4,5-tetrahYdro-l^-
benzo[|azepine Hydrochloride: To a stirred mixture of 3-tert-butoxycarbonyl-7-
chloro-6-[4-(3-dimethylaminoacryloyl)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (240 mg, 0.475 mmol), butylhydrazine oxalate (102 mg, 0.574 mmol),
sodium carbonate (55 mg, 0.444 mmol) in water (8 mL) and methanol (10 mL) add acetic
acid (ca. 3-6 drops) to pH 5. Heat overnight at 70 °C. Concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (10:1) to give a mixture of the
desired intermediates, 3-rer/-butoxycarbonyl-6-[4-(2-butyl-2i/-pyrazol-3-yl)-benzylthio]-
7-chIoro-2,3,4,5-tetrahydro-l//-benzo[rf|azepine (65 mg, 32%), MS (APCI+) m/z: 426
(M+H-Boc)+and3-/er/-butoxycarbonyl-6-[4-(l-butyl-l//-pyrazol-3-yl)-benzylthio]-7-
chloro-2,3,4,5-tetrahydro-l//-benzo[rflazepine (100 mg, 50%), MS (APCI+) m/z: 426
(M+H-Boc)+.
Use a method similar to the General Procedure 1-4, using 3-re/*/-butoxycarbonyl-
6-[4-(2-butyl-2//-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[(/lazepine, to give 6-[4-(2-butyl-2/f-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (Example 438) as a white solid. MS (APCI+) m/z: 426
(M+H)+.
Use a method similar to the General Procedure 1-4, using 3-/ert-butoxycarbonyl-
6-[4-(l-butyl-17/-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-li/-
benzoft/jazepine, to give 6-[4-(l-butyl-l//-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-
tetrahydro-l#-benzo[rf]azepine (Example 439) as a white solid. MS (APCI+) m/z: 426
(M+H)+.
Example 440
6.(4-^rt-Butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[]azepine Hydrochloride


3-fert-Butoxvcarbonvl-7-chlort>-6-{3-fluoro-4-methoxvcarbonvlbenzvlthio)-23,4,5-
tetrahydro-l/f-benzoftflazepine: Use a method similar to the Example 428, using 3-
ferr-butoxycarbonyl-7-chloro-6-dimethylcarbamoyIthio-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine and methyl 4-bromomethyl-2-fluorobenzoate, to give the desired
intermediate as a white solid.
3-fgit-ButoxYcarbonYl-6-f4-carboxv-3-fluorobenzvlthioV7-chloro-2>3,4 l//-benzo[ fluoro-4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine(3.56g,
7.44 mmol) in THF (50 mL) and water (40 mL) overnight at 65 °C in the presence of
potassium hydroxide (8.30 g, 148.77 mmol). Cool the mixture to 0 °C, add slowly a IN
solution of hydrochloric acid until pH 5. Extract three times with EtOAc, dry over
anhydrous Na2SC>4 and concentrate in vacuo to provide the desired intermediate as a
white solid (3.5 g, 99%).
6-{4-fer/-Butvlcarbamovl-3-fluorobenzYlthio)-7-chloro-23,4,5-tetrahydro-l/r-
benzof|azepine Hvdrochloride: To a solution of 3-tert-butoxycarbonyl-6-(4-carboxy-
3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (1.1 g, 2.36 mmol)
in DMF (7 mL), add terf-butylamine (12.05 g, 165.2 mmol), EDC (1.81 g, 9.44 mmol)
and HOBt (1.44g, 10.62 mmol) and stir in a sealed tube at 70 °C overnight. Dilute with
EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-
butoxycarbonyl-6-(4-rcr/-butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-
tetrahydro-l/7-benzo[cf]azepine as a clear oil. MS (APCI+) m/z: 421 (M+H)+. Use a
method similar to the General Procedure 1-4 to give the title compound as a white
powder. MS (APCI+) m/z: 421 (M+H)+.

Examples 441-447 may be prepared essentially as described in Example 440 by
reacting 3-/e/-/-butoxycarbonyl-6-(4-carboxy-3-fluorobenzylthio)-7-chloro-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine with the appropriate amine. MS (ES+) data are included
in the Table below.









Example 448
(£)-(+)-6-(4-5ec-Butylcarbamoyl-3-fluorobenzylthio)-7-chIoro-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride




3-fgrl-ButoxYcarbonvl-7-chloro-6-(4-chlorocarbonYl-3-fluorobenzYlthio)-2,3,4^-
tetrahydro-l//-benzot 3-fiuoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-l#-benzo[>/]azepine (1.95 g, 4.21
mmol) in DCM (20 tnL) at 0 ° C under nitrogen, add three drops of DMF and oxalyl
chloride (1.06 g, 8.41 mmol). Stir for 2 h and concentrate in vacuo to afford the desired
intermediate as a yellow oil (1.93 g, 95%).
ffl-3- 2,3,4,5-tetrahydro-lH-benzofrfiazepine: To a solution of 3-/er/-butoxycarbonyl-7-
chloro-6-(4-chlorocarbonyl-3-fluoro-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[f/]azepine
(415 mg, 0.860 mmol) in DCM (10 mL), add (S)-(+)-sec-butylamine (1.0 g, 13.7 mmol)
and stir at ambient temperature for 30 min. Concentrate in vacuo and purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to give the desired
intermediate as a pale oil (352 mg, 79%). MS (APCI+) m/r. 421 (M+H-Boc)+.

(5r)-r+V6-(4-^gc-Butvlcarbamovl-3-f1uorobenzylthioV7-chIoro-23,4t5-tetrahYdro-
l//-benzoft/]azepine Hydrochloride: Use a method similar to the General Procedure 1-
4, using (+)-3-/er/-butoxycarbonyl-6-(4-5ec-buty]carbamoyl-3-fluoro-benzylthio)-7-
chloro-2,3,4,5-tetrahydro-l//-benzo[t/]azepine, to give the title compound as a pale solid.
MS (APCI+) m/z: 421 (M+H)+. [a]20D +8.7° (c 0.5, CH3OH).
Examples 449-454 may be prepared essentially as described in Example 448 by
reacting 3-/ert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzyIthio)-7-chloro-2,3,4,5-
tetrahydro-l/7-benzo|//]azepine with the appropriate amine. Optical rotation and MS
(ES+) data are included in the Table below.








Example 455
7-Chloro-6-(3-fluoro-4-isobutylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-l//-
benzo[d]azepine Succinate

Use a method similar to the Example 448 to react 3-tert-butoxycarbonyl-6-(4-
carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[c?]azepinewith
isobutylamine. Use a method similar to the General Procedure 1-4, basic work-up, and a
method similar to the General Procedure 2-1 to give the title compound as a white solid.
MS (ES+) m/z: 403 (M+H)+.
Example 456
7-Chloro-6-(4-cyclohexylcarbamoylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate


Use a method similar to the Preparation 177 to react 3-?ert-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[£/]azepinewith4-
chloromethyl-TV-cyclohexylbenzamide. Use a method similar to the General Procedure 1-
5, basic workup, and a method similar to the General Procedure 2-1 to give the title
compound as a white solid. MS (ES+) m/z: 429 (M+H)+.
Examples 457-465 may be prepared essentially as described in Example 456 by
using 3-/ert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine and the appropriately substituted benzyl chloride. Optical rotation and
MS (ES+) data are included in the Table below.




Example 466
7-Chloro-6-[4-(2,2-dimethyl-propylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride


(HCl),
Use a method similar to the Example 456, using 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepineand4-chloromethyl-Ar-

(2,2-dimethyl-propyl)-benzamide to give, after deprotection by a method similar to the
General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 417 (M+H)+.
Examples 467-471 may be prepared essentially as described in Example 466 by
using 3-ter/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[t/]azepine and the appropriately substituted benzyl chloride. MS (ES+) data are
included in the Table below.







Example 472
(±)-7-Chloro-6-(l-methoxycarbonyl-l-phenyl-methyllthio)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride
Use a method similar to the General Procedure 1-4, using (±)-3-tert-
butoxycarbonyl-7-chloro-6-(l-methoxycart>onyl-l-phenyI-methyllthio)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine, to give the title compound as a white solid. MS (ES+)
m/z 362 (M+H)+.
Example 473
(±)-7-Chloro-6-(2-hydroxy-l-phenyl-ethylthio)-2,3,4,5-tetrahydro-l/f-benzo[f/Jazepine
Hydrochloride

To a stirred solution of (±)-3-terf-butoxycarbonyl-6-(l-carboxy-l-phenyl-
methyllthio)-7-chloro-2,3,4,5-tetrahydro-l.r7-benzo[rf|azepine (220 mg, 0.447 mmol) in
THF (10 mL) at 0° C, add a solution of 1M borane in THF (1.4 mL, 1.4 mmol). Continue
stirring for 2 h at 0° C and then overnight at ambient temperature. Quench by slow
addition of methanol, stir 1 h at ambient temperature and concentrate in vacuo. Add
aqueous saturated ammonium chloride, extract three times with EtOAc, dry over
anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel
eluting with 19:1 DCM/saturated ammonia in methanol. Use a method similar to the
General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 334
(M+H)+.

Example 474
7,9-Dichloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-l//-benzo[cOazepine
Hydrochloride

Obtain as minor product from the reaction of the 4:1 mixture of 3-tert-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-
2,3,4,5-tetrahydro-benzo[c/]azepine with methyl bromoacetate, using a method similar to
the Example 347. Use a method similar to the General Procedure 1 -4 to give the title
compound as a white solid. MS (ES+) m/z: 320 (M+H)+.
Example 475
6-(4-Benzyloxybenzylthio)-7-chloro-2,3,4,5-tetrahydro-l#-benzo[c(]azepine Succinate

Dissolve 3-/erf-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[t/]azepine (706 mg, 1.84 mmol) in methanol (20 mL). Add
potassium hydroxide (3.5 g, 55 mmol) and heat the mixture at reflux for 3h. Cool to
ambient temperature. Pour reaction in saturated aqueous NH4CI solution. Extract three
times with EtOAc. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo
to obtain crude 3-tert-butoxycarbonyI-7-chloro-6-mercapto-2,3,4,5-tetrahydro-li/-
benzo[c/]azepine (602 mg, 100%). Dissolve 3-/ert-butoxycarbonyl-7-chloro-6-mercapto-
2,3,4,5-tetrahydro-lJ7-benzo[rf]azepine (282 mg, 0.9 mmol) in acetone (30 mL). Add 4-
benzyloxybenzyl chloride (251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg,
2.7 mmol) and potassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. Cool
the reaction to ambient temperature, dilute with acetone, filter and concentrate in vacuo.

Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give
6-(4-benzyIoxybenzylthio)-3-tert'-butoxycarbonyI-7-chIoro-2,3,4,5-tetrahydro-l//-
benzo[c/|azepine (309 mg, 67%). MS (ES+) m/z: 510 (M+H)+.
Use a method similar to the General Procedure 1-4 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (95:5) to obtain the free base of
the title compound (230 mg, 92%). MS (ES+) m/z: 410 (M+H)+. Use a method similar to
the General Procedure 2-1 to obtain the title compound.
Example 476
7-Chloro-6-[(2-fluoro-4-phenoxy)benzylthio]-2,3,4,5-tetrahydro-l//-benzo[c/Iazepine
Succinate

Use a method similar to the Example 475, using 3-terf-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- l//-benzo[c/]azepine and 1 -bromomethyl-2-
fluoro-4-phenoxybenzene to provide, after chromatography on silica gel eluting with
hexane/EtOAc (85:15), 3-ter/-butoxycarbonyl-7-chloro-6-[(2-fluoro-4-phenoxy)-
benzylthio]-2,3,4,5-tetrahydro-l//-benzo[^azepine (384 mg, 83%). MS (ES+) m/z: 414
(M-Boc+2H)+.
Use a method similar to the General Procedure 1-4 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (95:5) to obtain the free base of
the title compound (203 mg, 65%). MS (ES+) m/z: 414 (M+H)+. Use a method similar to
the General Procedure 2-1 to obtain the title compound.
Example 477
7-Chloro-6-[2-(4-fluorophenyl)-2-oxo-ethylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride


Use a method similar to the Example 475, using crude 3-ter/-butoxycarbonyl-7-
chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[]azepineand2-bromo-4'-
fluoroacetophenone (239 mg, 1.1 mmol) to provide, after stirring at ambient temperature
for 16 h and purification by chromatography on silica gel eluting with hexane/EtOAc
(4:1), 3-/er/-butoxycarbonyI-7-chIoro-6-[2-(4-fIuorophenyl)-2-oxo-ethylthio]-2,3,4,5-
tetrahydro-l//-benzo[cdazepine (38 mg, 9%).
Use a method similar to the General Procedure 1-5 and purify by chromatography
on silica gel eluting with DCM/2M ammonia in methanol (95:5) to obtain the free base of
the title compound (23 mg, 78%). MS (ES+) m/z: 350 (M+H)+. Use a method similar to
the General Procedure 2-2 to obtain the title compound.
Example 478
7-Chloro-6-(2-hydroxyethylthio)-2,3,4,5-tetrahydro-l//-benzo[^azepineHydrochIoride

Use a method similar to the Example 347, using 3-/ert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/7-benzo[]azepine and methyl
bromoacetate to give 3-ter^butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-
2,3,4,5-tetrahydro-l//-benzo[t/]azepine.
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-
2,3,4,5-tetrahydro-l#-benzo[rf]azepine (750 mg, 1.94 mmol) in THF (25 mL) at-78 °C
under nitrogen, add 1M DIBAL in toluene (5.0 mL, 5.0 mmol) dropwise with stirring.
Warm to -30°C over 1 h and quench carefully with water. Extract with EtOAc, dry over

anhydrous MgSC>4, and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (4:1) to give 3-ter/-butoxycarbonyl-7-chloro-6-(2-hydroxy-
ethylthio)-2,3,4,5-tetrahydro-l//-benzo[c/)azepine(651 mg, 94%).
Use a method similar to the General Procedure 1-4, using 3-tert-butoxycarbonyl-
7-chIoro-6-(2-hydroxyethylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine (190 mg, 0.531
mmol) to give the title compound as a white solid (105 mg, 67%). MS (ES+) m/z: 258
(M+H)+.
Example 479
7-Chloro-6-(3-methoxycarbonylpropylthio)-2,3,4,5-tetrahydro-l//-benzo[^azepine
Hydrochloride



Use a method similar to the Example 347, using 3-rer/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/]azepine and methyl 4-
bromobutyrate to give, after deprotection by the General Procedure 1-4, the title
compound as a white solid. MS (ES+) m/z: 314 (M+H)+.
Example 480
7-Chloro-6-(4-methoxycarbonyl
-butylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine Hydrochloride

Use a method similar to the Example 387 to react 3-terf-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/|azepine with methyl-5-
bromovalerate. Purify by preparative TLC eluting with 19:1 DCM/saturated ammonia in
methanol. Use a method similar to the General Procedure 2-2 to give the title compound
as a white solid. MS (APCI+) m/z: 328 (M+H)+.

Example 481
7,9-Dichloro-6-(4-methoxycarbonylbutylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

Obtain the free base of the title compound as a minor product from Example 480,
after preparative TLC eluting with 19:1 DCM/saturated ammonia in methanol. Use a
method similar to the General Procedure 2-2 to obtain the title compound as a pale yellow
solid. MS (APCI+) m/r. 362 (M+H)+.
Example 482
7-Chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-l#-benzo[^azepineTrifluoroacetate

Use a method similar to the Example 387 to react 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine with bromoacetonitrile.
Purify by preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm;
Solvent A: 10 mM aqueous ammonium carbonate, Solvent B: acetonitrile; 30-100% B
over 20 minutes; flow rate 25 mL/min) to give the title compound as a white solid. MS
(APCI+) m/r. 253 (M+H)+.
Example 483
6-Cyanomethylthio-7,9-dichloro-2,3,4,5-tetrahydro-l//-benzo[

Obtain the title compound as a minor product from Example 482, after preparative
reverse phase HPLC (Column: Xterra Prep RP18 19x250mm; solvent A: 10 mM aqueous
ammonium carbonate, solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate 25
mL/min). MS (APCI+) m/z: 287 (M+H)+.
Example 484
(±)-7-Chloro-6-(l-cyanoethylthio)-2,3,4,5-tetrahydro-l//-benzo[c(]azepineHydrochloride

Use a method similar to the Preparation 177, using 3-terf-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepineand2-
bromopropionitrile to give, after deprotection using a method similar to the General
Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 267 (M+H)+.
Example 485
(±)-7-Chloro-6-( 1 -cyanopropylthio)-2,3,4,5-tetrahydro-l //-benzo[ JJazepine
Hydrochloride

To a stirred solution of 1.5M lithium diisopropylamide in cyclohexane (1.37 mL,
2.05 mmol) in dry THF (5 mL) at -78 °C under dry nitrogen, add a solution of 3-/er/-
butoxycarbonyl-7-chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-l//-benzo[J]-azepine
(600 mg, 1.70 mmol) in THF (5 mL) and continue stirring for 2 h. Rapidly transfer the
above solution via cannula to a solution of ethyl iodide (13.2 g, 84.9 mmol) in THF (5
mL) and continue stirring for 1 h. Quench with aqueous saturated ammonium chloride
solution, extract three times with EtOAc, dry over anhydrous Na2SC>4, and concentrate in
vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give

(±)-3-fm-butoxycarbonyl-7-chloro-6-(l-cyanopropylthio)-2,3,4,5-tetrahydro-l/7-
benzo[cOazepine as a pale oil (350 mg, 68%). Use a method similar to the General
Procedure 1-4 to give the title compound as an off-white solid. MS (ES+) m/z: 281
(M+H)+.
Example 486
7-chloro-6-(l-cyano-l-methylethylthio)-2,3,4,5-tetrahydro-l//-benzo[rf|azepine
Hydrochloride

To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-cyanomethylthio-
2,3,4,5-tetrahydro-l//-benzo[rf]-azepine (300 mg, 0.85 mmol) in THF (5 mL) at 0°C, add
potassium terf-butoxide (480 mg, 4.26 mmol) at ambient temperature. After 15 min, add
methyl iodide (3.02 g, 21.31 mmol) and continue stirring overnight at ambient
temperature. Concentrate in vacua and purify by chromatography on silica gel eluting
with hexane/EtOAc (9:1) to give 3-fert-butoxycarbonyl-7-chloro-6-(l-cyano-l-methyl-
ethylthio)-2,3,4,5-tetrahydro-l//-benzo[J]azepine (177 mg, 55%). MS (ES+) m/z: 282
(M+H-Boc)+. Use a method similar to the General Procedure 1-4 to give the title
compound as an off-white solid. MS (ES+) m/z: 282 (M+H)+.
Example 487
7-Chloro-6-(4-cyanobutylthio)-2,3,4,5-tetrahydro-1 //-benzo[|azepine Hydrochloride




Use a method similar to the Example 387 to react 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[tf]azepine with 5-
bromovaleronitrile. Purify by preparative reverse phase HPLC (Column: Xterra Prep
RP18 19x250mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent B:
acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min). Use a method similar to

the General Procedure 2-2 to give the title compound as an off-white solid. MS (APCI+)
m/z: 295 (M+H)+.
Example 488
7,9-Dichloro-6-(4-cyanobutyIthio)-2,3,4,54etrahydro-l//-benzo[
Obtain the free base of the title compound as a minor product from Example 487,
after preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm; Solvent
A: 10 mM aqueous ammonium carbonate, Solvent B: acetonitrile; 30-100% B over 20
minutes; flow rate 25 mL/min). Use a method similar to the General Procedure 2-2 to
obtain the title compound as a tan solid. MS (ES+) m/z: 329 (M+H)+.
Example 489
7-Chloro-6-(2-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-l//-benzo[J]azepine
Hydrochloride

Use a method similar to the Preparation 177, using 3-terf-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf|azepineand2-(2-
bromoethyl)-pyridine hydrobromide to give, after deprotection using a method similar to
the General Procedure 1-4, the title compound. MS (ES+) m/z 319 (M+H)+.
Example 490
6-[3-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-propylthio]-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[|azepine Hydrochloride


Use a method similar to the Example 387, using 3-/ert-butoxycarbonyl-7-chIoro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lF-benzo[rf]azepineand5-(3-bromopropyl)-
3-/ert-butyl-[l ,2,4]oxadiazole to give, after deprotection using a method similar to the
General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z 380
(M+H)+.
Example 491
(-)-7-Chloro-6-(tetrahydrofuran-3-ylthio)-2,3,4,5-tetrahydro-l//-benzo[|azepine
Hydrochloride

Use a method similar to the Example 332, using 3-rerf-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf|azepineand (5)-toluene-4-
sulfonic acid tetrahydrofuran-3-yl ester to give, after deprotection using a method similar
to the General Procedure 1-4, the title compound as an off-white solid. MS (APCI+) m/z:
284 (M+H)+; [a]20D -28.0° (c 0.5, CH3OH). ee = 97.8% [Chiral HPLC: Column: YMC
ODS-AQ 120A 4.6x50 mm [S-3um]; eluent: gradient from 95:5 to 5:95 A/B; solvent A:
water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile, 0.01% HFBA, 1%
isopropanol; flow rate 2 mL/min].
Example 492
(+)-7-Chloro-6-(tetrahydrofuran-3-ylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Hydrochloride


Use a method similar to the Example 332, using 3-/ert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[^azepineand(fl)-toluene-4-
sulfonic acid tetrahydro-furan-3-yI ester to give, after deprotection using a method similar
to the General Procedure 1-4, the title compound as an off-white solid. MS (APCI+) m/z:
284 (M+H); [oc]2OD +32.5° (c 0.5, CH3OH); ee = 95.7% [Chiral HPLC: Column: YMC
ODS-AQ 120A 4.6x50 mm [S-3um]; eluent: gradient from 95:5 to 5:95 A/B; solvent A:
water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile, 0.01% HFBA, 1%
isopropanol; flow rate 2 mL/min].
Example 493
(±)-7-Chloro-6-(tetrahydrofuran-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

Use a method similar to the Example 330, using 3-/ert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[|azepine and 2-
(bromomethyl)tetrahydrofuran to give, after deprotection by the General Procedure 1-4,
the title compound as white crystals. MS (APCI+) m/z: 298 (M+H)+.
Example 494
(±)-7-Chloro-6-(tetrahydropyran-2-ylmethylthio)-2,3,4,5-tetrahydro-l^-benzo[ Hydrochloride

Use a method similar to the Example 330, using 3-tert-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rf]azepine and 2-

(bromomethyl)tetrahydropyran to give, after deprotection by the General Procedure 1-4,
the title compound as a white solid. MS (APCI+) m/z: 312 (M+H)+.
Example 495
(S)-(+)-7-Chloro-6-(5-oxo-tetrahydrofuran-2-ylmethylthio)-2,3,4,5-tetrahydro-lH-
benzo[d]azepine Hydrochloride

Use a method similar to the General Procedure 1 -4, using (S)-3-tert-
butoxycarbonyl-7-chloro-6-(5-oxo-tetrahydrofuran-2-ylmethylthio)-2,3,4,5-tetrahydro-
l//-benzo[tf]azepine to give the title compound as a white solid. MS (ES+) m/z: 312
(M+H)+. [a]20D +78° (c 0.5, CH3OH).
Example 496
7-Chloro-6-(3-dimethylcarbamoylpropylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride

Treat a solution of 3-fcrr-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-
propylthio)-2,3,4,5-tetrahydro-l#-benzo[c/]azepine (385 mg, 0.90 mmol) in
dioxane/water (1:1, 3.5 mL) with lithium hydroxide (43.0 mg, 1.01 mmol) at 80 °C for
1.5 h. Cool to ambient temperature, add aqueous saturated ammonium chloride and
brine, extract three times with ethyl ether, dry over anhydrous MgSO/t, and concentrate in
vacuo. Dissolve the residue in DCM (3.5 mL) and add EDC (162 mg, 0.84 mmol), 1-
hydroxybenzotriazole (91.0 mg, 0.67 mmol), triethylamine (0.20 mL, 1.35 mmol), and
dimethylamine (0.700 mL, 1.35 mmol). Stir overnight at ambient temperature. Dilute
with water, extract with ethyl ether, dry over anhydrous MgSO4, and concentrate in
vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc/methanol

60:40:1 to give 3-rer/-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine.
Dissolve 3-ferr-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine in DCM (1 mL) at ambient temperature and add
4M hydrogen chloride in dioxane (200 ^L, 0.8 mmol). Continue stirring until TLC shows
consumption of starting material. Concentrate in vacuo, triturate the obtained solid with
dry diethyl ether and dry at 50° C under high vacuum overnight to give the title
compound as a hygroscopic white solid (45.0 mg, 57%). MS (ES+) m/z: 327 (M+H)+.
Example 497
7-Chloro-6-[3-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine Trifluoroacetate

Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[]azepine (2.0 g, 5.20 mmol) in methanol (58 mL) and add
potassium hydroxide (9.36 g, 167 mmol). Heat at 50 °C for 2 h. Cool to ambient
temperature, add aqueous saturated ammonium chloride and water, extract three times
with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo to give 3-tert-
butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[f/]azepine (1.62 g,
5.20 mmol). Dissolve the crude 3-fert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-
tetrahydro-l//-benzo[*/]azepine (1.40 g, 4.46 mmol) in dry DMF (49.8 mL) and add DBU
(0.80 mL, 5.35 mmol) and 3-bromopropyl phthalimide (1.55 g, 5.80 mmol). Stir at
ambient temperature for 3 h. Add aqueous saturated ammonium chloride and water.
Extract twice with EtOAc, dry over anhydrous Na2SC>4, and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give the free base of
title compound (1.64 g, 74%).

Use a method similar to the General Procedure 1-5, to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-propylthio]-2,3,4,5-
tetrahydro-l#-benzo[>Qazepine and purify by preparative reverse phase HPLC to give the
title compound. MS (APCI+)/w/z401 (M+H)+.
Example 498
6-(3-Benzoylaminopropylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rflazepine
Trifluoroacetate

Suspend 3-tert-butoxycarbonyl-7-chloro-6-[3-(l ,3-dioxo-l ,3-dihydroisoindol-2-
yl)-propylthio]-2,3,4,5-tetrahydro-l//-benzo[d]azepine (1.20 g, 2.39 mmol) in ethanol
(53.2 mL), add hydrazine (0.150 mL, 4.78 mmol) and heat at 65 °C for 2 h. Cool to
ambient temperature, filter from precipitate, and concentrate in vacua to provide the 6-(3-
aminopropylthio)-3-/er/-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(861 mg, 97%). MS (APCI+) m/z: 371 (M+H)+.
To a solution of 6-(3-aminopropylthio)-3-terf-butoxycarbonyl-7-chloro-2,3,4,5-
tetrahydro-l//-benzo[*/|azepine (46.7 mg, 0.126 mmol) in dry DCM (0.5 mL) at ambient
temperature under nitrogen, add triethylamine (19.3 u.L, 0.139 mmol) and benzoyl
chloride (16.1 fiL, 0.139 mmol). Stir at ambient temperature for 2.5 h. Add aqueous
saturated ammonium chloride and water, extract three times with EtOAc, dry over
anhydrous Na2SC>4, and concentrate in vacuo. Dissolve the residue in DCM (0.16 mL),
add trifluoroacetic acid (44.6 uL, 0.58 mmol) and stir for 18 h at ambient temperature.
Concentrate in vacuo and purify by preparative HPLC [Column: YMC ODS-AQ 120A
20x250mm [S10-20um]; eluent: 95:5 to 5:95 A/B; solvent A: water, 0.1% TFA, 1%
isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow rate 20 mL/min]
to give the title compound (7.0 mg, 12%). MS (APCI+) m/z 375 (M+H)+.

Example 499
6-[3-(3-Phenylureido)-propylthio]-7-chloro-2,3,4,5-tetrahydro-l//-benzo[^/]azepine
Trifluoroacetate

Use a method similar to the Example 498, using phenyl isocyanate, to give the
title compound. MS (APCI+) m/z 390 (M+H)+.
Example 500
7-Chloro-6-[3-(4-trifluoromethylbenzoylamino)-propylthio]-2,3,4,5-tetrahydro-lW-
benzo[rf|azepine Trifluoroacetate

To a stirred solution of 4-trifluoromethylbenzoic acid (60.0 mg, 0.316 mmol) in
anhydrous DMF (1.2 mL) at ambient temperature under nitrogen, add EDC (63.6 mg,
0.332 mmol), 1-hydroxybenzotriazole (44.8 mg, 0.332 mmol), 4-dimethylaminopyridine
(40.5 mg, 0.332 mmol) and a solution of 6-(3-aminopropylthio)-3-/er/-butoxycarbonyl-7-
chloro-2,3,4,5-tetrahydro-l//-benzo[]azepine (123 mg, 0.332 mmol) in DCM (2 mL).
Stir for 18 h at ambient temperature. Add water, extract twice with EtOAc, dry over
anhydrous Na2SC>4, and concentrate in vacuo. Treat the residue with trifluoroacetic acid
(0.272 mL, 0.640 mmol) in DCM (0.451 mL) at ambient temperature for 18 h.
Concentrate in vacuo and purify by preparative reverse phase HPLC [Column: YMC
ODS-AQ 120A 20x250mm [S10-20um]; eluent: 95:5 to 5:95 A/B; solvent A: water,
0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow
rate 20 mL/min] to give the title compound as a white solid (31.0 mg, 18%). MS
(APCI+) m/z 443 (M+H)+.

Example 501
7-Chloro-6-[3-(4-/er/-butylbenzoylamino)-propylthio]-2,3,4,5-tetrahydro-l//-
benzo[*/]azepine Trifluoroacetate

Use a method similar to the Example 500, using 6-(3-aminopropylthio)-3-terf-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[c/|azepine and 4-tert-butyl benzoic
acid to give the title compound as a white solid. MS (APCI+) m/z 431 (M+H)+.
Example 502
7-Chloro-6-(2-ethoxycarbonylamino-ethylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
Trifluoroacetate

Use a method similar to the Example 497, using 3-ter/-butoxycarbonyl-7-chloro-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//- benzo[cf|azepine and 3-bromoethyl
phthalimide to give 6-(3-aminoethylthio)-3-ter/-butoxycarbonyl-7-chloro-2,3,4,5-
tetrahydro-l/f-benzo[rf|azepine. MS (ES+) m/z 357 (M+H)+.
Use a method similar to the Example 498, using 6-(3-aminoethylthio)-3-/er/-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[c?]azepine and ethyl chloroformate
to give, after deprotection using a method similar to the General Procedure 1-5, the title
compound as a white solid. MS (APCI+) m/z: 329 (M+H)+.

Example 503
7-Chloro-6-{2-[(pyridine-4-carbonyl)amino]-ethylthio}-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Trifluoroacetate

Use a method similar to the Example 500, using 6-(3-aminoethylthio)-3-tert-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[*/]azepine and isonicotinic acid to
give the title compound. MS (ES+) m/z: 362 (M+H)+.
Example 504
7-Chloro-6-[2-(cyclopropanecarbonylamino)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Trifluoroacetate

Use a method similar to the Example 498, using 6-(3-aminoethylthio)-3-/ert-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepineand
cyclopropanecarbonyl chloride to give, after deprotection using a method similar to the
General Procedure 1-5, the title compound. MS (ES+) m/z: 325 (M+H)+.
Example 505
6-(2-Benzenesulfonylamino-ethylthio)-7-chloro-2,3,4,54etrahydro-l#-benzo[d]azepine
Trifluoroacetate

Use a method similar to the Example 498, using 6-(3-amino-ethylthio)-3-tert-
butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1 tf-benzo[rf]azepine and benzenesulfonyl

chloride to give, after de protection using a method similar to the General Procedure 1-5,
the title compound as a white solid. MS (APCI+) m/z: 397 (M+H)+.
Example 506
7-ChIoro-6-(3-pyrrol-l-yI-propylthio)-2,3,4,5-tetrahydro-l//-benzo[cflazepine
Trifluoroacetate

Use a method similar to the Example 497, using 3-/erf-butoxycarbonyl-7-chloro-
6-dimethylcarbarnoylthio-2,3,4,5-tetrahydro-l//-benzo[c/|azepine and iV-(3-
bromopropyl)pyrrole to give, after deprotection using a method similar to the General
Procedure 1-5, the title compound as a white solid. MS (ES+) m/z: 321 (M+H)+.
Example 507
7-Chloro-6-[2-(2,2-dimethylpropionyloxy)-ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[]azepine Hydrochloride

To a stirred solution of 3-/er/-butoxycarbonyl-7-chloro-6-(2-hydroxyethylthio)-
2,3,4,5-tetrahydrobenzo[d]azepine (85 mg, 0.238 mmol) in DCM (3 ml) at 0°C, add
triethylamine (331 uJ, 2.381 mmol) followed by trimethylacetyl chloride (147 u.1, 1.190
mmol). Continue stirring for 15 min, dilute with water, extract three times with EtOAc,
dry over anhydrous Na2SC>4, and concentrate in vacuo. Deprotection by the General
Procedure 1-5, basic workup, and by the General Procedure 2-2 give the title compound.
MS (ES+) m/z 342 (M+H).

Example 508
7-Chloro-6-(2-cyclohexanecarbonyloxy-ethylthio)-2,3,4,5-tetrahydro-l//-
benzo[*/]azepine Hydrochloride

Use a method similar to the Example 507, using cyclohexanecarbonyl chloride, to
give the title compound. MS (ES+) m/z 368 (M+H).
Example 509
7-Chloro-6-(3-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-li/-benzo[]azepine
Hydrochloride

Use a method similar to the Preparation 242, using 3-tert-butoxycarbonyl-7-
chloro-6-(3-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine to give,
after deprotection by the General Procedure 1-4, the title compound as a white solid. MS
(ES+) m/z: 334 (M+H)+.
Example 510
7-Chloro-6-(2-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[£/]azepine
Hvdrochloride


Use a method similar to the Preparation 242, using 3-ter/-butoxycarbonyl-7-
chloro-6-(2-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine to give,
after deprotection by the General Procedure 1-4, the title compound as a white solid. MS
(ES+)m/z:334(M+H)+.
Example 511
7-Chloro-6-(4-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-l/7-benzo[ Hydrochloride

Use a method similar to the General Procedure 1-4, using 3-ter/-butoxycarbonyl-
7-chloro-6-(4-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf|azepine, to give
the title compound as a white solid. MS (ES+) m/z: 334 (M+H)+.
Example 512
7-Chloro-6-(4-methoxymethylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[J]azepine
Hydrochloride

To a stirred solution of 3-ferNbutoxycarbonyl-7-chloro-6-(4-hydroxymethyl-
benzylthio)-2,3,4,5-tetrahydro-l//-benzo[cflazepine (133 mg, 0.306 mmol) in anhydrous
DMF (2 mL) under nitrogen, add sodium hydride (60% dispersion, 13-15 mg, 0.375
mmol) at ambient temperature and continue stirring for 30 min. Add methyl iodide (80
QL, 1.28 mmol). After 15 min, dilute with water, extract three times with EtOAc, dry
over anhydrous MgSC>4 and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (15:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-

methoxymethyl-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine as a clear oil, which
crystallizes on standing to a white solid (87 mg, 63%), along with recovered starting
material (22 mg, 17%). Use a method similar to the General Procedure 1-4 to give the
title compound as a white solid. MS (ES+) m/z: 348 (M+H-Boc)+.
Example 513
7-Chloro-6-(3-methoxymethylbenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride
Use a method similar to the Example 512, using 3-tert-butoxycarbonyl-7-chloro-
6-(3-hydroxymethylbenzylthb)-2,3,4,5-tetrahydro-l//-Denzo[(/]azepine to give the title
compound as a white solid. MS (ES+) m/z: 348 (M+H).
Example 514
7-Chloro-6-(2-methoxymethylbenzylthio)-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine
Hydrochloride
Use a method similar to the Example 512, using 3-terr-butoxycarbonyl-7-chloro-
6-(2-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-li/-benzo[]azepine to give the title
compound as a white solid. MS (ES+) m/z: 348 (M+H).

Example SIS
7-Chloro-6-(2-methoxyethylthio)-2,3,4,5-tetrahydro-l//-benzo[c/]azepinehydrochloride

Use a method similar to the Example 512, using 3-/erf-butoxycarbonyl-7-chloro-
6-(2-hydroxy-ethylthio)-2,3,4,5-tetrahydro-l//-benzo[if]azepine, to give the title
compound as a white solid. MS (ES+) m/z: 272 (M+H).
Example 516
7-Chloro-6-(4-methoxybutylthio)-2)3,4,5-tetrahydro-l//-benzo[c/lazepinehydrochloride

Use a method similar to the Example 478, using 3-fert-butoxycarbonyl-7-chloro-
6-(3-methoxycarbonyl-propylthio)-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine to give 3-ie«-
butoxycarbonyl-7-chloro-6-(4-hydroxybutylthio)-2,3,4,5-tetrahydro-l/f-benzo[]azepine.
Use a method similar to the Example 512, using 3-ferf-butoxycarbonyl-7-chloro-6-(4-
hydroxybutylthio)-2,3,4,5-tetrahydro-li/-benzo[t/]azepine to give the title compound as a
white solid. MS (ES+) m/z: 300 (M+H)+.

Example 517
(±)-7-ChIoro-6-(2-methoxy-l-phenylethylthio)-2, 3, 4 ,5-tetrahydro-l/f-benzo[]azepine
Hydrochloride

Use a method similar to the Example 512, using (±)-3-te/?-butoxycarbonyl-7-
chloro-6-(2-hydroxy-l -phenylethylthio)-2,3,4,5-tetrahydro-l//-benzo[f/]azepine to give,
after deprotection by a method similar to the General Procedure 1-4, the title compound
as an off-white solid. MS (ES+) m/z: 348 (M+H)+.
Example 518
(-)-7-Chloro-6-(2-methoxy-l-phenylethylthio)-2,3,4,5-tetrahydro-l//-benzo[|azepine
Hydrochloride

Separate the enantiomers of (±)-7-chloro-6-(2-methoxy-l-phenyl-ethylthio)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine by chiral normal phase chromatography
(Chiralcel OJ 8x33 cm column, eluting with 0.2% DMEA in ethanol/heptane, 40:60).
Collect the second eluting isomer and use the General Procedure 2-2 to give the title
compound as a white solid (76 mg, 29%). MS (ES+) m/z: 349 (M+H)+. [a]20D -176° (c
0.5, CH3OH).
Example 519
6-(4-Fluorobenzylthio)-7-methyl-2,3,4,5-tetrahydro-li/-benzo[(/]azepine Hydrochloride



Use a method similar to the General Procedure 7, using 3-ter/-butoxycarbonyl-6-
dimethylcarbamoylthio-7-memyl-2,3,4,5-tetrahydro-l//-benzo[rf)azepine (75 mg, 0.206
mmol) and 4-fluorobenzyl bromide (195 mg, 1.03 mmol) to give, after chromatography
on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1), 3-terM>utoxycarbonyl-6-(4-
fluorobenzylthio)-7-methyl-2,3,4,5-tetrahydro-l//-benzo[cf]azepine as an oil (59 mg,
71%). MS (ES+) m/r. 302 (M+H-Boc)+.
Use a method similar to the General Procedure 1-4, using 3-^erNbutoxycarbonyl-
6-(4-fluoro-benzylthio)-7-methyl-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (55 mg, 0.137
mmol) to give the title compound as a white solid (42 mg, 91%). MS (ES+) m/r. 285
(M+H)+.
Example 520
7-Cyano-6-(4-fluorobenzylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine Succinate

Use a method similar to the General Procedure 7, using 3-tert-butoxycarbonyl-7-
cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[c/jazepine (123 mg, 0.33
mmol) and 4-fluorobenzyl bromide (204 mg, 1.64 mmol), to give 3-/er/-butoxycarbonyl-
7-cyano-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-lW-benzo[c/Jazepine as a colorless oil
(118 mg, 87%).
Use a method similar to the General Procedure 1-4, using 3-/erf-butoxycarbonyl-
7-cyano-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-l//-benzo[cTlazepine (118 mg, 0.286

mmol) to give, after basic work-up, the free base of the title compound (89 mg, 100%).
MS (ES+) mlz 313 (M+H)+. Use a method similar to the General Procedure 2-1 to give
the title compound (123 mg, 100%). MS (ES+) mlz 313 (M+H)+.
Example 521
(±)-7-Cyano-6-[l-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-lH-benzo[]azepine
Succinate

Use a method similar to the General Procedure 7, using 3-ter/-butoxycarbonyl-7-
cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l#-benzo[rf]azepine (171 mg, 0.46
mmol) and (±)-l-(4-fluorophenyl)ethyl bromide (377 mg, 1.85 mmol) to give, after
purification by chromatography on silica gel, (±)-3-tert-butoxycarbonyl-7-cyano-6-[l-(4-
fluorophenyl)-ethylthio]-2,3,4,5-tetrahydro-l//-benzo[]azepine as a colorless oil (10.3
mg, 5.3%). MS (ES+) mlz 449 (M+Na)+, 465 (M+K)+.
Use a method similar to the General Procedure 1 -5, using (±)-3-tert-
butoxycarbonyl-7-cyano-6-[l-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-
benzofrfjazepine (10.3 mg, 0.024 mmol) to give, after basic work-up, the free base of the
title compound (6.8 mg, 87%). MS (ES+) mlz 327 (M+H)+. Use a method similar to the
General Procedure 2-1 to give the title compound as a white solid (9.3 mg, 87%). MS
(ES+) mlz 327 (M+H)+.
Example 522
7-Cyano-6-[l-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-17/-benzo[t/]azepine
Succinate, Isomer 1


Separate the two enantiomers of (±)-7-cyano-6-[l-(4-fluorophenyl)ethylthio]-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine by chiral HPLC (Chiralpak AD-H 15cm x 4.6mm
column with a 5 ^m packing size. Elute with heptane/ethanol (95:5) containing 0.2%
DEA at 0.5 mL/min with an injection volume of 10.00 uL).
Subject the first eluting isomer (tR = 17.2 min, ee > 99%) to the General Procedure
2-1 to afford the title compound as a white solid. MS (ES+) mlz 327 (M+H)+.
Example 523
7-Bromo-6-(3-ethoxycarbonylpropylthio)-2,3,4,5-tetrahydro-li/-benzo[t/Jazepine
Hydrochloride

Use a method similar to the Preparation 177, using 3-ter/-butoxycarbonyl-7-
bromo-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-benzo[c(]azepine and ethyl 4-
bromobutyrate to give, after deprotection by a method similar to the General Procedure 1-
4, the title compound. MS (ES+) m/z: 374 (M+H)+.
Example 524
7-Bromo-6-(3-dimethylcarbamoylpropylthio)-2,3,4,5-tetrahydro-l//-benzo[(i]azepine
Hydrochloride



Use a method similar to the Example 523, using 7-bromo-3-fer/-butoxycarbonyl-
6-(3-ethoxycarbonylpropylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine, to give the title
compound as a white solid. MS (ES+) m/z: 373 (M+H)+.
Example 525
7-Bromo-6-(4-oxo-4-pyrrolidin-l-yl-butylthio)-2,3,4,5-tetrahydro-l//-benzo[rfIazepine
Hydrochloride



Use a method similar to the Example 523, using 7-bromo-3-terf-butoxycarbonyl-
6-(3-ethoxycarbonylpropylthio)-2,3A5-tetrahydro-l//-benzo[c(Jazepineandpyrrolidine
to give the title compound. MS (ES+) m/z: 397 (M+H)+.
Example 526
7-Bromo-6-[3-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride




Use a method similar to the Example 497 to react 7-bromo-3-terf-butoxycarbonyl-
6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-benzo[ phthalimide. Use a method similar to the General Procedure 1-4 to give the title
compound as a white solid. MS (ES+) m/z 445 (M+H)+.

Example 527
6-[2-(2,2-Dimethylpropionyloxy)-ethylthio]-7-trifluoromethyl-2,3,4,5-tetrahydro-l/f-
benzo[*/]azepine Hydrochloride

3-re/f-ButoxYcarbonvl-6-dimelhvlcarbamovlthio-7-trifluoromethvl-2J,4,5-
tetrahvdro-benzofrflazepine: To a stirred solution of 7-bromo-6-
dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-ben2o[ (1.383 g, 3.254 mmol), in NMP (40 ml) add sodium trifluoromethyl acetate (3.54 g, 26.03
mmol), copper(I) iodide (2.47 g, 13.0 mmol) and heat the mixture at 180°C for 4 h. Cool
to ambient temperature. Dilute with EtOAc, water and remove the copper solid residue by
filtration. Separate the layers of filtrate and extract the aqueous layer three times with
EtOAc. Dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (6:1) to give the desired
intermediate as a yellow oil (882 mg, 74%).
3-ter/-Butoxvcarbonvl-6-[2-(tert-butYl-dimethvlsilanvloxv)ethylthioI-7-
trifluoromethYl-2y3,4,5-tetrahYdro-lfl-benzof|azepine: Use a method similar to the
Preparation 177, using 3-fer/-butoxycarbonyl-6-dimethylcarbamoylthio-7-
trifluoromethyl-2,3,4,5-tetrahydro-benzo[rf]azepine and (2-bromoethoxy)-rer/-
butyldimethylsilane to give the desired intermediate.
3-ferf-ButoxYcarbonvl-6-r2-hvdroxvethylthio)-7-trifluoromethvl-23.4,5-tetrahvdro-
l/T-benzoftflazepine: Dissolve 6-[2-(terf-butyl-dimethyl-silanyloxy)-ethylthio]-7-
trifluoromethyl-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (153 mg, 0.303 mmol) in THF
(3 mL). Add 1.0 M tetrabutylammonium fluoride in THF (600 ^L, 0.606 mmol,) and stir

overnight. Dilute with water, extract three times with EtOAc, dry over anhydrous
Na2SC>4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (85:15) to give the desired intermediate.
6-f2-(2^-DimethvlproDionvloxvVethvlthiol-7-trifluoromethvl-23,4,5-tetrahvdro-lH-
benzoU/lazepine hvdrochloride: Use a method similar to the Example 507, using 3-tert-
butoxycarbonyl-6-(2-hydroxyethylthio)-7-trifiuoromethyl-2,3,4,5-tetrahydro-l//-
benzo[cQazepinc to give, after deprotection using a method similar to the General
Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 376 (M+H)+.
General Procedure 8
Dissolve the appropriate bromide (2 equiv.) in isopropylamine (300-400 equiv.) at
room temperature, under nitrogen, then add palladium(II) bis(benzonitrile) dichloride (0.2
equiv.), triphenylphoshine (0.4 equiv.) and copper(I) iodide (0.2 equiv.). Degas the
solution and purge with nitrogen, then add the appropriate alkyne (1.0 equiv.). Seal the
reaction vessel, stir at room temperature for 30 min, then at 75 °C for 3-4 h. Remove
most of the solvent in vacuo, add diethyl ether and 2M aqueous HC1. Dry the organic
layer over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica
gel eluting with isohexane/EtOAc or hexane/EtOAc mixtures.
Preparation 249
2-Ethynyl-thiophene

Trimethyl-thiophen-2-ylethvnyl-silane: Use a method similar to the General Procedure
8 to couple 2-bromo-thiophene (0.97 mL, 10 mmol) with ethynyl-trimethylsilane (2.82
mL, 20 mmol). Purify by chromatography on silica gel eluting with isohexane to give the
desired intermediate (1.46 g, 81%). GC-MS m/z 180 (M*).

2-Ethynyl-thiophene: Add a saturated solution of potassium carbonate in methanol (7.5
mL) to trimethyl-thiophen-2-ylethynyl-silane (540 mg, 3 mmol) in deoxygenated
methanol (100 mL) at room temperature under nitrogen. Stir the reaction for 3.5 h, then
dilute with dichloromethane (100 mL) and wash with water (3 x 100 mL). Remove the
organic layer, dry using an ISCO® phase separator and then concentrate in vacuo to give
the title compound (302 mg, 93%).
Preparation 250
3-terr-Butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-l//-benzo[cnazepine

7-Chloro-3-(2JJ-trifluoroacetvlV6-trimethvlsilanvlethYnYl-23 benzofrflazepine: Use a method similar to the General Procedure 3 to couple 7-chloro-3-
(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (425 mg, 1 mmol) with 2-trimethylsilylacetylene (0.28 mL, 2 mmol).
Purify by chromatography on silica gel eluting with isohexane/EtOAc (100:0 to 85:15
gradient over 40 min) to give the desired intermediate (247 mg, 81%). MS (ES+) m/z:
306 (M+H)+.
3-te/t-ButoxYcarbonvl-7-chloro-6-ethvBvI-23.4.5-tetrahvdro-lflr-benzo[tnazepine;
Add a solution of potassium carbonate (999 mg, 7.2 mmol) in water (5 mL) to 7-chloro-3-
(2,2,2-trifluoroacetyl)-6-trimethylsiIanylethynyl-2,3,4,5-tetrahydro-li/-benzo[JJazepine
(180 mg, 0.48 mmol) in methanol (10 mL) and stir at room temperature, under nitrogen
for 1.5 h. Add di-terf-butyl-dicarbonate (115 mg, 0.53 mmol) in dichloromethane (8 mL)
and stir for 3 days. Add another solution of di-terf-butyl-dicarbonate (115 mg, 0.53
mmol) in dichloromethane (5 mL) and stir for 2 h. Add water (10 mL) and
dichloromethane (10 mL) and separate the organic layer. Extract the aqueous layer with
dichloromethane (3x10 mL) and combine the organic layers. Dry using an ISCO®
phase separator and concentrate. Purify by chromatography on silica gel eluting with

isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give the title compound as a solid
(150 mg, 100%). MS (ES+) m/z: 328 (M+Na)+.
Preparation 251
2-Chloro-pyridazine

Add 3(2//)-pyridazinone (2 g, 22 mmol) to neat phosphorus oxycloride (4 mL) in
a sealed tube and heat the mixture at 80 °C with stirring for 2 h. Add caustiously water
(10 mL), saturated aqueous NaHCO3 (50 mL ) and solid Na2CO3 until pH= 9. Extract the
mixture with dichloromethane (4 x 50 mL). Dry the organic layer over Na2SC>4, filtrate
and concentrate in vacua to give the title compound as brown oil (2 g, 84%).
Preparation 252
l-/ert-Butyl-3-prop-2-ynyl-imidazolidin-2-one

Dissolve l-tert-butyl-imidazoIidin-2-one (2 g, 14 mmol) in anhydrous THF (60
mL) and cool at-78 °C. Slowly add w-butyllithium (6.8 mL, 17 mmol, 2.5 M solution in
hexanes). Stir the solution for 30 min. Rapidly add propargyl bromide (3.2 mL, 28.2
mmol, 80% solution in toluene). Warm the solution to room temperature while stirring
overnight. Concentrate the reaction mixture in vacua and filter the residue on a short pad
of silica gel eluting with dichloromethane/diethyl ether (1:1) to give the title compound as
a yellow oil that solidifies on standing (1.77 g, 70%). GC-MS m/z (%) 180 (M+, 7), 165
(100), 123 (12), 84 (17).

Example 528
7-Chloro-6-pyridin-2-yIethynyl-2,3,4,5-tetrahydro-l//-benzo[t/JazepineSuccinate

Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lf/-benzo[J]azepine
(425 mg, 1 mmol) with 2-ethynyl-pyridine (0.20 mL, 2 mmol). Purify by
chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40
min) to give 7-chloro-6-pyridin-2-ylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[|azepine (342 mg, 90%). MS (ES+) m/z: 379 (M+H)+.
Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-6-
pyridin-2-ylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[ mg, 0.159 mmol). Purity by SCX chromatography to give the free base of the title
compound (33 mg, 73%). MS (ES+) m/z: 283 (M+H)+. Use a method similar to the
General Procedure 2-1 to give the title compound as a light brown solid (45 mg, 95%).
MS (ES+) m/z: 283 (M+H)+.
Examples 529-531
Examples 529-531 may be prepared essentially as described in Example 528 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluorornethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[]azepine and the appropriate alkyne. Overall yields and MS (ES+)
data are shown in the Table below.



Example 532
7-Chloro-6-thiazol-2-ylethynyl-2,3,4,5-tetrahydro-1 /f-benzo[
3-rert-Butorycarbonyl-7-chloro-6-fthiazol-2-vlethvnvn-2 bcnzoftflazepine: Use a method similar to the General Procedure 8 to couple 2-bromo-
thiazole (0.09 mL, 0.96 mmol) with 3-/ert-butoxycarbonyl-7-chloro-6-ethynyl-2,3>4,5-
tetrahydro-l//-benzo[c/]azepine (148mg, 0.48mmol). Puriiy by chromatography on silica
gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give the desired
intermediate (165 mg, 89%). MS (ES+) m/z: 389 (M+H)+.
7-Chloro-6-(thiazol-2-YlethvnYn-23.4^-tetrahvdro-l//-benzol Use a method similar to the General Procedure 1-5 to deprotect 3-terf-butoxycarbonyl-7-
chloro-6-(thiazol-2-ylethynyl)-2,3,4,5-tetrahydro-17/-benzo[rf]azepine (140 mg, 0.36
mmol). Elute through SCX column to give the free base of the title compound (89 mg,
86%). MS (ES+) m/z: 289 (M+H)+. Use a method similar to the General Procedure 2-1
to give the title compound as a light yellow solid (125 mg, 86%). MS (ES+) m/z: 289
(M+Hf.

Example 533
7-Chloro-6-pyridazin-3-ylethynyl-2,3,4,5-tetrahydro-l//-benzo[
3-fer/-ButoxvcarbonvI-7-chloro-6-PYridazin-3-YlethvnvI-23,4,5-tetrahvdro-l/f-
benzolrflazepine: Use a method similar to the General Procedure 8 to couple 2-chloro-
pyridazine (98 mg, 0.86 mmol) with 3-terf-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (104 mg, 0.34 mmol). Purify by chromatography on
silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give 3-/erf-
butoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(26 mg, 10 %). MS (ES+) m/z: 384 (M+H)+.
7-Chloro-6-Dvridazin-3-vlethvnvl-23.43-tetrahvdro-lg-benzo[rf|azepine(Z.)-
tartrate: Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine. Use a method similar to the General Procedure 2-6 to give the title
compound as a solid (15 mg, 51%). MS (ES+) m/z: 284 (M+H)+.
Example 534
7-Chloro-6-(3-fluoro-phenylethynyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine(I)-Tartrate

Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[d]azepine
(425 mg, 1 mmol) with (3-fluorophenyl)-ethyne (241 mg, 2 mmol). Purity by
chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40

min) to give 7-chloro-6-(3-fluoro-phenylethynyl)-3-(2,2,2-trifiuoroacetyl)-2,3)4,5-
tetrahydro-l#-benzo[rf]azepine (247 mg, 64%). MS (ES+) m/z: 396 (M+H)+.
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(3-
fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[^azepine
(68 mg, 0.18 mmol). Purify by SCX chromatography to give the free base of the title
compound (46 mg, 85%). MS (ES+) m/z: 300 (M+H)+. Use a method similar to the
General Procedure 2-6 to give the title compound as a white solid (61 mg, 94%). MS
(ES+) m/z: 300 (M+H)+.
Example 535
7-Chloro-6-(2-fluoro-phenylethynyl)-2,3,4,5-tetrahydro-l//-benzo[£f]azepine Succinate

Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-
trifluoroacetylJ^-trifluoromethanesulfonyloxy^S^jS-tetrahydro-l/f-benzofrflazepine
(425 mg, 1 mmol) with (2-fluorophenyl)-ethyne (241 mg, 2 mmol). Purify by
chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40
min) to give 7-chloro-6-(2-fluoro-phenylethynyl)-3-(2)2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-li/-benzo[cf|azepine (262 mg, 68%). MS (ES+) m/z: 396 (M+H)+.
Use methods similar to the General Procedures 1-1 and 2-1 to give the title
compound as a white solid (93%). MS (ES+) m/z: 300 (M+H)+.

Example 536
6-[3-(3-/er/-Butyl-2-oxo-imidazolidin-l-yl)-prop-l-ynyl]-7-chloro-2,3,4,5-tetrahydro-lF-
benzofrfjazepine (L)-Tartrate

Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[£/]azepine
(425 mg, 1 mmol) with 1 -tert-butyl-3-prop-2-ynyl-imidazolidin-2-one (360 mg, 2 mmol).
Purify by chromatography on silica gel eluting with isohexane/EtOAc (19:1 to 3:2
gradient) to give 6-[3-(3-ter/-butyl-2-oxo-imidazolidin-l-yl)-prop-l-ynyl]-7-chloro-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l#-benzo[rfJazepine (380 mg, 83%) as a yellow
oil. LC-MS (ES+) m/z: 478 (M+Na)+, 456 (M+H)+, tR = 4.43 min.
Use a method similar to the General Procedure 1-1, but adding water (10 mL) to
the ammonia/methanol solution (20 mL, 7N solution), to deprotect 6-[3-(3-/er/-butyl-2-
oxo-imidazolidin-l-yl)-prop-l-ynyl]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
1/f-benzojcfjazepine (329 mg, 0.72 mmol) and give the free base of the title compound
(217 mg, 84%). Use a method similar to the General Procedure 2-6 to give the title
compound as a solid (211 mg, 58% overall yield). LC-MS (ES+) m/z: 360 (M+H)+, tR =
4.54 min.


2J-Difluoro-2-phenyl-ethanol: Add lithium aluminum hydride (5.18 mL, 5.18 mmol,
1M solution in THF) to a solution of methyl difluorophenylethanoate (0.964 g, 5.18
mmol, prepared by following the procedure described in J. Org. Chem. 1995, 60, 5174-
5179) in anhydrous THF (10 mL) at 0 °C. Stir the mixture at room temperature for 45
min. Cool to 0 °C and quench with EtOAc and then water. Separate the organic phase
and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over
Na2SC>4, filter and concentrate in vacua to provide the desired intermediate (0.8 g, 98%)
that was used without any further purification.
2J-Difluoro-2-phenyl-ethvl trifluoromethanesulfonate: Add triflic anhydride (1.28
mL, 2.14 g) dropwise to a stirred solution of 2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06
mmol) and 2,6-di-terf-butyl-4-methvlpyridine (1.556 g, 7.59 mmol) in anhydrous
dichloromethane (25 mL) at -78 °C. Stir the reaction overnight while the temperature
warms up. Dilute the mixture with pentane and filter the precipitate over Celite®.
Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on
silica gel eluting with hexane and hexane/EtOAc (95:5) to provide the title compound
(946 mg, 64%).
(2-Azido-Ll-difluoro-cthvl)-benzene: Heat at 60 °C a solution of 2,2-difluoro-2-
phenyl-ethyl trifluoromethanesulfonate (759 mg, 2.617 mmol) and sodium azide (357 mg,
5.496 mmol) in anhydrous DMF (10 mL) under nitrogen for 3 h. Cool the reaction
mixture to room temperature. Dilute with water and extract the aqueous phase twice with

diethyl ether. Wash the combined organic extracts twice with ice-cold water, dry over
Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as an oil (475
mg, 99%) that was used without any further purification.
2,2-Difluoro-2-phenvl-ethylamine: Dissolve (2-azido-l,l-difluoro-ethyl)-benzene (475
mg, 2.59 mmol) in EtOAc (30 mL). Add 10% Pd/C and submit the mixture to
hydrogenation under atmospheric pressure (balloon) for 1 h. Filter the catalyst through
Celite® and concentrate the filtrate in vacuo to provide the title compound as an oil (400
mg, 98%) that was used without any further purification.
Preparation 254
2-Bromo-benzothiazole-6-carbonitrile
2-Oxo-2,3-dihvdro-benzothiazole-6-carbonitrile: Combine 6-bromobenzothiazolinone
(2 g, 8.69 mmol), copper cyanide (1.3 g, 1.48 mmol), anhydrous DMF (5 mL) and heat at
reflux for 15 h. Add water (20 mL) and sodium cyanide (1.4 g, 27.7 mmol) at 100 °C.
Cool the reaction mixture to room temperature and stir for 2 h. Extract the reaction
mixture with EtOAc (5 x 30 mL) at 70 °C. Combine the organic layers, wash with water
(3 x 40 mL) and dry over anhydrous Na2SO4. Concentrate in vacuo to obtain the desired
intermediate as a yellow solid (2 g, 87%). GC-MS mJr. 176 (lvf).
2-Bromo-benzothiazole-6-carbonitrile: Combine 2-oxo-2,3-dihydro-benzothiazole-6-
carbonitrile (1.1 g, 6.24 mmol), tetrabutylammonium bromide (3 g, 9.36 mmol),
phosphorus pentoxide (2.7 g, 18.7 mmol), anhydrous toluene (40 mL) and heat at reflux
for 2.5 h. Cool the reaction mixture to room temperature. Decant the toluene layer and
wash with saturated aqueous NaHCC>3 (3 x 10 mL). Concentrate the organic phase in
vacuo and purify the residue by chromatography on silica gel eluting with hexane/EtOAc
(1:0 to 4:1 gradient) to obtain the title compound as a colorless oil (0.9 g, 61%). GC-MS
m/z: 239 (lvl4).


Preparation 255
6-Aminomethyl-2-cycIohexylmethyl-benzothiazole
2-Cyclohexylmethyl-benzothiazole-6-carbonitrile: Place 2-bromo-benzothiazole-6-
carbonitrile (0.2 g, 0.96 mmol), anhydrous THF (3 mL), 1 -methyl-2-pyrrolidinone (3
mL), tetrabutylammonium iodide (1.1 g, 2.89 mmol),
tris(dibenzylideneacetone)dipalladium(0) (18 rng, 0.09 mmol) and [1,1'-
bis(diphenylphosphino)ferrocine]dichloropalladium (II) (I I mg, 0.09 mmol) in a flask.
Add 0.5M cyclohexylmethylzinc bromide in THF (3.8 mL, 1.92 mmol) to the mixture,
degas 3 times by partially evacuating the atmosphere and flushing with nitrogen and stir
the reaction mixture at 80 °C for 2 h. Cool the reaction mixture to room temperature,
dilute with EtOAc (10 mL) and wash with brine (10 mL). Dry the organic layer over
anhydrous Na2SC>4, filter and concentrate in vacuo. Purify the residue by chromatography
on silica gel eluting sequentially with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the
desired intermediate as a yellow solid (140 mg, 57%). GC-MS m/z: 256 (M*).
6-Amipomethvl-2-cvclohcxvlmcthyl-benzothiazole: Dissolve 2-cyclohexylmethyl-
benzothiazole-6-carbonitrile (0.2 g, 0.55 mmol) in anhydrous THF (2 mL) and add slowly
1M lithium aluminum hydride in THF (0.82 mL, 0.82 mmol) at room temperature. Stir
the reaction mixture at room temperature for 0.5 h. Quench the reaction mixture with
water until a granular precipitate starts to form and filter through a pad of Celite®.
Evaporate the solvent and purify the residue by SCX chromatography to obtain the title
compound as a yellow oil (0.1 g, 92%). MS (ES+) m/z: 260 (M+H)+.
Preparation 256
6-Aminomethyl-2-phenyl-benzothiazole


6-Methvl-2-phenyl-benzothiazole: Heat at reflux a mixture of 2-amino-5-methyl-
benzenethiol zinc salt (13.5 g, 24.9 mmol, prepared by following the procedure described
in Helv. Chim. Acta 1974, 57, 2664) and ethyl benzimidate hydrochloride (9.23 g, 49.7
mmol) in methanol (240 mL) for 9 h. Filter the mixture, evaporate the filtrate and purify
the residue by chromatography on silica gel eluting with hexane/EtOAc (100:0 to 85:15
gradient) to obtain the desired intermediate (5.7 g, 51%). MS (El) m/z: 225 (M*).
6-Bromomethvl-2-phenvl-benzothiazole: Heat 5-methyl-2-phenyl-benzothiazole (5.7
g, 25.3 mmol) and NBS (4.73 g, 26.6 mmol) in carbon tetrachloride (140 mL) at 80 °C for
3 h. Cool the mixture, double the volume with dichloromethane, filter and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel eluting with
hexane/EtOAc (1:0 to 7:3 gradient) to obtain the desired intermediate (3.1 g, 40%). MS
(El) m/z: 303, 305 (M4).
6-Aniinomethvl-2-phenyl-benzothiazole: Add 6-bromomethyl-2-phenyl-benzothiazole
(2 g, 6.57 mmol) as a suspension in methanol (100 mL) to 7M ammonia in methanol (400
mL) at 0 °C over 10 min and then stir for 3 h at room temperature. Concentrate in vacuo
and purify the crude mixture by chromatography on silica gel eluting with
dichloromethane/methanol (1:0 to 3:1) to obtain the title compound (1.2 g, 76%). MS
(ES+) m/z: 241 (M+H*).
Preparation 257
5-Aminomethyl-2-isobutyl-benzothiazole


2-Oxo-23-dihvdro-benzothiazolc-5-carbonitrile: Heat a mixture of 5-chloro-3//-
benzothiazol-2-one (9.3 g, 50 mmol), nickel(II) bromide (10.9 g, 50 mmol) and sodium
cyanide (4.91 g, 100 mmol) in l-methyl-pyrrolidinone (100 mL) in a microwave reactor
to 200 °C over 15 min and hold 1 h. Filter the cooled mixture through a glass frit, add
diethyl ether and brine and filter again. Wash the organic phase with brine three times
and concentrate in vacuo. Pass the residue through a plug of silica gel eluting with
hexane/EtOAc (2:1) and then dichloromethane/methanol (9:1) to obtain the desired
intermediate (3.2 g, 36%). MS (ES+) m/r. 177 (M+H)+.
2-Bromo-benzothiazole-5-carbonitrile: Heat 2-oxo-2,3-dihydro-benzothiazole-5-
carbonitrile (3.2 g, 18.2 mmol) in toluene (120 mL) with tetrabutylammonium bromide
(8.78 g, 27.2 mmol) and phosphorus pentoxide (7.73 g, 54.5 mmol) for 3 h at reflux.
Cool the mixture, decant the solution from the reaction residue and partition between
diethyl ether and brine. Add water and dichloromethane to the reaction residue and reflux
for 20 min. Wash the dichloromethane layer with saturated aqueous NaHCCb and brine,
and combine with the ether washing. Dry the organic mixture over Na2SO4 and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with hexane/EtOAc (1:0 to 3:7 gradient) to give the desired intermediate (0.85 g, 20%).
MS (El) m/z: 238, 240 (M*).
2-Isobuty-benzothiazole-S-carbonitrile: Heat 2-bromo-benzothiazole-5-carbonitrile
(0.3 g, 1.26 mmol) in l-methyl-pyrrolidinone (4.2 mL) with 2-methylpropylzinc bromide
(5 mL, 2.5 mmol, 0.5M solution inTHF), N-methylimidazole (0.15 g, 1.88 mmol) and
[1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with
dichloromethane (1:1) (20.5 mg, 0.025 mmol) at 80 °C for 3 h. Cool the mixture and
partition between diethyl ether and brine. Dry the organic layer over Na2SC
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with hexane/EtOAc (1:0 to 1:1 gradient) to give the desired intermediate (113 mg, 42%).
MS (El) m/r. 216 (M+).
5-Aminomethyl-2-isobutvl-benzothiazole: Add lithium aluminum hydride (0.78 mL,
0.78 mmol, 1M solution in THF) to 2-isobuty-benzothiazole-5-carbonitrile (113 mg, 0.52
mmol) in THF (5 mL) and stir for 4 h at room temperature. Add water (0.27 mL), 2N
sodium hydroxide (0.27 mL) and water (0.37 mL). Filter the precipitate and wash the
filtrate with brine. Dry over Na2SC>4 and concentrate in vacuo. Purify the crude mixture
by chromatography on silica gel eluting with hexane/EtOAc (1:1) and then 1M ammonia
in methanol/dichloromethane (1:9). Purify the polar fraction by SCX chromatography to
give the title compound (63 mg, 55%). MS (ES+) m/r. 221 (M+H*).
Preparation 258
6-Aminomethyl-benzo[ 1,2,3]thiadiazole

6-Hydroxyniethvl-benzo[l,2.31thiadiazole: Add sodium borohydride (1.35 g, 36 mmol)
in five portions over 4 h to a solution of benzo[l,2,3]thiadiazole-6-carboxylic acid methyl
ester (0.35 g, 1.8 mmol, prepared by following the procedure described in J. Heterocyclic
Chem. 1972,1149) in methanol (18 mL) at 0 °C. Add acetone to quench and evaporate
the mixture onto silica gel. Purify the residue by chromatography on silica gel eluting
with hexane/EtOAc (1:0 to 2:3 gradient) to give the desired intermediate (133 mg, 45%).
MS(GCMS)m/z: 166 M*.
6-Aminomethvl-benzoflt2.31thiadiazole: Stir 6-hydroxymethyl-benzo[l,2,3]thiadiazole
(133 mg, 0.8 mmol) in thionylchloride (5 mL) for 3 h at room temperature. Evaporate the
mixture then add 7M ammonia in methanol (10 mL) and stir at room temperature in a
sealed tube for 48 h. Evaporate the mixture and purify the residue by SCX
chromatography to give the title compound (115 mg, 87%). MS (ES+) m/z: 166 (M+H)+.


Preparation 259
6-Aminomethyl-3-phenyl-benzothiophene
2-(3-Bromo-phenvlthioH-phenyl-ethanone: Add potassium hydroxide (4.89 g, 87.3
mmol) and 2-bromoacetophenone (15.8 g, 79.3 mmol) to a solution of 3-
bromobenzenethiol (15 g, 79.3 mmol) in ethanol (200 mL, 70% in water) at 0 °C. After
stirring 16 h, add water to precipitate a yellow solid. Filter to obtain the desired
intermediate (24.6 g, 100%).
6-Bromo-3-phenylbenzothiophene: Heat2-(3-bromo-phenylthio)-l-phenyl-ethanone (4
g, 13 mmol) in polyphosphoric acid (4 g) at 80 °C for 4 h. Add EtOAc and water to the
mixture and wash with saturated aqueous NaHCOj and brine. Dry the organic layer over
Na2SC>4, filter and concentrate in vacuo. Slurry the residue in hexane and purify by
chromatography on silica gel eluting with hexane to give the desired intermediate that is
used without further purification (2.7 g, 72%). MS (GCMS) m/z: 289 M4".
6-Cvano-3-phenylbenzothiophene: Combine 6-bromo-3-phenylbenzothiophene (0.5 g,
1.73 mmol) and copper cyanide (0.56 g, 6.23 mmol) and reflux 3 h in l-methyl-2-
pyrrolidinone (1.73 mL). Add ferric chloride (2.11 g, 7.79 mmol) in concentrated HC1
(1.73 mL) and stir 1.5 h. Cool the mixture and partition between diethyl ether and brine.
Dry the organic layer over Na2SO4, filter and evaporate onto silica gel. Purify the residue
by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give
the desired intermediate that is used without further purification (0.27 g, 67%). MS
(GCMS) m/z: 235 M+.

6-Aminomethvl-3-phenyI-henzothiophene: Dissolve 6-cyano-3-phenylbenzothiophene
(0.27 g, 1.16 mmol) in anhydrous THF (6 mL) and add lithium aluminum hydride (3.45
mL, 1M solution in THF) at 0 °C. After 2 h, add water (0.86 mL), 2N aqueous NaOH
(0.86 mL) and water (1.24 mL). Filter off the solids and evaporate the residue. Purify by
prep HPLC (Zorbax SB-Phenyl column 21.2 x 250 mm, 5% to 50% acetonitrile in 0.1%
TFA-water solution) and obtain the free base by SCX chromatography to give the title
compound that is used without further purification (187 mg, 68%). MS (ES+) m/z: 223
(M-NH2)+.
Preparation 260
4-(Difluoro-phenyl-methyl)-benzylamine

Combine 4-(difluoro-phenyl-methyl)-toluene (0.29 g, 1.35 mmol, prepared by
following the procedure described in Tetrahedron 1996, 52,9), NBS (0.26 g, 1.48 mmol),
and AIBN (6 mg, 0.03 mmol) in carbon tetrachloride (8 mL) and heat at 80 °C for 16 h.
Evaporate the mixture and pass the residue through a pad of silica gel washing with
hexane and evaporate the filtrate. Dissolve the residue in methanol and add dropwise to
7M ammonia in methanol (100 mL) at 0 °C. After 4.5 h, evaporate the mixture and
isolate the amine by SCX chromatography (0.1 g, 32%). MS (ES+) m/z: 234 (M+H)+.
Preparation 261
4-(3,3-Dimethyl-butyryl)-benzylamine

3,3,4'-Trimethvlbutvrophenone: Add slowly terf-butylacetyl chloride (2 g, 14.858
mmol) to an ice-cold stirred solution of aluminum trichloride (2.972 g, 22.28 mmol) in

anhydrous toluene (40 mL). Stir the reaction mixture at ambient temperature overnight.
Add slowly ice-cold water and extract the mixture twice with EtOAc. Dry the combined
organic extracts over Na2SO4, filter and concentrate in vacuo to give the desired
intermediate (2.82 g, 100%) that was used without any further purification. GC-MS m/z:
190 (M+).
4-(33-DimethvI-butyrvl>-benzYl bromide: Heat a mixture of 3,3,4'-
trimethylbutyrophenone (2 g, 10.52 mmol), NBS (2.061 g, 11.57 mmol), and AIBN (43
mg, 0.263 mmol) in carbon tetrachloride (60 mL) for 14 h at reflux. Cool the reaction
mixture to ambient temperature and wash sequentially with water, 1M aqueous HC1, 5%
aqueous NaHCC^ and brine. Concentrate the organic layer in vacuo to provide the
desired intermediate as oil (2.54 g, 90%) that was used without any further purification.
2-|4-(33-DimethYl-butyry1)-benzvIl-isoindo1e-13-dione: Add 4-(3,3-dimethyl-
butyryl)-benzyl bromide (1 g, 3.731 mmol) to a stirred suspension of potassium
phthalimide (0.705 g, 3.805 mmol) in anhydrous DMF (20 mL). Stir the mixture
overnight at room temperature. Dilute with EtOAc and wash twice with ice-cold water.
Dry the organic layer over Na2SC»4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting sequentially with hexane and
hexane/EtOAc (19:1,4:1) to provide the desired intermediate as oil (1.24 g, 100%).
4-(33-Dimethvl-burvrvl)-bcnzvlamine: Add hydrazine hydrate (0.189 mL, 3.913
mmol) to a stirred suspension of 2-[4-(3,3-dmethyl-butyryl)-benzyl]-isoindole-l,3-dione
(875 mg, 2.609 mmol) in methanol (15 mL). Heat the mixture to reflux overnight. Cool
the mixture to room temperature and concentrate in vacuo. Partition the residue between
EtOAc and 5N aqueous HC1 and wash the acidic aqueous phase again with 5N aqueous
HC1. Basify with 5N aqueous NaOH to pH 12. Extract the basic aqueous solution three
times with chloroform. Dry the combined organic extracts over Na2SO4, filter and
concentrate in vacuo to give the title compound as a yellow oil (411 mg, 77%) that was
used without any further purification.

Preparation 262
4-(3,3-Dimethyl-butyryl)-3-fluoro-benzylamine

4-Azidomethyl-l-bromo-2-fiuoro-benzene: Add sodium azide (2.912 g, 44.8 mmol) to
a solution of 4-bromo-3-fluorobenzyl bromide (6 g, 22.4 mmol) in anhydrous DMF (127
mL) at room temperature under nitrogen. Heat the mixture at 90 °C for 1 h. Concentrate
in vacua and partition the residue between water and EtOAc. Extract the aqueous phase
twice with EtOAc. Wash the combined organics extracts with iced-water. Dry the
organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired
intermediate as a solid (4.92 g, 96%).
4-Bromo-VV-(Yert-butorvcarbonvI)-3-fluoro-benzvlamine: Add 10% Pd/C (492 mg)
and di-terf-butyl-dicarbonate (4.668 g, 21.4 mmol) to a solution of 4-azidomethyl-l-
bromo-2-fluoro-benzene (4.92 g, 21.4 mmol) in ethanol (90 mL) and submit the mixture
to hydrogenation at atmospheric pressure overnight. Filter the reaction mixture over
Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (85:15) to obtain the desired intermediate as a solid (1.55 g, 25%).
A^-(terf-Butoxvcarbonvn-3-fluoro-4-(l-hYdroxY-3J-dimethYl-butvn-benzvIaiiiine:
Add butyllithium (7.3 mL, 11.7 mmol) to a solution of 4-bromo-JV-(/erf-butoxycarbonyl)-
3-fluoro-benzylamine (1.55 g, 5.1 mmol) in diethyl ether (54 mL) at-78 °C under
nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (562 mg, 0.7 mL, 5.6
mmol), stir for 30 min at -78 °C and then warm to room temperature. Add water and
extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over

Na2SC>4, filter and concentrate in vacuo. Purity by chromatography on silica gel eluting
with hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (394 mg,
24%).
iV-(fert-ButoxvcarbonvlM-(33-dimethvI-butYrvl)-3-fluoro-benzvlaniine: Add
manganese dioxide (1.132 g, 13 mmol) to a solution of iV-(ter/-butoxycarbonyl)-3-fluoro-
4-(l-hydroxy-3,3-dimethyl-butyl)-benzylamine (283 mg, 0.87 mmol) in anhydrous 1,4-
dioxane (11.5 mL) at room temperature. Heat the reaction mixture at 70 °C overnight.
Filter the reaction mixture over Celite® and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired
intermediate as an oil (216 mg, 77%).
4-(33-Dimettryl-buryryl)-3-fluoro-benzvlamine: Add 4N hydrogen chloride in dioxane
(2.7 mL, 10.8 mmol) to a solution of iV-(/ert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-3-
fluoro-benzylamine (296 mg, 0.92 mmol) in dichloromethane (11 mL) and stir for 4 h.
Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid in
saturated aqueous NaHCOj and stir for 30 min. Extract twice with dichloromethane. Dry
the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the
title compound as an oil (175 mg, 82%).
Preparation 263
4-(3,3-Dimethyl-butyryl)-2-fluoro-benzylamine

4-Bromo-JV-(tert-butoxvcarbonvlV2-fluoro-benzvlamine: Add triethylamine (6.334 g,
8.8 mL, 52.6 mmol) and di-tert-butyl-dicarbonate (4.54 g, 20.8 mmol) to a solution of 4-
bromo-2-fluoro-benzylamine hydrochloride (5 g, 20.8 mmol) in dichloromethane (254
mL) and stir overnight. Wash the organic layer with water and then extract back the
aqueous phase with dichloromethane. Dry the combined organic extracts over Na2SO4,

filter and concentrate in vacuo to obtain the desired intermediate as a white solid (6.11 g,
Ar-ffgr/-Butoxvcarbonvl>-2-fluoro-4-n-hvdroxv-33-dimethvI-burvl)-benzylaniine:
Add butyllithium (14.2 mL, 22.7 mmol) to a solution of 4-bmmo-N-(tert-
butoxycarbonyl)-2-fluoro-benzylamine (3 g, 9.9 mmol) in diethyl ether (105 mL) at-78
°C under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (1.086 g, 1.4 mL,
10.8 mmol), stir for 30 min at -78 °C and then warm to room temperature. Add water and
extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over
Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1.179 g,
A^-(ter/-BMtorvcarbonYl)-4-(33-dimethYl-butYrvl>-2-fluoro-benzvlamine: Add
manganese dioxide (4.4 g, 50.6 mmol) to a solution of iv"-(fert-butoxycarbonyl)-2-fluoro-
4-(l-hydroxy-3,3-dirnethyl-butyl)-benzylamine (1.1 g, 3.38 mmol) in anhydrous 1,4-
dioxane (45 mL) at room temperature. Heat the reaction mixture at 70 °C overnight.
Filter the reaction mixture over Celite® and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired
intermediate as an oil (980 mg, 90%).
4-(3,3-Dimethvl-butvrvl)-2-fluoro-benzvlamine: Add 4N hydrogen chloride in dioxane
(5.5 mL, 22 mmol) to a solution of iV-(/er/-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-2-
fluoro-benzylamine (600 mg, 1.85 mmol) in dichloromethane (22 mL) and stir for 6.5 h.
Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid
into saturated aqueous NaHCCb and stir for 30 min. Extract the aqueous phase twice with
EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo
to obtain the title compound as an oil (420 mg, 99%).
Preparation 264
3-Chloro-4-(3,3 -dimethy l-butyryl)-benzylam ine


4-Bromo-3-chloro-benzvl bromide: Add NBS (5.266 g, 23.9 mmol) and benzoyl
peroxide (49 mg, 0.2 mmol) to a solution of 4-bromo-3-chlorotoluene (4.925 g, 23.9
mmol) in carbon tetrachloride (49 mL) and heat overnight at 90 °C. Cool to 0 °C and
filter the mixture. Concentrate the filtrate in vacua to obtain the desired intermediate as a
yellow oil (5.807 g, 85%).
4-Bromo-3-chloro-Ar-(di-fgrf-butoxvcarbonvlVbenzvlamine: Add sodium hydride
(382 mg, 15.9 mmol) to a solution of di-terr-butyl-iminodicarboxylate (2.533 g, 11.7
mmol) in anhydrous DMF (15 mL) at room temperature under nitrogen and stir for 15
min. Then add a solution of 4-bromo-3-chloro-benzyl bromide (3 g, 10.6 mmol) in
anhydrous DMF (5 mL) and stir for 1 h. Add water and extract the aqueous phase twice
with EtOAc. Wash the combined organic extracts with iced-water. Dry the organic layer
over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (2.783 g, 62%).
4-Bromo-3-chloro-Ar-(tert-butoxvcarbonyl)-benzylamine: Add a solution of sodium
hydroxide (264 mg, 6.6 mmol) in methanol (23.5 mL) to a solution of 4-bromo-3-chloro-
JV-(di-terf-butoxycarbonyl)-benzylamine (2.783 g, 6.6 mmol) in THF (11.7 mL) and stir
overnight. Concentrate in vacuo. Add water and filter the precipitate formed to obtain
the desired intermediate as a white solid (1.823 g, 86%).

^-(ferZ-ButoxvcarbonvD^-chloro-^fl-hydroxv^^-dimethvl-butYiVbenzvlamine:
Add butyllithium (8.2 mL, 13.1 mmol) to a solution of 4-bromo-3-chloro-./V-(tert-
butoxycarbonyl)-benzylamine (1.823 g, 5.7 mmol) in diethyl ether (46 mL) at -78 °C
under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (1.427 g, 1.7 mL,
14.3 mmol), stir for 30 min at -78 °C and then warm to room temperature. Add water and
extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over
Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc (4:1) to obtain the desired intermediate as a yellow oil (274 mg,
14%).
JV-(terf-ButoxvcarbonYl>-3-chloro-4-f33-dimethvl-butYrvl)-benzYlamine: Add
manganese dioxide (1.096 g, 12.6 mmol) to a solution of JV-(ter/-butoxycarbonyl)-3-
chloro-4-(l-hydroxy-3,3-dimethyl-butyl)-benzylamine (274 mg, 0.8 mmol) in anhydrous
1,4-dioxane (11.5 mL) at room temperature. Heat the mixture at 70 °C overnight. Filter
the reaction mixture over Celite® and concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as a
yellow oil (175 mg, 64%).
3-Chloro-4-(33-dimethvl-butvrvl)-bcnzYlamine: Add 4N hydrogen chloride in
dioxane (0.9 mL, 3.6 mmol) to a solution of AT-(te/-r-butoxycarbonyl)-3-chloro-4-(3,3-
dimethyl-butyryl)-benzylamine (100 mg, 0.3 mmol) in dichloromethane (6 mL) and stir
overnight. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend
the solid into saturated aqueous NaHCO3 and stir for 30 min. Extract twice with
dichoromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate
in vacuo to obtain the title compound as a yellow oil (66 mg, 92%).
Preparation 265
2-Chloro-4-(3,3-dimethyl-butyryl)-benzylamine


4-Bromo-2-chloro-benzyl bromide: AddNBS (13.171 g, 74 mmol) and benzoyl
peroxide (152 mg, 0.63 mmol) to a solution of 4-bromo-2-chlorotoluene (15.2 g, 74
mmol) in carbon tetrachloride (152 mL) and stir for 6 days at 90 °C. Cool to 0 °C, filter
the mixture and concentrate the filtrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (99:1) to obtain the desired intermediate as a yellow oil (12.7
g, 61%).
4-Bromo-2-chloro-A^-di-(ter/-butoxYcarboavlVbenzvlamine: Add sodium hydride
(382 mg, 15.9 mmol) to a solution of di-te/f-butyl-iminodicarboxylate (2.533 g, 11.7
mmol) in anhydrous DMF (15 mL) at room temperature under nitrogen and stir for 15
min. Then add a solution of 4-bromo-2-chloro-benzyl bromide (3 g, 10.6 mmol) in
anhydrous DMF (5 mL) and stir for 1 h. Add water and extract the aqueous phase twice
with EtOAc. Wash the combined organic extracts with iced-water. Dry the organic layer
over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting sequentially with hexane and hexane/EtOAc (4:1) to obtain the desired
intermediate (4.2 g, 94%).
4-Bromo-iV-(ferf-butoxvcarbonyO-2-chloro-benzvlamiiie: Add a solution of sodium
hydroxide (399 mg, 9.98 mmol) in methanol (35.5 mL) to a solution of 4-bromo-2-
chloro-iV-di-(terf-butoxycarbonyl)-benzylamine (4.2 g, 9.98 mmol) in THF (17.7 mL) and
stir overnight. Concentrate in vacuo and partition the residue between water and EtOAc.
Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over
Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting
with hexane/EtOAc (4:1) to obtain the desired intermediate (2.625 g, 82%).

iV-(terr-Butoxvcarbonvl)-2-chloro-4-n-hvdroxv-3.3-dimethYl-butvl)-benzvlainine:
Add butyllithium (11.7 mL, 18.65 mmol) to a solution of 4-bromo-N-(tert-
butoxycarbonyl)-2-chloro-benzylamine (2.601 g, 8.11 mmol) in diethyl ether (86 mL) at-
78 DC under nitrogen and stir for 2 h. Add 3,3-dimethylbutyraldehyde (1.868 g, 2.3 mL,
18.65 mmol), stir for 30 min at -78 °C and then warm to room temperature. Add water
and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over
Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting
hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1.825 mg, 66%).
Ar-(ferf-ButoyvcarbonYl)-2-chloro-4-(33-dimcthvl-buryrvl)-bcnzvlamine: Add
manganese dioxide (7.276 g, 83.7 mmol) to a solution of N-(terf-butoxycarbonyl)-2-
chloro-4-(l-hydroxy-3,3-dimethyl-butyl)-benzylamine (1.819 g, 5.3 mmol) in anhydrous
1,4-dioxane (75 mL) at room temperature. Heat the mixture at 70 °C overnight. Filter the
reaction mixture over Celite® and concentrate in vacuo. Purify by chromatography on
silica gel eluting with hexane/EtOAc (85:15) to obtain the desired intermediate as a
yellow oil (1.362 g, 76%).
2-Chloro-4-(33-dimethyl-hutvrvl>-benzvlamine: Add 4N hydrogen chloride in
dioxane (6 mL, 24 mmol) to a solution of iV-(tert-butoxycarbonyl)-2-chloro-4-(3,3-
dimethyl-butyryl)-benzylamine (700 mg, 2.06 mmol) in dichloromethane (25 mL) and stir
overnight. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend
the solid into saturated aqueous NaHCCb and stir for 30 min. Extract twice with
dichoromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate
in vacuo to obtain the title compound as a yellow oil (477 mg, 97%).
Preparation 266
4-[2-(3,3-Dimethyl-butyl>[l,3]dioxolan-2-yl]-benzylamine

4-(4,4-Dimethvl-pentanovl)-benzonitrile: Keep Mg turnings (402 mg, 15.251 mmol) in
vacuo in a two-neck round bottom flask for 2 h. Purge the flask with nitrogen/vacuo
several times. Add a couple crystals of iodine, anhydrous THF (60 mL) and 3,3-
dimethyl-bromobutane (0.8 mL, 5.59 mmol) slowly (exothermic reaction observed). Add
dropwise the remaining 3,3-dimethyl-bromobutane (1.6 mL, 11.18 mmol) and reflux the
mixture overnight. Add some additional 3,3-dimethyl-bromobutane (0.24 mL, 1.67
mmol) and reflux for 30 min. Cool the mixture to -10 °C and add a solution of 4-
cyanobenzaldehyde (4 g, 30.502 mmol) in anhydrous THF (40 mL). Warm the flask
gradually to room temperature overnight. Quench the mixture with 0.1M aqueous HC1
(100 mL) and extract twice with EtOAc. Dry the combined organic extracts over
Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane/EtOAc (19:1) to give the desired intermediate as an oil
(0.752 g, 23%).
4-f2-(33-Dimethyl-butylH1.31dioxoIaii-2-vll-benzoiiitrile: Dissolve 4-(4,4-dimethyl-
pentanoyl)-benzonitrile (275 mg, 1.28 mmol) in toluene (10 mL). Add ethylene glycol
(0.35 mL, 6.4 mmol) and p-toluenesulfonic acid monohydrate (24 mg, 0.128 mmol). Heat
the mixture at 135 °C in a Dean-Stark for 2 h and then at 120 °C overnight. Cool the
mixture to room temperature, dilute with EtOAc ans wash with saturated aqueous
NaHCCb. Dry the organic phase over MgSCM, filter and concentrate in vacuo. Purify the
crude mixture by chromatography on basic alumina eluting with hexane and
hexane/EtOAc (19:1) to give the desired intermediate as an oil (0.272 g, 82%).
4-l2-(33-Dimethvl-butvl)-[lJldioxolan-2-vll-benzvlamine: Dissolve 4-[2-(3,3-
dimethyl-butyl)-[l,3]dioxolan-2-yl]-benzonitrile (271 mg, 1.046 mmol) in anhydrous
THF (10 mL). Add under nitrogen 1M lithium aluminum hydride in THF (2.1 mL, 2.1

mmol) at 0 °C and stir the mixture at room temperature for 2 h. Cool to 0 °C, add water
and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over
MgSO4, filter and concentrate in vacuo to obtain the desired intermediate as an oil (0.263
mg) that was used without any further purification.
Preparation 267
4-Cyclohexanecarbonyl-benzylamine

Cvclohexvl-p-tolvl-methanone: Dissolve cyclohexanecarbonyl chloride (2 g, 13.6
mmol) in anhydrous toluene (30 mL). Cool the solution to 0 °C, add aluminum
trichloride (2.72 g, 20.46 mmol) in three portions and stir the reaction mixture at ambient
temperature overnight. Cool to 0 °C, add slowly water and extract the mixture with
EtOAc. Dry the organic layer over NajSO^ filter and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc
(19:1) to give the desired intermediate (2.75 g, 100%).
4-(Cvelohexanecarbonyl)-benzvl bromide: Heat a mixture of cyclohexyl-p-tolyl-
methanone (1 g, 4.943 mmol), NBS (1.232 g, 6.92 mmol), and AIBN (41 mg, 0.247
mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Add additional NBS (264 mg)
and AIBN (19 mg) and reflux the mixture for 4 h. Cool the reaction mixture to ambient
temperature and filter. Concentrate the filtrate in vacuo to provide the desired
intermediate as oil (1.132 g, 81%) that was used without any further purification.

(4-Azidomethvl-pheiryI>-cvclohexvl-methanone: Add sodium azide (441 mg, 6.785
mmol) to a stirred solution of 4-(cyclohexanecarbonyI)-benzyl bromide (954 mg, 3.393
mmol) in anhydrous DMF (20 mL) and heat the mixture to 90 °C for 2 h. Cool the
mixture to room temperature, add water and extract the aqueous solution with diethyl
ether. Dry the combined organic extracts over Na2SC>4, filter and concentrate in vacuo.
Purify the crude mixture by chromatography on silica gel eluting with hexane and
hexane/EtOAc (19:1) to give the desired intermediate as oil (310 mg, 38%).
A^-(fgi-/-ButoxYcarbonyl>-4-cvclohexanecarbonvI-benzvlamine: Add 10% Pd/C (100
mg) to a solution of (4-azidomethyl-phenyl)-cyclohexyl-methanone (310 mg, 1,274
mmol) and di-rer/-butyl-dicarbonate (278 mg, 1274 mmol) in ethanol (5 mL). Submit the
mixture to hydrogenation under atmospheric pressure (balloon) for 1 h. Filter the catalyst
through Celite® and concentrate the filtrate in vacua. Purify the crude mixture by
chromatography on silica gel eluting with hexane and hexane/EtOAc (92:8) to provide the
desired intermediate as a white solid (197 mg, 49%).
4-Cvclohexanecarbonyl-benzylamine: Add 4N hydrogen chloride in dioxane (1 mL) to
a stirred solution of AT-(terNbutoxycarbonyl)-4-cyclohexanecarbonyl-benzylarnine (197
mg, 0.621 mmol) in anhydrous dichloromethane (4 mL) and stir the mixture at ambient
temperature for 16 h. Concentrate in vacuo and partition the residue between
dichloromethane and saturated aqueous NaHCO3. Extract the aqueous phase twice with
dichloromethane. Dry the combined organic extracts over Na2SC>4, filter and concentrate
in vacuo to give the title compound (125 mg, 93%) that was used without any further
purification. MS (ES+) m/z: 218 (M+H)+.
Preparation 268
4-(2-Cyclopentyl-acetyl)-benzylamine


2-Cyclopentyl-l-p-torvl-ethanoiie: Add aluminum trichloride (2.719 g, 20.4 mmol) in
three portions to a solution of cyclopentylacetyl chloride (2 g, 13.6 mmol) in anhydrous
toluene (30 mL) at 0 °C. Stir the solution at room temperature overnight. Cool to 0 °C,
add water and extract the aqueous phase with EtOAc. Dry the organic phase over
MgSC>4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate
as an oil (2.5 g, 91%).
l-(4-Bromomethvl-phenvlV2-cvclopcnryl-cthanone: Add NBS (523 mg, 2.94 mmol)
and A1BN (44 mg, 0.267 mmol) to a solution of 2-cyclopentyl-l-/?-tolyl-ethanone (540
mg, 2.67 mmol) in carbon tetrachloride (80 mL) and heat overnight at 85 °C. Add water
and extract the aqueous phase with dichloromethane. Dry the organic phase over MgSO,j,
filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel
eluting with hexane and hexane/EtOAc (98:2, 95:5) to obtain the desired intermediate as
an oil (479 mg, 64%).
7V-Di-(fer/-butoxYcarbonYl>-4-('2-cvclopentvl-acetvlVbenzvlamine: Add sodium
hydride (42 mg, 1.65 mmol) to a solution of di-/er/-butyl-iminodicarboxylate (262 mg,
1.21 mmol) in anhydrous DMF (5 mL) at room temperature under nitrogen and stir for 5
min. Then add a solution of l-(4-bromomethyl-phenyl)-2-cyclopentyl-ethanone (310 mg,
1.1 mmol) in anhydrous DMF (15 mL) and stir for 1 h. Add water and extract the
aqueous phase twice with EtOAc. Wash the combined organic extracts with iced-water.
Dry the organic layer over MgSO-t, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (19:1) to obtain the desired
intermediate (360 mg, 78%).

4-(2-Cvclopentvl-acetYl)-benrylamine: Add 4N hydrogen chloride in dioxane (15 mL)
to a solution of N mg, 0.72 mmol) in EtOAc (20 mL) and stir overnight. Concentrate in vacuo, suspend the
solid obtained in diethyl ether and add hexane. Filter and wash the solid with hexane.
Suspend the solid into dichloromethane, add saturated aqueous NaHCO3 and stir until
both phases are clear (15 min). Extract the aqueous phase with dichoromethane and
EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo
to obtain the title compound as an oil that was used without any further purification.
Preparation 268
The compound of Preparation 269 may be prepared essentially as described in
Preparation 268 by using cyclohexylacetyl chloride. Overall yield and MS (ES+) data are
shown in the Table below.

Preparation 270

5-Azidomethvl-2-f3-methvl-butvrvlVpvridine; Add DBU (240 mg, 1.55 mmol) to a
solution of 5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (250 mg, 1.29 mmol) and
diphenylphosphorylazide (430 mg, 1.55 mmol) in anhydrous toluene (10 mL) at 0 °C.
Stir at 0 °C for 30 min, warm to room temperature and stir for 4 h. Dilute with EtOAc
and water. Extract the aqueous phase twice with EtOAc. Dry the combined organic
extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by

chromatography on silica gel eluting with hexane and hexane/EtOAc (9:1) to provide the
desired intermediate (300 mg, 99%). MS (ES+) Wz: 219 (M+H)+.
5-Aminomethvl-2-fl-hvdro,\v-3-methvl-butvl)-pvridinehvdrochloritlc: Add 10%
Pd/C (20 mg) to a solution of 5-azidomethyl-2-(3-methyl-butyryl)-pyridine (80 mg, 0.367
mmol) in ethanol (10 mL) containing concentrated HC1 (1 mL). Submit the mixture to
hydrogenation at atmospheric pressure for 2 h. Filter the reaction mixture over Celite®
and concentrate in vacuo to afford the desired intermediate (95 mg, 98%). MS (ES+) m/z:
195 (M+H)+.
5-ter/-ButoxycarbonYlaminomethvl-2-(l-hvdroxv-3-methvI-butYl>-PYridine: Add di-
terf-butyl-dicarbonate (78 mg, 0.356 mmol) and triethylamine (0.149 mL, 1.068 mmol) to
a solution of 5-aminomethyl-2-(l-hydroxy-3-methyl-butyl)-pyridine hydrochloride (95
mg, 0.356 mmol) in anhydrous dichloromethane (5 mL). Stir the solution at room
temperature for 3 h. Dilute the reaction mixture with dichloromethane and wash with
water. Extract the aqueous phase with dichloromethane. Dry the combined organic
extracts over Na2SC>4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to afford the desired
intermediate (60 mg, 59%).
5-terNButoxvcarbonylaminomethyl-2-(3-methyl-butyrvl)-pvridine: Add manganese
dioxide (240 mg) to a solution of 5-fe/?-butoxycarbonylaminomethyl-2-(l-hydroxy-3-
methyl-butyl)-pyridine (60 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1 mL) at room
temperature. Heat the reaction mixture at 70 °C for 2 h. Filter the reaction mixture over
Celite® and concentrate in vacuo to afford the desired intermediate (60 mg, 99%).
5-Aminomethvl-2-(3-methyl-butvrvlVDvridine: Add 4N hydrogen chloride in dioxane
(0.5 mL) to a solution of 5-ter^butoxycarbonylaminomethyl-2-(3-methyl-butyryl)-
pyridine (60 mg, 0.2 mmol) in anhydrous dichloromethane (2 mL) and stir the solution
overnight. Concentrate in vacuo and partition the residue between saturated aqueous
NaHCC>3 and dichloromethane. Extract the aqueous phase with dichloromethane (2x15

mL) and EtOAc (2x15 mL). Dry the combined organic extracts over Na2SC>4, filter and
concentrate in vacuo to obtain the title compound (37 mg, 95%) that was used without
any further purification.
Preparation 271
2-Bromo-5-ter/-butoxycarbonylaminomethyl-pyridine

2-Bromo-pyridine-5-carbaldehYdeoxime: Add hydroxylamine hydrochloride (1.494 g,
21.504 mmol) and a solution of NaHCO3 (2.71 g, 32.256 mmol) in water (15 mL) to a
solution of 2-bromo-5-formyl-pyridine (2 g, 10.752 mmol, prepared by following the
procedure described in J. Org. Chem. 2004, 69, 250-262) in absolute ethanol (100 mL).
Stir the mixture at room temperature for 2 h. Concentrate in vacuo and partition the
residue between EtOAc and water. Extract the aqueous phase with EtOAc. Dry the
combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (9:1,
4:1) to afford the desired intermediate as a solid (1.362 g, 63%).
5-Aminomethvl-2-bromo-Dvridine: Add dropwise a solution of 2-bromo-pyridine-5-
carbaldehyde oxime (0.5 g, 2.487 mmol) in DME (10 mL) to a solution of titanium(IV)
chloride (0.573 mL, 5.223 mmol) and sodium borohydride (395 mg, 10.445 mmol) in
DME (20 mL) at 0 °C. Allow the mixture to warm to room temperature and stir for 3 h.
Add water and remove the solvent in vacuo. Basify the mixture to pH 12 with IN
aqueous NaOH and extract with dichloromethane. Dry the combined organic extracts
over Na2SO4, filter and concentrate in vacuo to afford the desired intermediate (340 mg,
73%) that was used without further purification.
2-Bromo-5-fer/-butoxvcarbonylaminomethvl-pvridine: Add di-fert-butyl-dicarbonate
(397 mg, 1.818 mmol) and triethylamine (0.507 mL, 3.636 mmol) to a solution of 5-

aminomethyl-2-bromo-pyridine (340 mg, 1.818 mmol) in anhydrous dichloromethane (15
mL). Stir the solution overnight at room temperature. Dilute the reaction mixture with
dichloromethane and wash with water. Extract the aqueous phase with dichloromethane.
Dry the combined organic extracts over Na2SC>4, filter and concentrate in vacua. Purify
the crude mixture by chromatography on silica gel eluting with hexane and
hexane/EtOAc (4:1) to afford the title compound as a solid (322 mg, 62%).
Preparation 272
5-Aminomethyl-2-(3,3-dimethyl-butyryl)-pyridine

5-fgrf-Butoxvcarbonvlaniinomethvl-2-(l-hvdroxv-33-dimethvl-butvl)-pvridine: Add
slowly butyllithium (1.088 mL, 1.741 mmol, 1.6M solution in hexane) to a solution of 2-
bromo-5-/erf-butoxycarbonyiaminomethyl-pyridine (200 mg, 0.696 mmol) in anhydrous
THF (10 mL) at -78 °C. Stir the mixture at this temperature for 35 min. Add 3,3-
dimethylbutyraldehyde (0.219 mL, 1.741 mmol) and stir the mixture at-78 °C for 3 h.
Quench the reaction mixture at -78 °C with brine. Extract the aqueous phase with EtOAc
(3x15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and
hexane/EtOAc (3:2) to afford the desired intermediate as a colorless oil (118 mg, 55%).
MS (ES+) m/z: 309 (M+H)+.
5-fgr/-Butoxvcarbonvlaminomethvl-2-(33-dimethyl-butvrvl>Pvridine: Add
manganese dioxide (472 mg, 5.429 mmol) to a solution of S-tert-
butoxycarbonylaminomethyl-2-(l-hydroxy-3,3-dimethyl-butyl)-pyridine (118 mg, 0.383
mmol) in anhydrous 1,4-dioxane (5 mL) at room temperature. Heat the reaction mixture
at 70 °C overnight. Filter the reaction mixture over Celite® and concentrate in vacuo to
obtain the desired intermediate (104 mg, 89%).

5-Aminomethvl-2-(3,3-dimethvl-butyrvlVpvridine: Add 4N hydrogen chloride in
dioxane (1 mL) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(3,3-dimethyl-
butyryl)-pyridine (104 mg, 0.339 mmol) in anhydrous dichloromethane (4 mL) and stir
the solution overnight. Concentrate in vacuo and partition the residue between saturated
aqueous NaHCO3 and dichloromethane. Extract the aqueous phase with dichloromethane
(2 x 15 mL) and EtOAc (2x15 mL). Dry the combined organic extracts over Na2SO4,
filter and concentrate in vacuo to obtain the title compound as an oil (62 mg, 88%) that
was used without any further purification. MS (ES+) m/z: 207 (M+H)+.
Preparation 273
4-Aminomethyl-iV-cycloheptyl-2-fluoro-benzamide

Methyl 4-bromo-2-fluoro-benzoate: Dissolve 4-bromo-2-fluoro-benzoic acid (15 g,
68.5 mmol) in methanol (70 mL). Add concentrated sulfuric acid (500 u.1) to the solution
and heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to
room temperature and concentrate in vacuo. Dissolve the residue in EtOAc (200 mL) and
wash successively with saturated aqueous NaHCQj (50 mL) and water (2 x 50 mL). Dry
the organic layer over NajSO-t, filter and concentrate in vacuo to obtain the desired
intermediate (15.4 g, 96%). GC-MS m/z: 232 (M")-
Methyl 4-cvano-2-fluoro-benzoate: Slurry methyl 4-bromo-2-fluoro-benzoate (5 g,
21.5 mmol) and copper(I) cyanide (3.8 g, 42.9 mmol) in anhydrous DMF (90 mL). Heat
the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room
temperature, dilute with hexane/EtOAc (1:1, 300 mL) and water (150 mL). Filter the
mixture through Celite® washing with hexane/EtOAc (1:1) to reduce the emulsion layer.

Separate the organic layer and extract the aqueous layer with hexane/EtOAc (1:1,2 x 200
mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo.
Purity the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1
to 1:1 gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m/z: 179 (lvf).
4-Cyano-2-fluoro-benzoic acid: Dissolve methyl 4-cyano-2-fluoro-benzoate (2.9 g,
16.2 mmol) in absolute ethanol (100 mL). Add potassium hydroxide (4.5 g, 80.2 mmol)
and stir the milky white mixture for 1.5 h. Dilute the mixture with water (125 mL) and
wash with diethyl ether (50 mL). Collect the aqueous layer and concentrate in vacuo until
solids start to appear in the flask, then adjust the mixture to pH 1 with concentrated HC1.
Extract the aqueous mixture with diethyl ether (3 x 500 mL). Combine the organic
extracts and concentrate in vacuo to obtain the desired intermediate as a white solid (2.2
g, 83%).
4-Cvano-iV-cvcloheptyl-2-fluoro-benzamide: Dissolve 4-cyano-2-fluoro-benzoic acid
(1 g, 6.1 mmol) in anhydrous toluene (25 mL) and thionyl chloride (15 mL). Stir the
mixture for 1 h at 90 °C under a nitrogen atmosphere (quench aliquots with methanol and
assay by HPLC to determine if starting material has been consumed). Cool the reaction
to room temperature and concentrate in vacuo to obtain the acid chloride as a yellow oil
(1.25 g). Dissolve the acid chloride (1.25 g) in diethyl ether (75 mL), add triethylamine
(0.85 mL, 6.1 mmol) and cylcoheptylamine (0.78 mL, 6.1 mmol). Stir the mixture at
room temperature for 16 h under a nitrogen atmosphere. Quench the reaction with
saturated aqueous Na2CC>3 (20 mL). Extract the mixture with EtOAc (30 mL). Dry the
organic layer over Na2SC>4, filter and concentrate in vacuo to obtain the desired
intermediate (1.45 g, 91%). GC-MS m/z: 260 (M*)-
4-Aminomethyl-iV-cvclohcprvl-2-fluoro-benzaniide: Add 4-cyano-iV-cycloheptyl-2-
fluoro-benzamide (1.4 g, 5.4 mmol), 10% Pd/C (Degussa type E101, 415 mg), ethanol
(40 mL), water (15 mL) and acetic acid (1.8 mL) to a pressure vessel. Pressurize the
vessel to 55 psi with hydrogen, and stir the mixture for 0.5 h (monitor the reaction by
TLC). Filter the mixture through Celite® and wash the cake with warm ethanol followed

by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to
obtain the product as the acetic acid salt. Use SCX chromatography to obtain the title
compound (1.36 g, 95%). GC-MS m/z: 264 (M+).
Preparation 274
4-Aminomethyl-iV-cycloheptyl-3-fluoro-benzamide

4-Cvano-7V-cvcloheptyl-3-nuoro-benzamide: Dissolve 4-cyano-3-fluoro-benzoic acid
(1 g, 6.1 mmol) in anhydrous toluene (20 mL) and thionyl chloride (10 mL). Stir the
mixture for 1.5 h at 90 °C under a nitrogen atmosphere (quench aliquots with methanol
and assay by HPLC to determine if starting material has been consumed). Cool the
reaction to room temperature and concentrate in vacuo to obtain the acid chloride as a
yellow oil. Dissolve the yellow oil in diethyl ether (50 mL), add triethylamine (0.86 mL,
6.1 mmol) and cycloheptylamine (0.79 mL, 6.1 mmol). Stir the mixture at room
temperature for 16 h under a nitrogen atmosphere. Quench the reaction with saturated
aqueous Na2CC>3 (20 mL). Extract the mixture with EtOAc (2 x 50 mL). Dry the
combined organic extracts over Na2SO,t, filter and concentrate in vacuo to obtain the
desired intermediate (1.24 g, 77%). MS (ES-) m/z: 259.2 (M-H)+.
4-Aniinomethvl-7V-cvcloheptvl-3-fluoro-benzamide: Add 4-cyano-AT-cycloheptyl-3-
fluoro-benzamide (0.86 g, 3.3 mmol), 10% Pd/C (Degussa type E101, 250 mg), ethanol
(25 mL), water (9 mL) and acetic acid (1 mL) to a pressure vessel under a nitrogen
atmosphere. Pressurize the vessel to 50 psi with hydrogen, and stir the mixture for 0.5 h.
Filter the mixture through Celite® and wash the cake with warm ethanol followed by
dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain
the title compound as the acetic acid salt. Use SCX chromatography to obtain the title
compound (805 mg, 92%). MS (ES+) m/z: 265.3 (M+H)+.


BocHN H2N'
2-Chloro-4-cvanoWV-cvcloheptvl-benzamide: Dissolve 2-chloro-4-cyano-benzoic acid
(1.1 g, 6 mmol) in anhydrous toluene (20 mL) and thionyl chloride (15 mL). Stir the
mixture for 1 h at 90 °C under a nitrogen atmosphere (quench aliquots with methanol and
assay by HPLC to determine if starting material has been consumed). Cool the reaction
to room temperature and concentrate in vacuo to obtain the acid chloride as an oil.
Dissolve the oil in diethyl ether (40 mL), add triethylamine (0.84 mL, 6 mmol) and
cycloheptylamine (0.77 mL, 6 mmol). Stir the mixture at room temperature for 1 h under
a nitrogen atmosphere. Quench the reaction with saturated aqueous Na2CO3 (20 mL).
Extract the mixture with EtOAc (100 mL). Dry the organic layer over Na2SO4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with dichloromethane to obtain the desired intermediate (1.1 g, 66%). MS (ES+) m/z:
277.2 (M+H)+.
4- terf-ButoxvcarbonvlaminomethYl-2-chloro-JV-cvcloheptvI-benzamide: Dissolve 2-
chloro-4-cyano-AT-cycloheptyl-benzamide (460 mg, 1.7 mmol) in methanol (15 mL).
Cool the solution to 0 °C under a nitrogen atmosphere and add di-terr-butyl dicarbonate
(726 mg, 3.3 mmol) and nickel(ll) chloride hexahydrate (40 mg, 0.17 mmol). Add then
sodium borohydride (360 mg, 9.5 mmol) portionwise over 30 min. Stir at 0 °C for 1 h
then concentrate the mixture in vacuo. Dilute the residue with EtOAc (100 mL), wash
with saturated aqueous NaHCC>3 (40 mL). Extract the aqueous layer with EtOAc (3 x 40
mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo.
Purify the crude mixture by chromatography on silica gel eluting with EtOAc to obtain
the desired intermediate (627 mg, 99%). MS (ES+) m/z: 381.3 (M+H)+.

4-Aminomethvl-2-chloro-A/-cYcIoheptyl-benzamide: Dissolve 4- tert-
butoxycarbonylaminomethyl-2-chloro-AT-cycloheptyl-benzamide (624 tng, 1.6 mmol) in
dichloromethane (30 mL) then add trifluoroacetic acid (2 mL). Stir the solution at room
temperature under a nitrogen atmosphere for 1 h. Concentrate the mixture in vacuo.
Purify the crude mixture by SCX chromatography to obtain the desired intermediate (395
mg, 85%). MS (ES+) m/z: 281.2 (M+H)+.
Preparation 276
4-Aminomethyl-A'-cycloheptyl-2-methyl-benzarnide

4-Cvano-7V-cvcloheptvl-2-methyl-benzamide: Add cycloheptylamine (0.83 mL, 6.5
mmol), HOBT (838 mg, 6.2 mmol), EDC (1.2 g, 6.2 mmol) and diisopropylethylamine
(3.2 mL, 18.6 mmol) to a solution of 4-cyano-2-methyl-benzoic acid (1 g, 6.2 mmol) in
dichloromethane (20 mL) at room temperature under a nitrogen atmosphere. Stir the
mixture for 16 h at room temperature. Wash the mixture with water (20 mL), separate
and concentrate the organic layer in vacuo. Purify the crude mixture by chromatography
on silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain the desired
intermediate (830 mg, 52%). MS (ES+) m/z: 257.3 (M+H)4-Aminomethyl-iY-cvcloheptvl-2-methyl-benzamide: Add 4-cyano-A'-cycloheptyl-2-
methyl-benzamide (0.82 g, 3.2 mmol), ethanol (23 mL), water (8 mL) and acetic acid (1
mL) to a pressure vessel. Heat vessel to 50 °C to dissolve all solids. Add 10% Pd/C
(Degussa type E101, 250 mg) under a nitrogen atmosphere, then pressurize the vessel to
55 psi with hydrogen at ambient temperature. Stir the mixture for 40 min. Filter the
mixture through Celite® and wash the cake with warm ethanol (50 mL) followed by
dichloromethane (100 mL) under a nitrogen atmosphere. Concentrate the filtrate in vacuo

to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain
the title compound (820 mg, 98%). MS (ES+) m/z: 261.3 (M+H)+.
Preparation 277
(/?)-4-Aminomethyl-2-fluoro-A^-(2,2,2-trifluoro-l-methyl-ethyl)-benzamide

(gM-Cvano-l-fluoro-^-rZ^a-trifluoro-l-methvl-ethvD-benzamide: Add (#)-(2,2,2-
trifluoro-l-methyl)-ethylamine (0.909 g, 6.08 mmol), HOBT (0.82 g, 6.1 mmol),
diisopropylethylamine (2.1 mL, 12 mmol) and EDC (1.17 g, 6.08 mmol) to a mixture of
4-cyano-2-fluorobenzoic acid (1.004 g, 6.08 mmol) in anhydrous THF (40 mL) at room
temperature. Stir overnight and partition the mixture between EtOAc (250 mL) and
saturated aqueous NaHCC>3 (100 mL). Dry the organic extract over Na2SO4, filter and
concentrate in vacuo. Purify by chromatography on silica gel eluting with
dichloromethane/hexane (1:1 to 1:0 gradient over 71 min; 50 mL/min) to afford the
desired intermediate as a white solid (0.985 g, 62%).
(Jt)-4-Aminomethvl-2-fluoro-Ar-(2Jv2-trifluoro-l-methvl-ethvl)-benzaniide:
Combine a solution of (/f)-4-cyano-2-fluoro-A^-(2,2,2-trifluoro-l-methyl-ethyl)-
benzamide (0.904 g, 3.475 mmol) in absolute ethanol (26 mL), water (9.7 mL) and glacial
acetic acid (1.2 mL) with 10% Pd/C (Degussa type El 01, 0.27 g, 0.13 mmol) under
nitrogen. Purge the mixture with nitrogen and then with hydrogen. Stir the slurry at
room temperature under hydrogen at 55 psi for 30 min. Purge the reaction mixture with
nitrogen and then filter the slurry over Celite®. Wash the filter cake with ethanol (100
mL) and THF (100 mL). Concentrate the filtrate and purify by SCX chromatography
eluting with dichloromethane/methanol (1:1) to remove impurities and then with
dichloromethane/2M ammonia in methanol (1:1) to elute product. Concentrate to afford
the title compound as a colorless oil (0.86 g, 94%).

Preparation 278
3-rer/-Butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2(3,4,5-tetrahydro-
l//-benzo[c/]azepine

Methyl 4-aminomethyl-2-fluoro-benzoate: Combine a solution of methyl 4-cyano-2-
fluoro-benzoate (1 g, 5.58 mmol) in absolute ethanol (42 mL) and acetic acid (1.9 mL)
with a mixture of 10% Pd/C (Degussa type E101,0.17 g, 0.078 mmol) in water (15.6 mL)
at room temperature under nitrogen. Purge with nitrogen and then with hydrogen at 55
psi and stir for 1 h. Purge the reaction with nitrogen, filter through Celite® and wash the
filter cake with ethanol (100 mL), THF (100 mL) and isopropanol (100 mL). Concentrate
in vacuo and purify by SCX chromatography and then chromatography on silica gel (40 g
RediSep® column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 9:1
gradient over 30 min; 35 mL/min) to afford the desired intermediate as a white solid
(0.602 g, 59%).
7-Chloro-6-(3-fluoro-4-methoxvcarbonvl-benzvlamino)-3-f2v2^-trifluoroacetvl)-
23.4,5-tetrahvdro-l//-benzo[t/|azepine: Use a method similar to the General Procedure
5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-
fluoro-benzoate (1.065 g, 5.821 mmol) by using tris(dibenzylideneacetone)dipalladium(0)
(0.533 g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol) and cesium carbonate (3.32 g, 10.2
mmol) under nitrogen in anhydrous toluene (20 mL). Purify by chromatography on silica
gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min) to afford
the desired intermediate as a yellow oil (1.3 g, 100%).

7-Chloro-6-(3-fluoro-4-methoxvcarbonvl-benzYlamino>-2,3,4,5-tetrahvdro-lJy-
benzof|azepine: Add 1M aqueous NaOH (2.8 mL, 2.8 mmol) to a solution of 7-chloro-
6-(3-fluoro-4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (1.31 g, 2.86 mmol) in 1,4-dioxane (13.3 mL) and water
(2.6 mL) at 11 °C. Allow mixture to warm to room temperature and stir for 1 h.
Concentrate in vacuo and partition the residue between dichloromethane (250 mL) and
saturated aqueous NaHCO3 (100 mL). Dry the organic phase over Na2SO4, filter and
concentrate in vacuo to afford the desired intermediate that was used without further
purification.
3-terr-BntoxYcarbonvl-6-(4-carboxv-3-fluoro-benzvlamino)-7-chIoro-2.3,4t5-
tetrahydro-1/y-benzoUflazepine: Add 1M aqueous NaOH (5.7 mL, 5.7 mmol) to a
mixture of 7-chloro-6-(3-fluoro-4-methoxycarbonyl-benzylamino)-2,3,4,5-tetrahydro- \H-
benzo[]azepine (1.04 g, 2.86 mmol) in 1,4-dioxane (13.3 mL) and water (2.6 mL) at
room temperature. Heat the mixture at 50 °C for 2 h. Cool the mixture to 0 °C, add a
solution of di-ferf-butyl-dicarbonate (0.62 g, 2.9 mmol) in 1,4-dioxane (2 mL) and stir at
0 °C for 2 h. Concentrate in vacuo, add EtOAc (50 mL), IN aqueous KHSO4 (5.7 mL,
5.7 mmol) and water (20 mL) to pH=l. Dry the organic phase over NajSOt, filter and
concentrate in vacuo to afford the title compound as a yellow oil (1.25 g, 98%) that was
used without further purification. MS (ES+) m/r. 449.1 (M+H)+.
Preparation 279
5-Aminomethyl-2-cyclohexylamino-pyridine

•v
6-Cvelohexvlamino-nicotinonitrile: Add cyclohexylamine (7.1 g, 72 mmol) to a
mixture of 6-chloronicotinitrile (1 g, 7.2 mmol), potassium carbonate (3 g, 21.7 mmol)
and anhydrous DMF (10 mL). Heat the mixture in a sealed flask at 120 °C for 1.5 h.

Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 100 mL) and
wash the mixture with aqueous 5% sodium chloride (3 x 30 mL). Collect the organic
layer and concentrate in vacua to obtain the desired intermediate (1.4 g, 97%). GC-MS
m/z: 201 (M1).
5-Aminomethvl-2-evclohexvIamino-pvridine: Charge a solution of 6-
cyclohexylamino-nicotinonitrile (1.4 g, 7.1 mmol) in methanol (70 mL) and
trifluoroacetic acid (5 mL) to a pressure vessel containing 10% Pd/C (Degussa type E101,
600 mg). Pressurize the vessel to 40 psi with hydrogen and stir for 2 h. Filter the mixture
through Celite®, wash with warm ethanol, and dichloromethane. Concentrate the filtrate
in vacuo. Purify the crude mixture by chromatography on silica gel eluting with
dichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to obtain the title
compound (920 mg, 54%). MS (ES+) m/z: 206.1 (M+H)+.
Preparation 280
Preparation 281
6-Benzylamino-pyridin-3-ylmethylamine
The compound of Preparation 280 may be prepared essentially as described in
Preparation 279 using 6-chloronicotinonitrile and cylclohexylmethylamine. Overall yield
and MS (ES+) data are shown in the Table below.



6-Benzylamino-nicotinonitriIe: Heat 6-chloroniconitrile (0.58 g, 4.2 mmol) and
benzylamine (4.6 mL, 42 mmol) in anhydrous DMF (3 mL) at 120 °C for 4.5 h. Cool at
room temperature. Dilute with water and extract with EtOAc. Wash the organic phase
with brine, dry over MgSC>4, filter, and concentrate in vacua. Purify by chromatography
on silica gel eluting sequentially with hexane/EtOAc (4:1, 2:1, 1:2) to give the desired
intermediate as a white solid (840 mg, 96%). MS (ES+) m/z: 210 (M+H)+.
6-Benzvlamino-pyridin-3-vlmethvlamine: Stir 6-benzylamino-nicotinonitrile (680 mg,
3.3 mmol) and 10% Pd/C (Deg^issa type E101) vigorously in absolute ethanol (80 mL)
under hydrogen at 25 psi for 1 h. Filter the solution through Celite® and concentrate in
vacuo. Purify by chromatography on silica gel eluting sequentially with 2M ammonia in
methanol/dichloromethane (4:96, 9:91) to give the title compound as a white solid (320
mg,45%). MS(ES+)Wz:214(M+H)+.
Preparation 282
(±)-4-[l-(l(l,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine

(±">-4-fl-(1.1.2.2J-Pentafluoroethvn-ethoxvl-benzonitrile: Add potassium carbonate
(27.4 g, 198 mmol) to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±)-3,3,4,4,4-
pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). Heat the mixture
in a sealed flask for 4 h at 130 °C. Cool the reaction to ambient temperature, dilute with

hexane/EtOAc (1:1, 350 mL) and wash with aqueous 5% sodium chloride (3 x 100 mL).
Collect the organic layer, dry over Na2SO4, filter and concentrate in vacuo to obtain the
desired intermediate (17.1 g, 98%). GC-MS m/r. 432 (M+).
(±V4-H-n.lJ^^-PentafluoroethYlVethoxvl-benzylamine: Add (±)-4-[l-( 1,1,2,2,2-
pentafluoroethyl)-ethoxy]-benzonitrile (1 g, 3.8 mmol) to a slurry of lithium aluminum
hydride (400 mg, 10 mmol) in diethyl ether (30 mL) at 0 °C under a nitrogen atmosphere.
Stir the mixture at ambient temperature for 2 h, and then quench the reaction sequentially
with water (1 mL) and 5N sodium hydroxide (1 mL). Filter the slurry through Celite®,
dry the filtrate over Na2SO4, filter and concentrate in vacuo to obtain the title compound
(990 mg, 98%). GC-MS m/r. 268 (lvf).
Preparation 283
4-[l -(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine Isomer

4-|l-(lX2,2v2-Pcntafluoroethvl)-ethoxv1-benzonitrile Isomer 2: Separate (±)-4-[l-
(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile by normal phase chiral chromatography
(Chiralcel OJ, 8 x 33 cm, elute with heptane/3A ethanol 97:3, flow rate 375 mL/min).
Collect the 2nd eluting isomer as the desired intermediate (11.3 g, 40% recovery, 98.6% ee
(Chiralcel OJ, 4.6 x 250 mm, elute with heptane/3A ethanol 97:3, 1 mL/min). GC-MS
m/z: 265 (M4).
4-[l-(l,l,2,2,2-PentafliioroethvO-ethoxvl-benzvlamine Isomer 2: Reduce 4-[l-
(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile isomer 2 (11.4 g, 43 mmol) using
General Procedure 6-4 to obtain the title compound (11.38 g, 98%). GC-MS m/r. 268
(M+).

Preparation 284
4-[l-(l,l,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine Isomer 1

4-|l-(l,l,2,2,2-Pentafluoroethvl)-ethoxvl-benzonitrile Isomer 1: Separate (±)-4-[l-
(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile by normal phase chiral chromatography
(Chiralcel OJ, 8 x 33 cm, elute with heptane/3A ethanol 97:3, flow rate 375 mL/min).
Collect the 1st eluting isomer as the desired intermediate (4.5 g, 33% recovery, 99.3% ee
(Chiralcel OJ, 4.6 x 250 mm, elute with heptane/3A ethanol 97:3, 1 mL/min). GC-MS
m/z: 265 (M+).
4-[l-(l,1,2,2,2-PentafluoroethyQ-ethoxvl-benzvlamine Isomer 1: Reduce 4-[l-
(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile isomer 1 (4.5 g, 17mmol) using
General Procedure 6-4 to obtain the title compound (4.3 g, 94%). GC-MS m/z: 268 (M+).
Preparation 285
(±)-2-Aminomethyl-5-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-pyridine

5-Chloro-pvridine-2-carbonitrile: Slurry 2,5-dichloropyridine (6 g, 40.5 mmol), zinc
cyanide (2.9 g, 24.7 mmol), zinc (dust) (116 mg, 1.8 mmol) and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane
(720 mg, 0.98 mmol) in anhydrous DMF (40 mL). Heat the mixture to reflux under a
nitrogen atmosphere for 4.5 h. Cool the mixture to room temperature, dilute with EtOAc

(300 mL), wash with aqueous 10% sodium chloride (3 x 75 mL). Collect organic layer,
dry over Na2SC>4, filter and concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.6 g,
46%). GC-MS m/z: 138 (M+).
(±)-4-[l-fl,lv2vZ^-Pentafluoroethvl)-ethoxvl-pvridine-2-carbonitrile: Add (±)-
3,3,4,4,4-pentafluoro-2-butanol (710 mg, 4.3 mmol) slowly to a slurry of sodium hydride
(104 mg, 1.2 equiv, 60% mineral oil, washed with hexane) in hexamethylphosphoramide
(2 mL) under nitrogen at 0 °C. Allow the slurry to warm to ambient temperature and stir
for 5 min. Add 5-chloro-pyridine-2-carbonitrile (300 mg, 2.2 mmol), then heat the
mixture in a sealed flask at 130 °C for 4 h (monitor reaction by GC/MS). Cool the
reaction to room temperature, adjust the mixture to pH 9 with saturated aqueous Na2COj,
then extract with diethyl ether (2 x 50 mL). Dry the combined organic extracts over
Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient) to obtain the desired
intermediate (380 mg, 66%). GC-MS m/z: 266 (NT).
(±V2-Aminomethvl-5-H-(ia^ja-peBtafluoroethvlVethoxvl-pvridine: Add(±)-4-[l-
(l,l,2,2,2-pentafluoroethyl)-ethoxy]-pyridine-2-carbonitrile(280mg, 1 mmol), 10%Pd/C
(Degussa type El01, 100 mg), methanol (20 mL) and trifluoroacetic acid (3 mL) to a
pressure vessel. Pressurize the vessel to 40 psi with hydrogen, and stir the mixture for 1 h
(monitor the reaction by TLC). Filter the mixture through Celite® and wash the cake
with warm ethanol followed by dichloromethane under a nitrogen atmosphere.
Concentrate the filtrate in vacuo to obtain the crude product as a trifluoroacetic acid salt.
Prepare the free base using SCX chromatography, then purify by chromatography on
silica gel eluting with dichloromethane/2M ammonia in methanol (20:1) to obtain the title
compound (172 mg, 61%). GC-MS m/z: 270 (NT1).
Preparation 286
4-( 1 -Methyl-cyclohexylmethoxy)-benzylamine hydrochloride


O OH O'^NH2 ^NH2 HCI
4-(l-MethYl-cYcIohexvlmethoxvVbenzamide: Add a drop of anhydrous DMF to a
mixture of 4-(l-methyl-cyclohexylmethoxy)-benzoic acid (prepared by following the
procedure described in Chem. Pharm. Bull. 1982, 30, 3601-3616) (1 g, 4.03 mmol) and
thionyl chloride (3.5 mL) at room temperature. Stir the mixture for 1.5 h and then
remove the excess of thionyl chloride in vacuo. Take-up the crude acid chloride in
anhydrous THF (10 mL) and add the resulting solution to cold concentrated NH4OH (50
mL). Stir for 2.5 h at room temperature and concentrate in vacuo. Collect the solid
formed via filtration and dry in vacuo to obtain the desired intermediate (0.94 g, 94%).
MS (ES+) m/z: 248 (M+H)+.
4-(l-Methvl-cvclohexylmethoxv)-benzY>amine hydrochloride: Add a solution of 4-(l-
methyl-cyclohexylmethoxy)-benzamide (6.82 g, 27.6 mmol) in anhydrous THF (75 mL)
dropwise over 45 min to a slurry of lithium aluminium hydride (1.57 g, 41.3 mmol) in
diethyl ether (100 mL) at room temperature. After the addition is completed, heat the
mixture at reflux for 5.5 h. Cool the reaction mixture with an ice bath and quench
sequentially with water (1.6 mL), 5N aqueous NaOH (1.6 mL) and water (4.8 mL). Stir
the resulting suspension for 1 h and remove the solids formed via filtration through
Celite® eluting with THF. Dry the filtrate over Na2SO4 and treat the solution with an
excess of hydrogen chloride in diethyl ether. Concentrate the mixture in vacuo to obtain
the title compound (6.68 g, 90%). MS (ES+) m/z: 233 (M+H)+.
Preparation 287
4-Cyclopentyloxy-benzylamine


4-CYdopentyloxy-benzonitrile: Suspend sodium hydride (336 mg, 2.8 mmol, 60%
suspension in mineral oil) in anhydrous 1,4-dioxane (10 mL) under nitrogen atmosphere.
Add cyclopentanol (620 mg, 7.2 mmol) and stir the resulting solution for 30 min. Add
the preformed solution (3.35 mL, 2.4 mmol) to neat 4-fluorobenzonitrile (240 mg, 2
mmol) in a microwave tube and heat the sealed mixture at 100 °C for 30 min. Cool to
room temperature and concentrate in vacuo. Purify by chromatography on silica gel
eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain the desired intermediate
(300 mg, 80%). GC-MS m/z\ 187 (M+).
4-Cvclopenrvloxy-benzvlamine: Add a solution of 1M BH3-THF complex in THF (4.8
mL, 4.8 mmol) to neat 4-cyclopentyloxy-benzonitrile (300 mg, 1.6 mmol) and stir the
mixture for 3 h at room temperature and then for 3 h at reflux. Cool to room temperature,
pour the reaction into 2N aqueous HC1 (10 mL) and stir the mixture for 1 h at room
temperature then concentrate in vacuo. Dissolve the crude mixture in methanol and filter
through SCX column eluting with methanol followed by 3M ammonia in methanol to
obtain the title compound (223 mg, 73%).
Preparations 288-292
The compounds of Preparations 288-292 may be prepared essentially as described
in Preparation 287 using the appropriate alcohols. For Preparations 288, 290 and 291,
sodium bis(trimethylsilyl)amide (1.2 equiv., 2M solution in THF) was used as base in the
first step. Overall yields and MS (El) data are shown in the Table below.



6-(33-Dimethvl-butoxv)-nicotinonitrile: Add sodium bis(trimethylsilyl)amide (3.95
mL, 7.9 mmol, 2M solution in THF) to a solution of 3,3-dimethyl-butan-l-ol (960 DL,
7.9 mmol) in anhydrous THF (10 mL). Stir for 30 min at room temperature and then add
a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at
room temperature overnight and then quench the reaction mixture with saturated aqueous

NaHC03 (100 mL). Extract the aqueous layer with dichloromethane (3 x 100 mL) and
wash the organic layer with brine (100 mL). Dry the combined organic extracts over
MgSOt and concentrate in vacuo to give the desired intermediate as a yellow solid (1.4 g,
94%). GC-MS m/z: 204 (M*).
5-Aminomethyl-2-(33-dimethvl-butoxv>-pvridine: Dissolve 6-(3,3-dimethyl-butoxy)-
nicotinonitrile (1.4 g, 6.86 mmol) in anhydrous THF (10 mL) under nitrogen and add 1M
BH3-THF complex in THF (20.6 mL, 20.6 mmol). Stir the mixture overnight under
nitrogen and then pour the reaction carefully into 5N aqueous HC1 (20 mL). Stir the
resulting suspension for 6 h at room temperature. Then basify by adding 2N aqueous
NaOH (50 mL) and extract with dichloromethane (3 x 100 mL). Dry the combined
organic extracts over MgSC>4, filter and concentrate in vacuo. Take-up the resulting oil in
methanol and filter it through an SCX column eluting with methanol followed by 3M
ammonia in methanol. Concentrate in vacuo to obtain the title compound (754 g, 50%).
GC-MS m/r. 208 (NT).
Preparation 294
3,3-Dimethylbutanethiol

Into four separate microwave tubes add thiourea (630 mg, 8.3 mmol) to a solution
of l-chloro-3,3-dimethylbutane (0.5 g, 4.4 mmol) in ethanol (5 mL) and heat in a sealed
tube in a microwave reactor at 150 W at 100 °C for 4 h. Cool to room temperature then
stand over three days. Combine the reactions and concentrate in vacuo to afford a white
solid. Add 2M aqueous NaOH (50 mL) and heat at reflux overnight. Cool to room
temperature then acidify to pH 2 with 5M aqueous HC1 (20 mL). Extract into diethyl
ether (50 mL), wash with brine (30 mL) then dry over MgSCv and concentrate in vacuo to
give the title compound as a clear oil (2 g, 100%).
Preparation 295
5-Aminomethyl-2-terf-butylthio-pyridine


6-(terf-Butvlthio)nicotinonitrile: Add sodium ethoxide (12 mL of 21% w/v in ethanol,
36 mmol) to a solution of 2-methyl-2-propanethiol (4.06 mL, 36 mmol) in anhydrous
ethanol (90 mL) at 0 °C under nitrogen atmosphere. Stir the solution and allow it to
warm to room temperature over 30 min. Add 6-chloronicotinonitrile (5 g, 36 mmol) and
then heat the reaction to reflux overnight. Cool to room temperature, add saturated
aqueous NaHCO3 and concentrate in vacua. Extract into EtOAc or dichloromethane and
wash with brine. Dry over MgSO4 and concentrate in vacuo to give the desired
intermediate as orange crystals (6.31 g, 91%). MS (ES+) mJr. 193 (M+H)+.
5-Aminomethvl-2-te/7-burvlthio-pyridine: Use a method similar to the General
Procedure 6-5 to react 6-(terf-butylthio)nicotinonitrile (4.4 g, 22.7 mmol) in anhydrous
THF (25 mL) with 1M BH3-THF complex in THF (25 mL, 25 mmol). Add 5M aqueous
HC1 (10 mL) cautiously and stir the mixture overnight at room temperature. Extract into
EtOAc, wash with brine, dry over MgSCU and concentrate in vacuo to give an orange
solid. Dissolve the crude mixture in methanol and filter through an SCX column eluting
with methanol followed by 3M ammonia in methanol to obtain the title compound (2.74
g, 61%). MS (ES+) m/z: 197 (M+H)+.
Preparations 296-303
The compounds of Preparations 296-303 may be prepared essentially as described
in Preparation 295 using the appropriate thiol and 6-chloronicotinonitrile (Preparations
296-298) or the appropriate aryl fluoride (Preparations 299-303). Overall yields and MS
(ES+) data are shown in the Table below.




6-(Ethoxy)nicotinonitrile: Add sodium ethoxide (1.6 mL of 21% w/v in ethanol, 4.8
mmol) to a solution of 6-chloronicotinonitrile (612 mg, 4.41 mmol) in anhydrous ethanol
(15 mL) and heat the reaction at reflux for 3 h. Cool to room temperature and stir
overnight under nitrogen atmosphere. Concentrate in vacuo and dissolve the residue into
dichloromethane. Wash with saturated aqueous NaHCCb, dry over MgSO4 and
concentrate in vacuo to give the desired intermediate as an off-white solid (545 mg, 83%).
5-Aminomethvl-2-ethoxv-pyridine: Add a solution of 1M BH3-THF complex in THF
(7 mL, 7 mmol) to a solution of 6-(ethoxy)nicotinonitrile (911 mg, 4.41 mmol) in
anhydrous THF (7 mL) and stir the mixture overnight at reflux. Add a second aliquot of
1M BH3-THF complex in THF (7 mL, 7 mmol) and stir the mixture overnight at reflux.
Add 5N aqueous HC1 (10 mL) cautiously and stir the mixture overnight at room
temperature. Concentrate in vacuo then dissolve the crude mixture in methanol and filter
through an SCX column eluting with methanol followed by 3M ammonia in methanol to
obtain the title compound (250 mg, 40%). MS (ES+) mJr. 153 (M+H)+.
Preparation 305
4-Ethoxy-3-chloro-benzylamine

The compound of Preparation
305 may be prepared essentially as described in Preparation 304 using the appropriate
aryl fluoride (38% yield, MS (ES+) m/z 169
(M+H-NH3)*).
Preparation 306

4-(Tetrahydro-pyran-4-yIoxymethyl)-

4-(Tetrahvdro-pvran-4-vloxvmethvl)-benzonitrile: Add sodium
bis(trimethylsilyl)amide (2.8 mL, 5.61 mmol, 2M solution in THF) to a solution of
tetrahydro-pyran-4-ol (572 mg, 5.61 mmol) in anhydrous THF (20 mL) and stir for 30
min. Add a solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) in anhydrous THF (5
mL) and stir the resulting mixture overnight at room temperature. Concentrate in vacuo
and purify the crude mixture by chromatography on silica gel eluting with
cyclohexane/EtOAc (98:2 to 1:1 gradient) to obtain the desired intermediate as a white
solid (845 mg, 76%). GC-MS m/z: 217 (NT").
4-rretrahvdro-pyran-4-yloxvmethvl)-benzylamine: Use a method similar to the
General Procedure 6-5 to reduce 4-(tetrahydro-pyran-4-yloxymethyl)-benzonitrile (845
mg, 4 mmol). Reflux overnight to obtain the title compound (812 mg, 91%). MS (ES+)
m/z: 222.2 (M+H)+.
Preparations 307-309
The compounds of Preparations 307-309 may be prepared essentially as described
in Preparation 306 using 4-bromomethyl-benzonitrile and the appropriate alcohol.
Overall yields and MS (ES+) data are shown in the Table below.



4-(2,2-DimethYl-proporymethvl>-benzonitrile; Add sodium bis(trimethylsilyl)amide (3
mL, 6 mmol, 2M solution in THF) to a solution of 2,2-dimethyl-l-propanol (528 mg, 6
mmol) in anhydrous 1,4-dioxane. Stir until the suspension becomes homogenous. Then
add a solution of 4-cyanobenzyl bromide (980 mg, 5 mmol) in anhydrous 1,4-dioxane (3
mL). Heat the mixture in a microwave oven at 100 °C for 30 min. Cool to room
temperature, add water (50 mL) and extract with EtOAc (3 x 50 mL). Dry the combined
organic extracts over MgSC>4, and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to
obtain the desired intermediate (811 mg, 80%).
4-(2,2-Dimethyl-pronoxvmethvl)-benzvlamine: Add 1M BH3-THF complex in THF
(16 mL, 16 mmol) to neat 4-(2,2-dimethyl-propoxymethyl)-benzonitrile (3.043 g, 15
mmol) and stir the mixture overnight at room temperature. Add methanol and stir until
hydrogen evolution stops. Concentrate the solution in vacuo. Dissolve the crude mixture
in methanol and filter through an SCX column eluting with methanol followed by 3M
ammonia in methanol. Concentrate in vacuo to obtain the title compound (3 g, 96%).

Preparation 311
4-Cycloheptyloxy-benzylamine

4-Cyeloheptyloxy-benzonitrile: Under a nitrogen atmosphere, add 4-
hydroxybenzonitrile (4 g, 33.5 mmol), cycloheptanol (2.55 g, 22.3 mmol), tri-w-
butylphosphine (8.25 mL, 33.5 mmol), and azodicarboxylate dipiperidine (8.45 g, 33.5
mmol) to anhydrous THF (60 mL) at 0 °C. Stir the mixture at 0 °C for 1 h and then at
room temperature for 12 h. Dilute with EtOAc (50 mL) and water (50 mL). Separate the
layers and extract the aqueous phase with EtOAc (4 * 30 mL). Wash the combined
organic extracts with water (30 mL) and brine (20 mL). Dry over Na2SC«4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g
RediSep column) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h; 80
mL/min) to provide the desired intermediate as a colorless oil (2.77 g, 58%). MS (APCI)
m/z:216(M+H)+.
4-CvcloheptvloxY-benzvlamine: Dissolve 4-cycloheptyloxy-benzonitrile (2 g, 9.29
mmol) in anhydrous THF (20 mL) and cool to 0 °C. Add borane dimethylsulfide
complex (2.8 mL, 27.9 mmol, 10-12 M solution), stir at 0 °C for 0.5 h and then heat at
reflux for 1 h. Cool the mixture to 0 °C, add methanol (5 mL) and stir for 15 min. Add
2M aqueous HC1 (15 mL) and stir for 30 min at room temperature. Concentrate the
mixture in vacuo and purify the residue by chromatography on silica gel (45 g RediSep
column) eluting with a gradient of dichloromethane in chloroform/methanol/concentrated
ammonium hydroxide (80:18:2) over 30 min (80 mL/min) to provide the title compound
as a colorless oil (1.87 g, 97%). MS (APCI) m/z: 220 (M+H)+.

Preparation 312
4-Cyc loheptylthio-benzy lam ine

Methyl 4-cyeIoheptvlthio-benzoate: Under a nitrogen atmosphere, add methyl 4-
mercaptobenzoate (2.5 g, 15 mmol), cycloheptanol (2.55 g, 22.3 mmol), tri-n-
butylphosphine (5.26 g, 26 mmol) and azodicarboxylate dipiperidine (6.56 g, 26 mmol) to
anhydrous THF (50 mL) at 0 °C. Stir the mixture at 0 °C for 1 h and then at room
temperature for 12 h. Dilute with EtOAc (50 mL) and water (50 mL) and extract the
aqueous phase with EtOAc (4 x 30 mL). Wash the combined organic extracts with water
(30 mL) and brine (20 mL). Dry the organic phase over Na2SC>4, filter and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel (120 g RediSep
column) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h; 80 mL/min) to
provide the desired intermediate as a colorless oil (1.12 g, 40%). MS (APCI) m/z: 265
(M+H)+.
4-Cycloheptylthio-beiizoic acid: Add methyl 4-cycloheptylthio-benzoate (1.1 g, 4.16
mmol) and sodium hydroxide (500 mg, 12.5 mmol) to methanol (20 mL) and stir
overnight. Add 2M aqueous HC1 (20 mL) and extract the aqueous phase with
dichloromethane. Wash the combined organic extracts with water (20 mL) and brine (20
mL). Dry the organic solution over Na2SO4, filter and concentrate in vacuo to provide the
desired intermediate as a white solid (984 mg, 94%). MS (APCI) m/z: 251 (M+H)+.
4-Cvcloheptvlthio-benzamide: Add thionyl chloride (1.35 mL, 18.4 mmol) to a mixture
of 4-cycloheptylthio-benzoic acid (984 mg, 3.93 mmol) in dichloromethane (15 mL) at 0
°C. Heat the mixture to reflux for 1 h. Cool the mixture to room temperature and
concentrate in vacuo. Dissolve the residue in dichloromethane (20 mL) and cool to 0 °C.
Add triethylamine (1.1 mL, 7.86 mmol) and bubble ammonia gas through the solution.

Warm the mixture to room temperature and stir for 1 h. Dilute with water (20 mL) and
extract the aqueous phase with dichloromethane (3 * 20 mL). Wash the combined
organic extracts with saturated aqueous NaHCO3 (20 mL). Dry the organic solution over
Na2SC>4, filter and concentrate in vacuo to provide the desired intermediate as an off-
white solid (976 mg, 99%). MS (APCI) m/z: 250 (M+H)+.
4-Cycloheptylthio-benzylamine: Under a nitrogen atmosphere, add 4-cycloheptylthio-
benzamide (976 mg, 3.91 mmol) to a slurry of lithium aluminum hydride (0.398 mg, 11.7
mmol) in anhydrous THF (25 mL) at 0 °C. Heat the mixture for 1 h. Cool the mixture to
0 °C and add diethyl ether (50 mL). Carefully add water (0.4 mL), 3M aqueous NaOH
(0.4 mL) and water (1.2 mL). Filter the solid residue and concentrate the filtrate in vacuo.
Purify the crude mixture by chromatography on silica gel (45 g RediSep column) eluting
with a gradient of dichloromethane in chloroforrn/rnethanol/concentrated ammonium
hydroxide (80:18:2) over 45 min (80 mL/min) to give the title compound as a colorless
oil (530 mg, 57%). MS (ES+) m/z: 236 (M+H)+.
Preparation 313
4-Cyclohexylmethyl-benzylamine hydrochloride




4-(Cvclohexvl-hydroxv-methyl)-benzoiiitrile: Dissolve 4-formyl-benzonitrile (5 g,
38.1 mmol) in anhydrous toluene (50 mL). Add chlorodicyclohexylborane (39 mL, 39
mmol, 1M solution in hexane) and 2,6-lutidine (4.25 mL, 39 mmol) and stir the mixture
overnight at room temperature. Cool to 0 °C, add aqueous hydrogen peroxide (5.4 mL,
48 mmol, 30%) and 3M aqueous NaOH (16 mL, 48 mmol) and stir for 15 min. Add
EtOAc and extract the aqueous phase with EtOAc. Wash the combined organic extracts
with water and brine. Dry the organic solution over Na2SO4, filter and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel (45 g RediSep column)

eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min; 80 mL/min) to provide the
desired intermediate as a clear oil (2.3 g, 23%). MS (APCI) mJz: 197 (M-H20)+.
4-(Cyclohexyl-methanesiilfonvloxv-methvl)-benzonitrile: Dissolve 4-(cyclohexyl-
hydroxy-methyl)-benzonitrile (1 g, 4.66 mmol), and triethylamine (1.3 mL, 9.3 mmol) in
dichloromethane (20 mL). Cool the mixture to 0 °C, add methanesulfonyl chloride (1.49
mL, 5.34 mmol) and stir the solution for 2 h at 0 °C. Add water (10 mL) and saturated
aqueous NaHCO3 (10 mL). Separate the layers and extract back the aqueous phase with
dichloromethane (3 * 20 mL). Combine the organic layers, wash with water (20 mL), dry
over Na2SC yellow oil (1.29 g, 94%). MS (APCI) m/r. 294 (M+H)+.
4-Cvclohexvlmethyl-benzvlamine hydrochloride: Dissolve 4-(cyclohexyl-
methanesulfonyloxy-methyl)-benzonitrile (1.36 g, 4.64 mmol) in diethyl ether (20 mL)
and cool the solution to 0 °C. Add lithium aluminum hydride (528 mg, 13.9 mmol) and
stir the mixture at 0 °C for 2 h and then at room temperature for 3 h. Cool the mixture to
0 °C and carefully add water (0.5 mL), 3M aqueous NaOH (0.55 mL), and water (1.5
mL). Filter the solid residue and concentrate the filtrate in vacuo. Dissolve the crude
mixture in diethyl ether and bubble hydrogen chloride to form a white precipitate. Filter
and dry the solid in vacuo to provide the title compound as a white solid (420 mg, 44%).
MS (APCI) m/z: 204 (M+H)+.
Preparation 314
4-(l-Hvdroxv-2-methvl-butyl)-l-bromo-benzene: Add slowly a solution of 2-bromo-
butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) to a stirring mixture of magnesium
4-(2-Methyl-butyl)-benzylamine


(980 mg, 37 mmol) and anhydrous THF (10 mL) under a nitrogen atmosphere. Heat the
mixture at reflux for 30 min. Cool the mixture to room temperature and add 4-bromo-
benzaldehyde (5.36 g, 29 mmol). After stirring for 5 min, cool the mixture in an ice-bath
and acidify with 3N aqueous HC1 (50 mL). Dilute the mixture with water and extract
twice with diethyl ether. Wash the combined organic extracts with water and brine. Dry
the organic phase over Na2SO4, filter and concentrate in vacua. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0, 20:1 and 1:1) to provide
the desired intermediate as a clear oil (2 g, 28%). MS (APCI) m/z: 243 (M+H)+.
4-n-Hvdroxv-2-methyI-butvO-benzonitrile: Add 4-( 1 -hydroxy-2-methy 1-butyl)-1 -
bromo-benzene (1.9 g, 7.8 mmol), zinc cyanide (1.82 g, 15.6 mmol), and
tetrakistriphenylphosphine palladium(O) (260 mg, 0.22 mmol) to anhydrous DMF (40
mL) under a nitrogen atmosphere. Heat the mixture at 90 °C for 12 h. Cool the mixture
to room temperature, dilute with water and extract the aqueous phase twice with
dichloromethane. Wash the combined organic extracts with water and brine. Dry the
organic solution over Na2SO4, filter and concentrate in vacuo. Purify by chromatography
on silica gel eluting with hexane/EtOAc (1:0 and 20:1) to provide the desired
intermediate (1.2 g, 75%). MS (APCI) m/z: 190 (M+H)+.
4-(l-Methanesulfonvloxv-2-methvl-butvD-benzonitrile: Add methanesulfonyl chloride
(540 mg, 4.72 mmol) to a solution of 4-(l-hydroxy-2-methyl-butyl)-benzonitrile (800 mg,
4.23 mmol) and triethylamine (0.88 mL, 6.35 mmol) in dichloromethane (10 mL) at 0 °C.
Warm the mixture to room temperature and stir for 1 h. Dilute the mixture with water
and dichloromethane. Extract the aqueous layer with dichloromethane. Wash the
combined organic extracts with water. Dry the organic solution over Na2SC>4, filter and
concentrate in vacuo to provide the desired intermediate as a clear oil (1.38 g) that was
used without further purification. MS (APCI) m/z: 268 (M+H)+.
4-(2-Methyl-butyl)-benrylamine: Under a nitrogen atmosphere, add a mixture of 4-(l-
methanesulfonyloxy-2-methyl-butyl)-benzonitrile (1.3 g, 4.9 mmol) in diethyl ether (5
mL) to a slurry of lithium aluminum hydride (820 mg, 19.5 mmol) in diethyl ether (25

mL) at 0 °C. Heat the mixture under reflux for 1 h. Cool the mixture in an ice-bath and
add water (0.9 mL), 15% aqueous NaOH (0.9 mL) and water (2.8 mL). Apply the
mixture to a silica gel column eluting with dichloromethane and 5:1 dichloromethane in
chloroform/methanol/concentrated ammonium hydroxide (80:18:2) to provide the title
compound (450 mg, 52%). MS (ES+) mJr. 178 (M+H)+.
Preparation 315
4-(3,3-Dimethyl-butyl)-benzylamine

4-(3,3-Dimethvl-but-l-vnyl)-benzonitrile: Dissolve 4-bromobenzonitrile (3 g, 16.48
mmol) in anhydrous DMF (30 mL) in a sealed tube. Degas the solution, purge with
nitrogen and add tris(dibenzylideneacetone)dipalladium(0) (453 mg, 0.49 mmol),
copper(I) iodide (188 mg, 0.99 mmol), triphenylphosphine (1.08 g, 4.12 mmol),
triethylamine (10 mL) and 3,3-dimethylbutyne (6.1 mL, 49.44 mmol). Heat the mixture
at 90 °C overnight. Cool to room temperature, add water and extract the aqueous phase
twice with EtOAc. Dry the combined organic extracts over MgSC in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane
and hexane/EtOAc (19:1,9:1) to give the desired intermediate as a solid (2.75 g, 92%).
JV-(tert-Butoxvcarbonvl>-4-(33-dimethvl-butvl)-bcnzYlamine: Dissolve 4-(3,3-
dimethyl-but-l-ynyl)-benzonitrile (0.85 g, 4.64 mmol) in methanol (50 mL). Add 10%
Pd/C (Degussa type E101, 0.68 g) and di-fert-butyl-dicarbonate (1.21 g, 5.57 mmol).
Submit the mixture to hydrogenation under atmospheric pressure (balloon) for 6 h. Filter
the catalyst through Celite® and concentrate the filtrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (9:1,
4:1) to provide the desired intermediate as an oil (1.25 g, 93%). MS (ES+) m/z: 314
(M+Na)+.

4-(33-Dimethyl-butvl)-benzvlainine: Add 4N hydrogen chloride in dioxane (15 mL) to
a stirred solution of A/-(/er/-butoxycarbonyl)-4-(3,3-dimethyl-butyl)-benzylamine (1.25 g,
4.29 mmol) in methanol (20 mL) and stir at room overnight. Concentrate in vacua and
wash the solid with diethyl ether. Suspend the solid in dichloromethane and saturated
aqueous NaHCC>3 and stir until both phases are clear (15 min). Extract the aqueous phase
twice with dichloromethane. Dry the combined organic extracts over MgSC>4, filter and
concentrate in vacuo to give the title compound as an oil (0.654 g, 80%) that was used
without any further purification. MS (ES+) m/z: 192 (M+H)+.
Preparation 316
3-Aminomethyl-6-(3,3-dimethyl-butyl)-pyridine

The title compound may be prepared essentially as described in Preparation 315
by using 6-bromonicotinonitrile (45% yield, MS (ES+) m/z 193 (M+H)*).
Preparation 317
3-Aminomethyl-6-cyclohexylmethyl-pyridine

3- 5-/ert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5
mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1 '-
[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5M
cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60 °C

overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add
water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter
and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel
eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an
oil (359 mg, 68%). MS (ES+) m/r. 305 (M+H)+.
3-Aminotnethvl-6-CYclohexvlmethyl-pvridine: Add 4N hydrogen chloride in dioxane
(10 mL) to a solution of 3-ter/-butoxycarbonylaminomethyl-6-cyclohexylmethyl-pyridine
(345 mg, 1.13 mmol) in EtOAc (10 mL) and stir overnight. Concentrate in vacuo,
suspend the solid obtained in diethyl ether and add hexane. Filter and wash the solid with
hexane. Suspend the solid into dichloromethane, add saturated aqueous NaHCO3 and stir
until both phases are clear (15 min). Extract the aqueous phase twice with
dichoromethane. Dry the combined organic extracts over MgSCU, filter and concentrate
in vacuo to obtain the title compound as an oil (205 mg, 97%) that was used without any
further purification. MS (ES+) m/r. 205 (M+H)+.
Preparation 318
2-Aminomethyl-5-(3,3-dimethyl-butyl)-pyridine

5-(3«3-Dimethvl-but-l-vnvn-2-cvan(>-PYridine: Dissolve 5-bromo-2-cyano-pyridine
(316 mg, 1.72 mmol) in anhydrous DMF (7 mL) in a sealed tube. Degas the solution,
purge with nitrogen and add tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05
mmol), copper(I) iodide (20 mg, 0.1 mmol), triphenylphosphine (113 mg, 0.43 mmol),
triethylamine (2 mL) and 3,3-dimethylbutyne (0.64 mL, 5.16 mmol). Heat the mixture at
90 °C overnight. Cool to room temperature, add water and extract the aqueous phase
twice with EtOAc. Dry the combined organic extracts over MgSC>4, filter and concentrate

in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane
and hexane/EtOAc (19:1) to give the desired intermediate as a solid (310 mg, 97%).
2-Aminomethvl-5-(33-dimcthvl-burvl)-pvridine: Dissolve 5-(3,3-dimethyl-but-l-
ynyl)-2-cyano-pyridine (255 mg, 1.5 mmol) in methanol (15 mL). Add 10%Pd/C
(Degussa type E101, 230 mg) and submit the mixture to hydrogenation under
atmospheric pressure (balloon) overnight. Filter the catalyst through Celite® and
concentrate the filtrate in vacuo to provide the title compound as a solid (231 mg, 87%)
that was used without any further purification. MS (ES+) m/z: 193 (M+H)+.
Preparation 319
4-(l,3,3-Trimethyl-butyl)-benzylamine

4-(l-Hvdroxv-U.3-trimethvl-butvl)-benzonitrile: Dissolve 4-acetylbenzonitrile (1 g,
6.88 mmol) in diethyl ether/THF (1:1, 60 mL) and cool the solution to 0 °C. Add 1M
neopentylmagnesium chloride in diethyl ether (8.3 mL, 8.3 mmol) under nitrogen and stir
the mixture at room temperature overnight. Add saturated aqueous NH4CI and extract the
mixture twice with EtOAc. Dry the combined organic extracts over MgSC>4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with hexane and hexane/EtOAc (19:1,9:1) to give the desired intermediate (364 mg,
24%).
4-f3J-Dimethvl-l-methylene-butYl)-benzonitrile: Add p-toluenesulfonic acid
monohydrate (308 mg, 1.62 mmol) to a solution of 4-(l-hydroxy-l,3,3-trimethyl-butyl)-
benzonitrile (352 mg, 1.62 mmol) in toluene (10 mL). Heat the solution to 100 °C for 30
min. Cool the reaction mixture to room temperature, dilute the reaction mixture with
EtOAc and wash the organic phase with saturated aqueous NaHCC^. Dry the organic
phase over MgSC>4, filter and concentrate in vacuo. Purify the crude mixture by

chromatography on silica gel eluting with hexane and hexane/EtOAc (98:2, 19:1) to give
the desired intermediate as an oil (200 mg, 62%).
Ar-(fert-ButoxvcarbonylV4-(133-trimethyl-biityI)-beiizvlamine: Dissolve 4-(3,3-
dimethyl-l-methylene-butyl)-benzonitrile (164 mg, 0.82 mmol) in methanol (15 mL).
Add 10% Pd/C (Degussa type E101, 130 mg) and di-/m-butyl-dicarbonate (197 mg,
0.902 mmol). Submit the mixture to hydrogenation under atmospheric pressure (balloon)
for 3 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify
the crude mixture by chromatography on silica gel eluting with hexane and
hexane/EtOAc (19:1, 9:1) to provide the desired intermediate as an oil (227 mg, 90%).
MS (ES+) m/z: 328 (M+Na)+.
4-(l,3,3-Trimethvl-butv!>-benzvlamine: Add 4N hydrogen chloride in dioxane (10 mL)
to a stirred solution of JV-(fer/-butoxycarbonyl)-4-(l,3,3-trimethyl-butyl)-benzylamine
(225 mg, 0.74 mmol) in EtOAc (15 mL) and stir the mixture at ambient temperature
overnight. Concentrate in vacuo and wash the solid with diethyl ether. Suspend the solid
in dichloromethane and saturated aqueous NaHCCb and stir until both phases are clear
(15 min). Extract the aqueous phase twice with dichloromethane. Dry the combined
organic extracts over MgSCU, filter and concentrate in vacuo to give the title compound
as an oil (0.136 g, 90%) that was used without any further purification. MS (ES+) m/z:
206 (M+H)+.
Example 537

Use a method similar to the General Procedure 5-1 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine(3
7-Chloro-6-(2,4-difluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rfJazepineSuccinate

g, 7.06 mmol), palladium(II) acetate (0.16 g, 0.71 mmol), BINAP (0.88 g, 1.41 mmol),
2,4-difluorobenzylamine (3.03 g, 21.18 mmol) and cesium carbonate (3.22 g, 9.88 mmol)
in degassed toluene (120 mL). Degas the mixture with vacuum/nitrogen purge and heat
to 100 °C for 16 h. Cool the mixture to room temperature, dilute with EtOAc, filter
through Celite® and concentrate in vacuo to give a brown oil. Purify the crude mixture
by chromatography on silica gel eluting with hexane and then hexane/THF (95:5) to
obtain 7-chloro-6-(2,4-difluorobenzylamino)-3-(2,2,2,trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine as oil (2.25 g, 76%). MS (ES+) m/z: 419 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-(2,4-
difluorobenzylamino)-3^2,2,2,trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[*/]azepine
(2.2 g, 5.26 mmol), to give the free base of the title compound as an oil (1.66 g, 98%) that
solidified upon standing at room temperature and was used without further purification.
MS (ES+) m/z: 323 (M+H)+. Use a method similar to the General Procedure 2-1, using 7-
chloro-6-(2,4-difluorobenzylamino)-2,3,4,5-tetrahydro-l//-benzo[rflazepine (1.66 g, 5.14
mmol) to give the title compound as a white solid (2.03 g, 90%). MS (ES+) m/r. 2,23
(M+H)+.
Example 538
7-Chloro-6-(2,5-difluorobenzylamino)-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine
Succinate

Example 538 may be prepared essentially as described in Example 537 using 7-
chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[
Example 539
7-Chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-2,3,4,5-tetrahydro-l//-benzotrf)azepine
Succinate

Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[]azepine
(541 mg, 1.274 mmol), palladium(II) acetate (57 mg, 0.225 mmol),
tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.127 mmol), BINAP (0.506 g, 0.764
mmol), 2,2-difluoro-2-phenyl-ethylamine (400 mg, 2.547 mmol) and cesium carbonate
(830 mg, 2.548 mmol) in degassed toluene (35 mL). Degas the mixture with
vacuum/nitrogen purge and heat to 100 °C for 16 h. Cool the mixture to room
temperature, dilute with EtOAc and filter over Celite®. Purify the crude mixture by
chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to obtain 7-
chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l/7-benzo[rf]azepine as oil (335 mg, 61%). MS (ES+) m/z: 433 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-(2,2-
difluoro-2-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lflr-
benzo[tf)azepine (317 mg, 0.734 mmol), to give the free base of the title compound as an
oil (215 mg, 87%) that was used without further purification. MS (ES+) m/z: 337
(M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-(2,2-
difluoro-2-phenyl-ethylamino)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (215 mg, 0.64
mmol) to give the title compound as a white solid (220 mg, 76%). MS (ES+) m/z: 337
(M+H)+.
Example S40
7-Chloro-6-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine Succinate


Example 540 may be prepared essentially as described in Example 539 using 7-
chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[*/]azepine and 2,2-difluoro-2-pyridin-2-yl-ethylamine (prepared by following the
procedure described in J. Med Chem. 2003, 46,461-473), (37% yield, MS (ES+) m/z 338
(M+H)*).
Examples 541-544
Examples 541-544 may be prepared essentially as described in Example 262 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[ data are shown in the Table below.


Example 545
7-Chloro-6-(3-phenyl-benzothiophen-6-yl-methylamino)-2,3,4,5-tetrahydro-l#r-benzo
[c/]azepine Hydrochloride

Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c/]azepine
(0.28 g, 0.66 mmol) and 6-aminomethyl-3-phenyl-benzothiophene (0.19 g, 0.8 mmol)
with tris(dibenzylideneacetone)dipalladium(0) (120 mg, 0.13 mmol), BINAP (165 mg,
0.26 mmol) and cesium carbonate (0.3 g, 0.93 mmol) at 90 °C for 17 h, to obtain 7-
chloro-6-(3-phenyl-benzothiophen-6-yl-methylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo []azepine that is used without further purification (234 mg, 69%).
MS (ES+) m/z: 515 (M+H)+.
Use a procedure similar to General Procedure 1-1 to deprotect 7-chloro-6-(3-
phenyl-benzothiophen-6-yl-methylamino)-3-(2,2,2-trifluoroacetyl)-2,3»4,5-tetrahydro-
IH-benzo [cfjazepine (234 mg, 0.45 mmol) in 7M ammonia in methanol (20 mL). Purify
by reverse phase HPLC (Vydac C18 5 x 25 cm, 30% to 100% acetonitrile in 0.1% TFA-
water solution). Recover the free base by SCX chromatography and form the salt
according to General Procedure 2-3 to obtain the title compound (38 mg, 17%). HRMS
(ES+) m/z: 419.1340 (M+H)+.
Example 546
7-Chloro-6-[(difluoro-phenyl-methyl)-benzylamino]-2,3,4,5-tetrahydro-l/f-
benzo[]azepine Succinate


o
Use a procedure similar to Example 262 using 7-chloro-3-(2,2,2-trifluoroacetyI)-
6-trifluoromemanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[d]azepineand4-(difluoro-
phenyl-methyl)-benzylamine, followed by deprotection according to General Procedure
1-2 and salt formation according to General Procedure 2-1 to obtain the title compound
(175 mg, 77%). MS (ES+) m/z 413 (M+H)+.
Example 547
7-Chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine Succinate

Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[ (250 mg, 0.588 mmol), palladium(II) acetate (26 mg, 0.118 mmol),
tris(dibenzylideneacetone)dipalladium(O) (53 mg, 0.059 mmol), BINAP (0.22 g, 0.353
mmol), 4-(3,3-dimethyl-butyryl)-benzylamine (241 mg, 1.176 mmol) and cesium
carbonate (383 mg, 1.176 mmol) in degassed toluene (10 mL). Degas the mixture with
vacuum/nitrogen purge and heat to 100 °C for 16 h. Cool the mixture to room
temperature, dilute with EtOAc and wash with saturated aqueous NaHCC>3. Dry the
organic layer over Na2SC>4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with hexane and then hexane/EtOAc (90:10, 85:15)
to obtain 7-chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-

2,3,4,5-tetrahydro-l//-benzo[]azepine as oil (185 mg, 65%). MS (ES+) m/z: 481
(M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(3,3-
dimethyl-butyiyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/|azepine (165 mg, 0.343 tnmol), to give the free base of the title compound as an
oil (130 mg, 98%) that was used without further purification. MS (ES+) m/z: 385
(M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-[4-(3,3-
dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzo[ mmol) to give the title compound as a white solid (128 mg, 76%). MS (ES+) m/z: 385
(M+H)+.
Example 548
7-Chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-li/-
benzo[*/]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[(/lazepine
(96 mg, 0.225 mmol) with 4-(3,3-dimethyl-butyryl)-3-fiuoro-benzylamine (105 mg, 0.45
mmol) by using tris(dibenzylideneacetone)dipalladium(0) (41 mg, 0.045 mmol), BINAP
(56 mg, 0.09 mmol) and cesium carbonate (103 mg, 0.315 mmol) in anhydrous toluene
(15 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give
7-chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzyIamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l#-benzo[rf]azepine as a yellow oil (54 mg, 49%). MS (ES+) m/z: 499
(M+H)+.

Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(3,3-
dimethyl-butyryl)-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[c/|azepine (53 mg, 0.11 mmol) to give the free base of the title compound as a
yellow oil (42 mg, 96%) that was used without further purification. Use a method similar
to the General Procedure 2-1, using 7-chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-
benzylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (42 mg, 0.105 mmol) to give the
title compound as a white solid (30 mg, 60%). MS (ES+) m/z: 403 (M+H)+.
Example 549
7-Chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(127 mg, 0.3 mmol) with 4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine (120 mg, 0.54
mmol) by using tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), BINAP
(40 mg, 0.06 mmol) and cesium carbonate (137 mg, 0.42 mmol) in anhydrous toluene (20
mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 and 9:1)
followed by reverse phase HPLC [Zorbax Bonus RP, 5 DM 21.2 x 100 mm, eluting with
water/acetonitrile (0.05% TFA in each) (35:65 to 15:85 gradient over 5 min), flow rate 25
mL/min, UV detector (230 nm)] to give 7-chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-
benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf|azepine as an oil
(72 mg, 49%). MS (ES+) m/z: 499 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(3,3-
dimethyl-butyryl)-2-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/r-

benzo[rf]azepine (26 mg, 0.052 tnmol) to give the free base of the title compound as a
yellow oil (19 mg, 91%) that was used without further purification. Use a method similar
to the General Procedure 2-1, using 7-chloro-6-[4-(3,3-dimethyl-butyry])-2-fluoro-
benzylamino]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (18 mg, 0.045 mmol) to give the
title compound as a white solid (20 mg, 86%). MS (ES+)m/z: 403 (M+H)+.
Example 550
7-Chloro-6-[3-chloro-4-(3,3-dimethyI-butyiyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[c?Jazepine Succinate




Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifiuoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[J|azepine
(90 mg, 0.212 mmol) with 3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine (102 mg, 0.43
mmol) by using tris(dibenzylideneacetone)dipalladium(O) (39 mg, 0.0424 mmol), BINAP
(53 mg, 0.0848 mmol) and cesium carbonate (97 mg, 0.297 mmol) in anhydrous toluene
(10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give
7-chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[c?]azepine as an oil (72 mg, 49%). MS (ES+) m/z: 516
(M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[3-chloro4-
(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine (70 mg, 0.136 mmol) to give the free base of the title compound as a
yellow oil (57 mg, 99%) that was used without further purification. Use a method similar
to the General Procedure 2-1, using 7-chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-

benzylamino]-2,3,4,5-tetrahydro-l//-benzo[]azepine (57 mg, 0.136 mmol) to give the
title cbmpound as a white solid (50 mg, 68%). MS (ES+) m/z: 420 (M+H)+.
Example 551
7-Chloro-6-[2-chloro-4-(3,3-diniethyl-butyryl)-benzyIamino]-2,3,4,5-tetrahydro-l/^-
benzo[i/]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesuIfonyloxy-2,3,4,5-tetrahydro-l//-benzo[d]azepine
(300 mg, 0.71 mmol) with l-(4-aminomethyl-3-chloro-phenyl)-3,3-dimethyl-butan-l-one
(338 mg, 1.41 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (130 mg, 0.142
mmol), BINAP (177 mg, 0.284 mmol) and cesium carbonate (324 mg, 0.994 mmol) in
anhydrous toluene (31 mL). Purify by chromatography on silica gel eluting with
hexane/EtOAc (92:8) followed by reverse phase HPLC [Hichrom Kromasil C18, 5 DM
21.2 x 100 mm, eluting with water/acetonitrile (0.05% TFA in each) (1:4 to 1:19 gradient
over 5 min), flow rate 25 mL/min, UV detector (230 nm)] to give 7-chloro-6-[2-chloro-4-
(3,3-dimethyl-butyryl)-benzylaminol-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine as an oil (77 mg, 21%). MS (ES+) m/z: 516 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[2-chloro-4-
(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[Jlazepine (77 mg, 0.15 mmol) to give the free base of the title compound as a
yellow oil (93 mg, 99%) that was used without further purification. Use a method similar
to the General Procedure 2-1, using 7-chloro-6-[2-chloro-4-(3,3-dirnethyl-butyryl>
benzylamino]-2,3,4,5-tefrahydro-lfl-benzo[c/)azepine (63 mg, 0.15 mmol) to give the title
compound as a white solid (52 mg, 65%). MS (ES+) m/z: 420 (M+H)+.

Example 552
7-Chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-2,3,4,5-tetrahydro-lW-
benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[tflazepine
(233 mg, 0.55 mmol), tris(dibenzylideneacetone)clipalladium(0) (50 mg, 0.055 mmol),
BINAP (73 mg, 0.11 mmol), 4-[2-(3,3-dimethyl-butyl)-[l,3]dioxolan-2-yl]-benzylamine
(263 mg, 1 mmol) and cesium carbonate (250 mg, 0.77 mmol) in degassed toluene (20
mL). Degas the mixture with vacuum/nitrogen purge and heat to 100 °C for 14 h. Cool
the mixture to room temperature, dilute with EtOAc and filter through Celite®. Purify
the crude mixture by chromatography on silica gel eluting with hexane and then
hexane/EtOAc (19:1, 9:1 and 4:1) to obtain 7-chloro-6-{4-[2-(3,3-dimethyl-butyl)-
[l,3]dioxolan-2-yl]-benzylamine}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-17/-
benzo|>/]azepine as oil (185 mg, 63%). MS (ES+) m/r. 539 (M+H)+.
Dissolve 7-chloro-6-{4-[2-(3,3-dimethyl-butyl)-[l,3]dioxolan-2-yl]-
benzylamine}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[fif]azepine (185 mg,
0.34 mmol) in methanol (10 mL) and add IN aqueos HC1 (2 mL). Stir the mixture for 2 h
and concentrate in vacuo. Dissolve the residue in dichloromethane and wash with
saturated aqueous NaHCCb. Dry the organic phase over MgS(>4, filter and concentrate in
vacuo to obtain 7-chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l#-benzo[rflazepine as an oil (150 mg, 89%).
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(4,4-
dimethyl-pentanoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/7-

benzo[J]azepine (150 mg, 0.3 mmol), to give the free base of the title compound as an oil
(100 mg, 83%) that was used without further purification. Use a method similar to the
General Procedure 2-1, using 7-chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine (100 mg, 0.25 mmol) to give the title compound
as a solid (100 mg, 78%). MS (ES+) m/z: 399 (M+H)+.
Example 553
7-Chloro-6-(4-cyclohexanecarbonyl-benzylamino)-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-benzo[c/]azepine
(150 mg, 0.353 mmol), tris(dibenzylideneacetone)dipalladium(0) (64 mg, 0.071 mmol),
BINAP (88 mg, 0.141 mmol), 4-cyclohexanecarbonyl-benzylamine (125 mg, 0.576
mmol) and cesium carbonate (230 mg, 0.706 mmol) in degassed toluene (10 mL). Degas
the mixture with vacuum/nitrogen purge and heat to 100 °C for 6 h. Cool the mixture to
room temperature, dilute with EtOAc and filter through Celite®. Purify the crude
mixture by chromatography on silica gel eluting with hexane and then hexane/EtOAc
(90:10 and 85:15) to obtain 7-chloro-6-(4-cyclohexanecarbonyl-benzylamino)-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[c/]azepine as oil (130 mg, 75%). MS (ES+)
m/z: 493 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-(4-
cyclohexanecarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (120 mg, 0.243 mmol), to give the free base of the title compound as an
oil (86 mg, 89%) that was used without further purification. MS (ES+) m/z: 397 (M+H)+.

Use a method similar to the General Procedure 2-1, using 7-chloro-6-(4-
cyclohexanecarbonyl-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[ 0.217 mmol) to give the title compound as a solid (85 mg, 77%). MS (ES+) m/z; 397
(M+H)+.
Examples 554-557
Examples 554-557 may be prepared essentially as described in Example 553 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine and the appropriate amine. Overall yields and MS (ES+) data are shown
in the Table below.




Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[ (1.1 g, 2.5 mmol) with 4-aminomethyl-N-cycloheptyl-2-fluoro-benzamide (1.35 g, 5.1
mmol) in anhydrous toluene (25 mL). Purify by chromatography on silica gel eluting
with hexane/EtOAc (19:1 to 1:1 gradient) followed by SCX chromatography to obtain 7-
chloro-6-[4-cycloheptylcarbamoyl-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[rfJazepine (720 mg, 53%). MS (ES+) m/z: 540.2 (M+H)+.
Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-6-[4-
cycloheptylcarbamoyl-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[ dichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to obtain the free
base of the title compound. Use a method similar to the General Procedure 2-1 to obtain
the title compound (665 mg, 89%). MS (ES+) m/z: 444.2 (M+H)+.
Example 559
7-Chloro-6-(4-cycloheptylcarbamoyl-2-fluoro-benzylamino)-2,3,4,5-tetrahydro-li/-
benzo[cf]azepine (L)-Tartrate


H
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[rf]azepine

(640 mg, 1.5 mmol) with 4-aminomethyl-JV-cycloheptyl-3-fluoro-benzamide (795 mg, 3
mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on
silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain 7-chloro-6-(4-
cycloheptylcarbamoyl-2-fluoro-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
ltf-benzo[rf]azepine (568 mg, 70%). MS (ES+) m/r. 540.2 (M+H)+.
Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-6-(4-
cycloheptylcarbamoyl-2-fluoro-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[|azepine. Purify by chromatography on silica gel eluting with
dichloromethane/2M ammonia in methanol (99/1 to 93/7 gradient) to give the free base of
the title compound. Dissolve the free base (400 mg, 0.9 mmol) and I-tartaric acid (135
mg, 0.9 mmol) in methanol. Concentrate in vacuo to an oil. Triturate oil with
dichloromethane and remove solvent in vacuo to obtain the title compound as a solid (460
mg, 74%). MS (ES+) m/r. 444.2 (M+H)+.
Example 560
7-Chloro-6-(3-chloro-4-cycloheptylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-l//-
benzofcflazepine (I)-Tartrate

NH
' OH
Example 560 may be prepared essentially as described in Example 559 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-
benzo[]azepine and 4-aminomethyl-2-chloro-iV-cycloheptyl-benzamide (50% yield, MS
(ES+) m/z 460.2 (M+H)+).
Example 561
7-Chloro-6-(4-cycloheptylcarbamoyl-3-methyl-benzylamino)-2,3,4,5-tetrahydro-l/2-
benzo[J]azepine Succinate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5 -tetrahydro-1 #-benzo[rflazepine
(660 mg, 1.6 mmol) with 4-aminomethyl-A'-cycloheptyl-2-methyl-benzamide (810 mg,
3.1 mmol) in anhydrous toluene (18 mL). Purify the crude mixture by chromatography
on silica gel eluting with hexane/THF (19:1 to 7:3 gradient) to obtain 7-chloro-6-(4-
cycloheptylcarbamoyl-3-methyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[cT|azepine (690 mg, 83%). MS (ES+) m/r. 536.3 (M+H)+.
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-(4-
cycloheptylcarbamoyl-3-methyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-lfl-benzo[JJazepine (680 mg, 1.3 mmol). Purify by chromatography on silica
gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 97:3 gradient) to
give the free base of the title compound. Use a method similar to the General Procedure
2-1 to obtain the title compound (473 mg, 65%). MS (ES+) m/z: 4403 (M+H)+.
Example 562
(/J)-7-Chloro-6-[3-fluoro-4-(2,2,2-trifluoro-l-methyl-ethylcarbamoyl)-benzylamino]-
2,3,4,5-tetrahydro-l//-benzo[c/]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[(/]azepine

(0.561 g, 1.319 mmol) with (i?)-4-aminomethyl-2-fluoro-;V-(2,2,2-trifluoro-l-methyl-
ethyl)-benzamide (0.698 g, 2.642 mmol) by using
tris(dibenzylideneacetone)dipalladium(0) (0.241 g, 0.264 mmol), BINAP (0.33 g, 0.53
mmol) and cesium carbonate (1.51 g, 4.63 mmol) in anhydrous toluene (13 mL). Purify
by chromatography on silica gej (40 g RediSep® column) eluting with hexane/EtOAc
(19:1 to 1:1 gradient over 30 min; 35 mL/min) and then by SCX chromatography to
afford (/?)-7-chIoro-6-[3-fluoro-4-(2,2,2-trifluoro-1 -methyl-ethylcarbamoyl)-
benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro- 17/-benzo[c(Jazepine as a
colorless oil (0.444 g, 62%). MS (ES+) m/z: 540.1 (M+H)+.
Use a method similar to the General Procedure 1-3 to deprotect (i?)-7-chloro-6-[3-
fluoro-4-(2,2,2-trifluoro-l-methyl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-
trifluoroaceryl)-2,3,4,5-tetrahydro-l#-benzo[)azepine (0.224 g, 0.415 mmol). Purify by
chromatography on silica gel (12 g RediSep® column) eluting with dichloromethane/2M
ammonia in methanol (99:1 to 90:10 gradient over 30 min; 35 mL/min) to afford the free
base of the title compound as a white foam (0.142 g, 77%). Use a method similar to the
General Procedure 2-1, using (/?)-7-chloro-6-[3-fluoro-4-(2,2,2-trifluoro-l-methyl-
ethylcarbamoyl)-benzylamino]-2,3,4,5-tefrahydro-l//-benzo[rf]azepine (0.132 g, 0.299
mmol) to afford the title compound as a white solid (0.135 g, 80%). MS (ES+) m/z: ^AA2
(M+H)+.
Example 563
7-Chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-l//L
benzo[
Add isopropylamine (0.15 mL, 1.8 mmol), HOBT (0.24 g, 1.8 mmol),
diisopropylethylamine (0.63 mL, 3.6 mmol) and EDC (0.34 g, 1.8 mmol) to a mixture of

3-rer/-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzyIamino)-7-chloro-2,3,4,5-tetrahydro-
l//-benzo[|azepine (0.403 g, 0.9 mmol) in anhydrous THF (11.8 mL) at room
temperature. Stir overnight at room temperature and partition the mixture between
EtOAc (250 mL) and saturated aqueous NaHCCb (100 mL). Dry the organic phase over
Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g
RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 50
mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-
benzylarnino)-2,3,4,5-tetrahydro-l//-benzo[fif]azepine as a thick colorless oil (0.439 g,
100%). MS (ES+) m/z: 490.2 (M+H)Use a method similar to the General Procedure 1-4 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-
tetrahydro-l//-benzo[rf)azepine (0.406 g, 0.83 mmol) in 1,4-dioxane (12.8 mL). Purify
by SCX chromatography eluting with dichloromethane and dichloromethane/2M
ammonia in methanol (1:1) followed by chromatography on silica gel (40 g RediSep
column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10 over 30
min) and then dichloromethane/2M ammonia in methanol (90:10 over 30 min; 35
mL/min) to afford 7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-
tetrahydro-l#-benzo[rf)azepine as a colorless oil (0.3237 g). MS (ES+) m/z: 390.1
(M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-(3-fluoro-
4-isopropylcarbamoyl-benzylamino)-2,3»4,5-tetrahydro-l//-benzo[rf]azepine (0.301 g,
0.772 mmol) to provide the title compound as a beige solid (0.328 g, 84%). MS (ES+)
m/z: 390.1 (M+H)+.
Example 564
7-Chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3.4,5-tetrahydro-l//-
benzo[cf|azepine (Z)-Tartrate


Add a solution of n-propylamine (6.3 mg, 0.11 mmol) in anhydrous THF (0.5
mL), HOBT (14.5 mg, 0.11 mmol), a solution of diisopropylamine (27.7 mg, 0.21 mmol)
in anhydrous THF (0.5 mL) and EDC (20.5 mg, 0.11 mmol) to a mixture of 3-tert-
butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (48.1 mg, 0.11 mmol) in anhydrous THF (1.4 mL) at room temperature.
Stir overnight at room temperature and partition the mixture between EtOAc (50 mL) and
saturated aqueous NaHCO3 (20 mL). Dry the organic phase over Na2SC>4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (12 g RediSep® column)
eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 35 mL/min) to afford 3-
tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-propyIcarbamoyl-benzylamino)-2,3,4,5-
tetrahydro-l/f-benzo[rf)azepine as a thick colorless oil (37.1 mg, 71%). MS (ES+) m/z:
490.2 (M+H)+.
Use a method similar to the General Procedure 1-4 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-
tetrahydro-l//-benzo[cf]azepine (33.1 mg, 0.83 mmol) in 1,4-dioxane (1 mL). Purify by
SCX chromatography eluting with dichloromethane and dichloromethane/2M ammonia in
methanol (1:1) to afford 7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-
tetrahydro-l#-benzo[]azepine as a colorless oil (25.2 mg, 96%). MS (ES+) m/z: 390.1
(M+H)+. Use a method similar to the General Procedure 2-6, using 7-chloro-6-(3-fluoro-
4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-l#-benzo[)azepine (25 mg, 0.064
mmol) to provide the title compound as a white foam (31.4 mg, 91%). MS (ES+) m/z:
390.1 (M+H)+.

Example 565
7-Chloro-6-[4-(cyclohexylmethylcarbamoyl)-3-fluoro-benzylatnino]-2,3)4,5-tetrahydro-
l//-benzo[]azepine (I)-Tartrate

Example 565 may be prepared essentially as described in Example 564 by using
3-/err-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine and cyclohexylmethylamine (67% yield, MS (ES+) mJz 444
(M+H)4).
Example 566
7-Chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-li/-
benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine
(800 mg, 1.9 mmol) with 5-aminomethyI-2-cyclohexy]amino-pyridine (910 mg, 4.4
mmol) in anhydrous toluene (15 mL). Purify the residue by chromatography on silica gel
eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain 7-chloro-6-(6-
cyclohexylamino-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[c/]azepine (520 mg, 58%). MS (ES+) m/z: 481.0 (M+H)+.

Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-(6-
cyclohexylamino-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[cQazepine. Purify by chromatography on silica gel eluting with
dichloromethane/2M ammonia in methanol (99/1 to 85/15 gradient) to give the free base
of the title compound. Use a method similar to the General Procedure 2-1 to obtain the
title compound (360 mg, 66%). MS (ES+) mJr. 385.1 (M+H)+.
Example 567
7-Chloro-6-(6-cyclohexylmethyIamino-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-l^T-
benzo[J)azepine Succinate

The title compound may be prepared essentially as described in Example 566 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[af]azepineand 5-aminomethyl-2-cyclohexylmethylamino-pyridine
(22% yield, MS (ES+) m/z 399.1 (M+H)+).
Example S68
6-[6-(Benzylamino)-pyridin-3-ylmethylamino]-7-chloro-2,3,4,5-tetrahydro-l/f-
benzo[
Use a method similar to General Procedure 5-2 to couple 6-benzylamino-pyridin-
3-ylmethylamine and 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-

2,3,4,5-tetrahydro-l.//-benzo[]azepine to give, after deprotection and salt formation by
methods similar to the General Procedures 1-3 and 2-1, the title compound as an off-
white solid (45% overall yield). HRMS (ES+) m/z: 393.1836 (M+H)+.
Example 569
(±)-7-Chloro-6- {4-[ 1 -(1,1,2,2,2-pentafluoroethy l)-ethoxy]-benzy!amino}-2,3,4,5-
tetrahydro-l/f-benzo[rf]azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifIuoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[aT|azepine
(751 mg, 1.8 mmol) with (±)-4-[l-(l)l,2^,2-pentafluoroethyl)-ethoxy]-benzylamine (95i
mg, 3.5 mmol) in anhydrous toluene (20 mL). Purify the crude mixture by
chromatography on silica gel eluting sequentially with hexane/EtOAc (10:1, 5:1, 3:1) to
obtain (±)-7-chloro-6-{4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[]azepine (990 mg, 99%).
Use a method similar to the General Procedure 1-3 to deprotect (±)-7-chloro-6-{4
[ 1 -(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino} -3 -(2,2,2-trifluoroacetyl)-2,3,4,5 -
tetrahydro-l//-benzo[t/]azepine (980 mg, 1.8 mmol). Purify by chromatography on silic;
gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to
give the free base of the title compound. Use a method similar to the General Procedure
2-1 to obtain the title compound (650 mg, 64%). MS (ES+) m/z: 449.1 (M+H)+.
Example 570
(-)-7-Chloro-6-{4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-2,3,4,5-
tetrahydro-l#-benzo[rf]azepine Succinate


Chiral
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rfJazepine(9
g, 21.1 mmol) with 4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine isomer 2 (11.4
g, 42.3 mmol) in anhydrous toluene (270 mL). Purify the crude mixture by
chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1 gradient) to obtain
7-chloro-6-{4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[£/|azepine isomer 2 (9.5 g, 83%).
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-{4-[l-
(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino} -3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[c/]azepine isomer 2 (9.5 g, 17.4 mmol). Purify by chromatography
on silica gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10
gradient) to give the free base of the title compound. Use a method similar to the General
Procedure 2-1 to obtain the title compound (5.9 g, 60%). MS (ES+) m/r. 449.1 (M+H)+.
[a]20D-11.6°(c0.5,MeOH).
Example 571
(+)-7-Chloro-6-{4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine Succinate


Chiral
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(3.4 g, 8 mmol)with4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine isomer 1 (4.3
g, 16 mmol) in anhydrous toluene (100 mL). Purify the crude mixture by
chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:1 gradient) to obtain
7-chloro-6-{4-[l-(l,l,2,2^-pentafluoroe%l)-ethoxy]-benzylamino}-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf)azepine isomer 1 (3.7 g, 85%).
Use a method similar to the General Procedure 1-3 to deprotect 7-chloro-6-{4-[l-
(1 J,2,2,2-pentafluoroethyl)-ethoxy]-be]lzylarnino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[)azepine isomer 1 (3.7 g, 6.8 mmol). Purify by chromatography
on silica gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 97:3
gradient) to give the free base of the title compound. Use a method similar to the General
Procedure 2-1 to obtain the title compound (2.8 g, 74%). MS (ES+) m/z: 449.1 (M+H)+.
[a]20D +13.0° (c 0.5, MeOH).
Example 572
(±)-7-Chloro-6-{4-[ 1 -(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino} -
2,3,4,5-tetrahydro-lfl-benzo[rf]azepine Succinate

_OH
O

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cQazepine
(268 mg, 0.6 mmol) with (±>2-aminomethyl-5-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-
pyridine (170 mg, 0.6 mmol) in anhydrous toluene (3 mL). Purify the crude mixture by
chromatography on silica gel eluting sequentially with hexane/EtOAc (10:1, 5:1, 3:1) to
obtain (±)-7-chloro-6-{4-[ 1 -(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-
ylmethylamino} -3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1 /7-benzo[>/|azepine (270
mg, 79%). MS (ES+) m/z: 546.1 (M+H)+.

Use a method similar to the General Procedure 1-3 to deprotect (±)-7-chloro-6-{4-
[ 1 -(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylrnethylamino} -3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[t/]azepine (265 mg, 0.5 mmol). Purity by
chromatography on silica gel eluting with dichloromethane/2M ammonia in methanol
(99:1 to 90:10 gradient) to give the free base of the title compound. Use a method similar
to the General Procedure 2-1 to obtain the title compound (172 mg, 63%). MS (ES+) m/z:
450.1 (M+H)+.
Example 573
(-)-7-Chloro-6-{4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-
2,3,4,5-tetrahydro-l/f-benzo[

Chiral
Separate (±)-7-chloro-6-{4-[ 1 -(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-
ylmethylamino}-2,3,4,5-tetrahydro-l//-benzo[rf]azepine succinate (172 mg) by normal
phase chiral chromatography (Chiralcel OD, 8 x 35 cm, eluting with heptane/isopropanol
4:1 with 0.2% DMEA). Collect the 1st eluting isomer, then use a method similar to the
General Procedure 2-1 to obtain the title compound [50 mg, 96.3% ee (Chiralcel OD-H,
4.6 x 150 mm, eluting with heptane/isopropanol 4:1 with 0.2% DMEA, 0.6 mL/min)].
MS (ES+) m/z: 450.1 (M+H)+. [a]20D -10.5° (c 0.5, MeOH).
Example 574
(+)-7-Chloro-6-{4-[l-(l,l,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-
2,3,4,5-tetrahydro- l//-benzo[rf|azepine Succinate

Chiral
Separate (±)-7-chloro-6- {4-[ 1 -(1,1,2,2,2-pentafluoroethyl>ethoxy]-pyridin-2-
ylmethylamino}-2,3,4,5-tetrahydro-li/-benzo[cf]azepine succinate (172 mg) by normal
phase chiral chromatography (Chiralcel OD, 8 x 35 cm, eluting with heptane/isopropanol
4:1 with 0.2% DMEA). Collect the 2nd eluting isomer, then use a method similar to the
General Procedure 2-1 to obtain the title compound [41 mg, 95.6% ee (Chiralcel OD-H,
4.6 x 150 mm, eluting with heptane/isopropanol 4:1 with 0.2% DMEA, 0.6 mL/min)].
MS (ES+) m/z: 450.1 (M+H)+. [a]20D +13.1° (c 0.5, MeOH).

Example 575
7-Chloro-6-[4-(l-methyl-cyclohexylmethoxy)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (I)-Tartrate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4)5-tetrahydro-lf/-benzo[c(]azepine
(200 mg, 0.47 mmol) with 4-(l-methyl-cyclohexylmethoxy)-benzylamine (120 mg, 0.51
mmol) in anhydrous 1,4-dioxane (7 mL). Purify the crude mixture by chromatography on
silica gel eluting with isohexane/EtOAc (19:1 to 4:1 gradient) to obtain 7-chloro-6-[4-(l-
methyl-cyclohexylmethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
lH-benzo[flT|azepine (101 mg, 39%).
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-[4-(l-
>methyl-cyclohexylmemoxy)-beiizylammo]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (100 mg, 0.19 mmol). Purify by SCX chromatography eluting with
methanol and 3M ammonia in methanol. Use a method similar to the General Procedure
2-6 to obtain the title compound (78 mg, 73%). MS (ES+) m/z: 413.2 (M+H)+.
Examples 576-580
Examples 576-580 may be prepared essentially as described in Example 575 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[cT|azepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.


Example 581
7-Chloro-6-(4-cyclohexyloxy-benzylamino)-2,3,4,5-tetrahydro-lif-benzo[rf]azepine(Z,)-
Tartrate


Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rfjazepine
(100 mg, 0.43 mmol) with 4-cyclohexyloxy-benzylamine (58 mg, 0.285 mol) in
anhydrous toluene (1 mL). Purify the crude mixture by chromatography on silica gel
eluting with cyclohexane/EtOAc (9:1) to give 7-chloro-6-(4-cyclohexyloxy-
benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[cflazepine(78mg,
69%).
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(4-
cyclohexyloxy-benzylarnino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[c/Jazepine (237 mg, 0.49 mmol) to obtain the free base of the title compound. Use
a method similar to the General Procedure 2-6 to obtain the title compound (208 mg,
80%). MS (ES+) m/z: 385.2 (M+H)+.
Example 582
7-Chloro-6-[4-(tetrahydro-pyran-4-yloxy)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine (i)-Tartrate

Example 582 may be prepared essentially as described in Example 581 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l/f-
benzo[cf]azepine and 4-(tetrahydro-pyran-4-yloxy)-benzylamine (4% yield, MS (ES+) m/z
387 (M+H)+).

Example 583
(±)-7-Chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-2,3,4,5-tctrahydro-l//-
benzo[)azepine Succinate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cf]azepine
(387 mg, 0.91 mmol) with (±)-4-(3,3-dimethyl-cyclohexyloxy)-benzylamine (233 mg, 1
mmol) in anhydrous 1,4-dioxane (14 mL). Purify the crude mixture by chromatography
on silica gel eluting with cyclohexane/EtOAc (19:1 to 1:1 gradient) to obtain (±)-7-
chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[rflazepine (227 mg, 50%).
Use a method similar to the General Procedure 1-1 to deprotect (±)-7-chloro-6-[4-
(3,3-dimethyl-cyclohexyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
li/-benzo[rf]azepine (220 mg, 0.43 mmol). Purify by SCX chromatography eluting with
methanol and 3M ammonia in methanol. Further purify the residue by preparative HPLC.
Use a method similar to the General Procedure 2-1 to obtain the title compound (65 mg,
13%). MS(ES+)Wz:4132(M+H)+.
Example 584
7-Chloro-6-(4-cyclohexylthio-pyridin-3-yImethyIamino)-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine Succinate


Add cesium carbonate (2.04 g, 6.27 mmol), palladium(II) acetate (46 mg, 0.209
mmol) and BINAP (195.21 mg, 0.313 mmol) to a solution of 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[f/]azepine
(1.79 g, 4.18 mmol) and 5-aminomethyl-2-cyclohexylthio-pyridine (1.11 g, 5.02 mmol) in
anhydrous toluene (30 mL). Sonicate the resulting suspension for 30 min then heat at 100
°C for 18 h. Cool the reaction to room temperature. Purify the crude mixture by
chromatography on silica gel eluting with cyclohexane/EtOAc (98:2 to 60:40 gradient) to
give 7-chloro-6-(4-cyclohexylthio-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tctrahydro-lJ/-benzo[d]azepine as an oil (1.1 g, 53%).
Use a method similar to the General Procedure 1-1 to deprotect 7-chloro-6-(4-
cyclohexylthio-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (1.1 g, 2.21 mmol). Purify by SCX chromatography eluting with
methanol and 3M ammonia in methanol. Use a method similar to the General Procedure
2-1 to obtain the title compound as a white solid (0.884 g, 77%). MS (ES+) mJz: 402
(M+H)+.
Example 585
6-(4-rer/-Butylthio-pyridin-3-ylmethylamino)-7-chloro-2,3,4,5-tetrahydro-l//-
benzo[c(]azepine (I)-tartrate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-17/-benzo[rf]azepine
(990 mg, 2.32 mmol) with 5-aminomethyl-2-/err-butylthio-pyridine (500 mg, 2.55 mmol)
in anhydrous toluene (15 mL). Purify the crude mixture by chromatography on silica gel
eluting with isohexane/EtOAc (1:0 to 3:1 gradient) to obtain 6-(4-terM>utylthio-pyridin-
3-yImethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l#-
benzo[rf|azepine (650 mg, 59%). MS (ES+) m/z: All (M+H)+.
Use a method similar to the General Procedure 1-2 to deprotect 6-(4-ter/-
butylthio-pyridin-3-ylmethylamino)-7-chIoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[c(Jazepine (650 mg, 1.37 mmol). Purify by SCX chromatography eluting with
methanol and 3M ammonia in methanol. Use a method similar to the General Procedure
2-6 to obtain the title compound (362 mg, 50%). MS (ES+) m/z: 376 (M+H)+.
Examples 586-593
Examples 586-593 may be prepared essentially as described in Example 585 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l#-benzo[d]azepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.



Example 594
7-Chioro-6-[4-(2,2-dimethyl-propoxymethyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf)azepine (Z)-Tartrate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[cf)azepine
(426 mg, 1 mmol) with 4-(2,2-dimethyl-propoxymethyl)-benzylamine (230 mg, 1.1
mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on
silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient) to obtain 7-chloro-6-[4-(2,2-
dimethyl-propoxymethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[d]azepine (380 mg, 79%). MS (ES+) m/z: 483 (M+H)+.
Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-6-[4-
(2,2-dimethyl-propoxymethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3j4,5-tetrahydro-
l//-benzo[rf]azepine (380 mg, 0.88 mmol). Purify by SCX chromatography eluting with
methanol and 3M ammonia in methanol. Use a method similar to the General Procedure
2-6 to obtain the title compound (319.2 mg, 70%). MS (ES+) m/z: 387 (M+H)+.
Example 595
7-Chloro-6-(4-cyclohexylthio-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[]azepine (£)-
Tartrate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[rf]azepine
(167 mg, 0.392 mmol) with 4-cyclohexylthio-benzylamine (95.4 mg, 0.431 mmol) in
anhydrous 1,4-dioxane (5 mL). Purify the crude mixture by chromatography on silica gel
eluting with isohexane/EtOAc (1:0 to 13:7 gradient) to obtain 7-chloro-6-(4-
cyclohexylthio-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l/f-
benzo[d/)azepine (155 mg, 79%). MS (ES+) m/z: 519 (M+Na)+.

Use a method similar to the General Procedure 1-2 to deprotect 7-chloro-6-(4-
cyclohexylthio-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (155 mg, 0.312 mmol). Purify by SCX chromatography eluting with
methanol and 3M ammonia in methanol. Use a method similar to the General Procedure
2-6 to obtain the title compound (95 mg, 75%). MS (ES+) m/z: 401 (M+H)+.
Examples 596-597
Examples 596-597 may be prepared essentially as described in Example 595 by
using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l//-benzo[cf]azepine and the appropriate amine. Overall yields and MS (ES+)
data are shown in the Table below.

Example 598
7-Chloro-6-(3-chloro-4-ethoxy-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[rflazepine(Z)-
Tartrate


Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(150 mg, 0.35 mmol) with 4-ethoxy-3-chloro-benzylamine (94.7 mg, 0.51 mmol) in
anhydrous 1,4-dioxane (10 mL). Purify the crude mixture by chromatography on silica
gel eluting with isohexane/EtOAc (100:0 to 77:23 gradient) to obtain 7-chloro-6-(3-
chloro-4-ethoxy-benzylamino)-3-(2,2,2-trifluoroacetyI)-2,3,4,5-tetrahydro-l//-
benzo[ Use a method similar to the General Procedure 1-1, but adding water (10 mL) to
the 7M ammonia in methanol solution (20 mL), to deprotect 7-chloro-6-(3-chloro-4-
ethoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[J|azepine(27
mg, 0.072 mmol) to give the free base of the title compound. Use a method similar to the
General Procedure 2-6 to give the title compound as a solid (29 mg, 78%). MS (ES+)
m/r. 365 (M+H)+.
Example 599
7-Chloro-6-(4-cycloheptyloxy-benzylamino)-2,3,4,5-tetrahydro-1 //-benzo [rf]azepine
Succinate

Under a nitrogen atmosphere, add 4-cycloheptyloxy-benzylamine (451 mg, 2.06
mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l#-benzo[tf]azepine (500 mg, 1.17 mmol), palladium(Il) acetate (26 mg, 0.117
mmol), BINAP (110 mg, 0.176 mmol), and cesium carbonate (1.15 g, 3.52 mmol) to
toluene (20 mL). Heat the mixture at 90 °C for 12 h. Cool the mixture to room
temperature and dilute with EtOAc (25 mL). Filter the solids through cellulose (20 g) and

concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g
RediSep column) eluting with hexane/EtOAc (1:0 to 4:1 gradient over 1 h; 80 mL/min) to
provide 7-chloro-6-(4-cycloheptyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l//-benzo[]azepine as a colorless oil (384 mg, 61%). MS (APCI) m/z: 495
(M+H)+.
Dissolve 7-chloro-6-(4-cycIoheptyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[ monohydrate (153 mg, 3.73 mmol) in methanol (5 mL) and stir for 6 h. Concentrate the
mixture in vacuo and dissolve the residue in water (20 mL). Extract the mixture with
EtOAc (3 x 20 mL). Dry the combined organic extracts over Na2SO4, filter and
concentrate in vacuo. Purify the crude mixture by reverse phase HPLC [Phenomonex
C18(2) column, 5 * 25 cm, eluting with a gradient of water/acetonitrile (0.1% TFA in
each) (9:1 through 1:9 over 40 min), 118 mL/min] to provide the trifluoroacetate salt of
the title compound. Dissolve the residue in methanol and elute through an SCX column
with saturated ammonia in methanol to provide the free base of the title compound (197
mg, 65%). Use a method similar to the General Procedure 2-1 to give the title compound
as an off-white solid (250 mg, 100%). MS (APCI) m/z: 399 (M+H)+.
Example 600
7-Chloro-6-(4-cycloheptylthio-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[cf|azepine
Succinate

Example 600 may be prepared essentially as described in Example 599 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[ii]azepine and 4-cycloheptylthio-benzylamine (6% yield, MS (ES+) m/z 415
(M+H)+).

Example 601
7-Chloro-6-(4-cyc!ohexylmethyl-benzylamino)-2,3,4,5-tetrahydro-l//-benzofc/]azepine
Succinate

Under a nitrogen atmosphere, add 4-cyclohexylmethyl-benzylamine
hydrochloride (352 mg, 1.47 mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[]azepine (500 mg, 1.17
mmol), palladium(II) acetate (52.7 mg, 0.235 mmol), BINAP (293 mg, 0.47 mmol) and
cesium carbonate (1.53 g, 4.7 mmol) to toluene (20 mL). Heat the mixture at 90 °C for
12 h. Cool the mixture to room temperature and dilute with EtOAc (25 mL). Filter the
solids through cellulose (20 g) and concentrate the filtrate in vacuo. Purify the crude
mixture by chromatography on silica gel (45 g RediSep column) eluting with
hexane/EtOAc (1:0 to 4:1 gradient over 1 h; 80 mL/min) to provide 7-chloro-6-(4-
cyclohexylmethyl-benzylamino)-3-(2^,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[^lazepine as a colorless oil (354 mg, 63%). MS (APCI) m/r. 479 (M+H)+.
Dissolve 7-chloro-6-(4-cyclohexylmethyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[c/jazepine (354 mg, 0.739 mmol) and lithium hydroxide
monohydrate (100 mg, 2.43 mmol) in methanol (5 mL) and stir overnight. Concentrate
the mixture in vacuo and dissolve the residue in water (20 mL). Extract the mixture with
EtOAc (3 x 20 mL). Dry the combined organic extracts over Na2SC»4, filter, and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g
RediSep column) eluting with a gradient of dichloromethane and
chloroform/methanol/concentrated ammonium hydroxide (80:18:2) over 1 h (80 mL/min)
followed by reverse phase HPLC [Phenomonex Cl 8(2) column (5 x 25 cm), eluting with
water/acetonitrile (0.1% TFA in each) (9:1 to 1:9 gradient over 40 min), 118 mL/min] to
obtain the trifluoroacetate salt of the title compound. Dissolve the residue in methanol

and elute through SCX column with saturated ammonia in methanol to provide 7-chloro-
6-(4-cyclohexylmethyI-benzylamino)-2,3,4,5-tetrahydro-l//-benzo[]azepine (184 mg,
64%). Use a method similar to the Genera! Procedure 2-1 to give the title compound as a
white solid (240 mg, 100%). MS (ES) m/z: 383 (M+H)+.
Example 602
7-Chloro-6-[4-(2-methyl-butyl)-benzylamino]-2,3,4,5-tetrahydro-li/-benzo[rflazepine
Succinate

Under a nitrogen atmosphere, add 4-(2-methyl-butyl)-benzylamine (450 mg, 2.54
mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-
tetrahydro-l#-benzo[rf]azepine (720 mg, 1.7 mmol), palladium(II) acetate (40 mg, 0.17
mmol), BINAP (222 mg, 0.34 mmol) and cesium carbonate (1.4 g, 4.3 mmol) to toluene
(20 mL). Heat the mixture at 95 °C for 12 h. Cool the mixture to room temperature and
apply the mixture to a silica gel column eluting with hexane/EtOAc (10:1) to provide 7-
chloro-6-[4-(2-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[rf|azepine (450 mg, 59%). MS (ES+) m/z: 453 (M+H)+.
Dissolve 7-chloro-6-[4-(2-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-
2,3,4,5-tetrahydro-l//-benzo[)azepine (450 mg, 1 mmol) and concentrated ammonium
hydroxide (5 mL) in methanol (10 mL) and stir overnight. Concentrate the mixture in
vacuo. Purify the crude mixture by SCX chromatography eluting with methanol and 3M
ammonia in methanol. Concentrate the product in vacuo and purify the residue by
reverse phase HPLC [Phenomonex Luna C18(2), 50 mm * 250 mm, eluting with
acetonitrile/water with 0.1% TFA (2:3)]. Concentrate in vacuo, basify with potassium
carbonate and extract into dichloromethane. Dry the organic solution over Na2SO4, filter

and concentrate in vacuo to provide the free base of the title compound (205 mg, 57%).
Use a method similar to the General Procedure 2-1 to give the title compound as a white
solid (280 mg, 59%). MS (APCI) m/z: 357 (M+H)+.
Example 603
7-Chloro-6-[4-(3,3-dimethyl-butyl)-benzylamino]-2,3,4,5-tetrahydro-l//-benzof]azepine
Succinate

Use a method similar to the General Procedure 5-1 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[c(]azepine
(623 mg, 1.46 mmol), palladium(II) acetate (33 mg, 0.146 mmol), BINAP (182 mg, 0.292
mmol), 4-(3,3-dimethyl-butyl)-benzylamine (560 mg, 2.93 mmol) and cesium carbonate
(666 mg, 2.04 mmol) in degassed toluene (40 mL). Degas the mixture with
vacuum/nitrogen purge and heat to 100 °C for 16 h. Cool the mixture to room
temperature, dilute with EtOAc and wash with water. Dry the organic phase over
MgSC>4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane and then hexane/EtOAc (19:1, 9:1) to obtain 7-chloro-6-[4-
(3,3-dimethyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine as oil (622 mg, 91%). MS (ES+) m/z: 467 (M+H)4".
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[4-(3,3-
dimethyI-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-17/-
benzo[rf]azepine (448 mg, 0.96 mmol), to give the free base of the title compound as an
oil (320 mg, 90%) that was used without further purification. MS (ES+) m/z: 371
(M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-[4-(3,3-
dimethyl-butyl)-berizylamino]-2,3,4,5-tetrahydro-l#-benzo[]azepine (315 mg, 0.85

mmol) to give the title compound as a white solid (340 mg, 82%). MS (ES+) m/z: 371
(M+H)+.
Example 604
7-Chloro-6-[6-(3,3-dimethy]-butyl)-pyridin-3-yl-methyIamino]-2,3,4,5-tetrahydro-lH-
benzo[rf)azepine Succinate

Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-
trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo[d]azepme
(166 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (71 mg, 0.078 mmol),
BINAP (103 mg, 0.156 mmol), 3-aminomethyl-6-(3,3-dimethyl-butyl)-pyridine (150 mg,
0.78 mmol) and cesium carbonate (178 mg, 0.546 mmol) in degassed toluene (20 mL).
Degas the mixture with vacuum/nitrogen purge and heat to 100 °C for 14 h. Cool the
mixture to room temperature, dilute with EtOAc and filter through Celite®. Purify the
crude mixture by chromatography on silica gel eluting with hexane and then
hexane/EtOAc (19:1,9:1 and 4:1) to obtain 7-chloro-6-[6-(3,3-dimethyl-butyl)-pyridin-3-
yl-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-li/-benzo[(/lazepineasoil
(149 mg, 82%). MS (ES+) m/z: 468 (M+H)+.
Use a method similar to the General Procedure 1-2, using 7-chloro-6-[6-(3,3-
dimethyl-butyl)-pyridin-3-yl-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
l//-benzo[/i]azepine (140 mg, 0.29 mmol), to give the free base of the title compound as
an oil (96 mg, 86%) that was used without further purification. MS (ES+) m/z: 372
(M+H)+. Use a method similar to the General Procedure 2-1, using 7-chloro-6-[6-(3,3-
dimethyl-butyl)-pyridin-3-yl-methylamino]-2,3,4,5-tetrahydro-lH-benzo[d]azepine(96
mg, 0.258 mmol) to give the title compound as a solid (119 mg, 94%). MS (ES+) m/z:
372 (M+H)+.

Examples 605-607
Examples 605-607 may be prepared essentially as described in Example 604 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[c/Jazepine and the appropriate amine. Overall yields and MS (ES+) data are shown
in the Table below.




2-Vinyl-I13,41-thiadiazole: Combine 2-bromo-[l,3,4]-thiadiazole (3.5 g, 21.2 mmol),
tributylvinyltin (6.20 mL, 21.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (735
mg, 0.6 mmol) in anhydrous toluene (141 mL). Heat the mixture at reflux for 18 h. Add
methanol and dichloromethane to dissolve the residue and evaporate onto silica gel.

Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:4
gradient) to give the desired intermediate (0.49 g, 21%). GC-MS m/z: 112 (M+).
2-Hydroxvmethvl-tl,3,4]-thiadiazoIe: At -10 °C bubble ozone through a solution of 2-
vinyl-[l ,3,4]-thiadiazole (400 mg, 3.57 mmol) in methanol (18 mL). After 20 min the
starting material is consumed. Add then sodium borohydride (37 mg, 0.98 mmol) and
warm to room temperature. Evaporate the mixture and purify the residue by passage
through a pad of silica gel eluting with methanol/dichloromethane (98:2 to 96:4 gradient)
to give the title compound (0.24 g, 60%). MS (ES+) m/z: 117 (M+H)+.
Preparation 321
5-Chloromethylthiazole

Combine 5-methyIthiazole (1.5 g, 15.1 mmol), iV-chlorosuccinimide (2.6 g, 19.4
mmol) and AIBN (0.26 g, 1.6 mmol) in carbon tetrachloride (15 mL). Reflux under
nitrogen for 3 h. Cool the reaction mixture and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to give the title compound
as a yellow oil (0.38 g, 19%).
Preparation 322
5-Bromomethyl-2-chlorothiazole

LJI
5-Chloromethvl-2-chlorothiazole: Combine 5-methyl-2-chlorothiazole (1.05 g, 7.5
mmol), NBS (1.7 g, 9.6 mmol) and AIBN (0.12 g, 0.73 mmol) in carbon tetrachloride (10
mL). Reflux under nitrogen for 7 h. Cool and concentrate in vacuo. Purify by

chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound
as a yellow oil (0.82 g, 51%).
Preparation 323
(±)-1 -Methanesulfonyloxy-1 -thiazol-2-yl-ethyl

QfcM-Thiazol-2-yl-ethanol: Add sodium borohydride (357 mg, 9.4 mmol) portionwise,
over 5 min, to a solution of 2-acetylthiazole (1.0 g, 7.8 mmol) in mcthanol (25 mL) at 0
°C under a nitrogen atmosphere. Stir the mixture for 2 h at room temperature.
Concentrate the mixture in vacuo, dilute the residue with brine (30 mL) and adjust the
mixture to pH 6 with 5N aqueous HC1 (10 mL). Extract the mixture with EtOAc (40
mL). Dry the organic layer over Na2SC>4, filter and concentrate in vacuo to obtain the
desired intermediate (1.0 g, 99%). GC-MS m/z: 129 (lvT).
(±Vl-Methanesulfonvloxv-I-thiazol-2-vl-ethYl: Dissolve l-thiazol-2-yl-ethanol (l.Og,
7.7 mmol) in dichloromethane (30 mL) and triethylamine (1.2 mL, 8.5 mmol). Cool the
solution to 0°C, then add methanesulphony chloride (690 p], 8.9 mmol) under a nitrogen
atmosphere. Stir the solution for 1.5 h at room temperature, then wash with saturated
aqueous NaHCC^ (30 mL). Dry the organic layer over Na2SC»4, filter and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel eluting with
dichloromethane/hexane/methanol (50:45:5) to obtain the title compound (1.3 g, 81%).
GC-MS m/z: 2Q1 (M4)-
Preparation 324
(±)-1 -(3-Fluorophenyl)ethyl bromide


Dissolve (±)-l-(3-fluorophenyl)ethanol (250 mg, 1.786 mmol) in carbon
tetrachloride (10 mL). Add phosphorus tribromide (0.1 mL, 1.786 mmol) at 0 °C and stir
the solution at room temperature overnight. Dilute the reaction mixture with
dichloromethane and wash with brine. Dry the organic phase over Na2SO4, filter and
concentrate in vacuo to obtain the title compound (285 mg) that was used without any
further purification.

OH AcO* ^ HO>-
l-[4-(DiethoxvmethY0-phenvII-3,3-dimetlivlbutan-l-ol: Dissolve l-bromo-4-
(diethoxymethyl)-benzene (6.1 g, 23.55 mmol) in anhydrous THF (150 mL) and cool the
solution to -78 °C. Add w-butyllithium (11.3 mL, 28.26 mmol, 2.5M solution in hexane)
and stir the mixture for 30 min. Add 3,3-dimethylbutyraldehyde (4.7 mL, 35.33 mmol)
and stir the mixture for 1 h. Add water and EtOAc. Warm the solution to room
temperature and extract the aqueous layer three times with EtOAc. Dry the combined
organic extracts with NajSCU, filter and concentrate in vacuo. Purify the crude mixture
by chromatography on silica gel eluting with hexane/EtOAc (93:7) to give the desired
intermediate as a colorless oil (3.8 g, 58%).
l-|4-(DiethoxYmethvl)-phenvII-3,3-dimethylbutan-l-one: Dissolve l-[4-
(diethoxymethyl)-phenyl]-3,3-dimethylbutan-l-ol (3.8 g, 13.57 mmol) in hexane (50
mL). Add manganese dioxide (3.5 g, 40.71 mmol) and stir the mixture at 60 °C

overnight. Filter the solid and concentrate the filtrate in vacuo to give the desired
intermediate as a colorless oil (3.49 g, 93%).
4-(3,3-DimethyI-butyrvl)-benzaldehYde: Dissolve l-[4-(diethoxymethyl)-phenyl]-3,3-
dimethylbutan-l-one (3.49 g, 12.55 mmol) in acetone (50 mL). Addp-toluenesulfonic
acid monohydrate (238 mg, 1.256 mmol). Heat the mixture under reflux for 3 h.
Concentrate in vacuo and partition the residue between water and EtOAc. Extract the
aqueous phase three times with EtOAc. Dry the combined organic extracts over Na2SCU,
filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel
eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (1.67
g, 65%).
l-[4-fl-Hvdroxvethvn-phenvn-33-dimethylbutan-l-one: Dissolve 4-(3,3-dimethyl-
butyryO-benzaldehyde (1.67 g, 8.186 mmol) in anhydrous THF (20 mL) and cool the
solution at -10 °C. Add methyl magnesium bromide (2.7 mL, 8.186 mmol, 3M solution
in diethyl ether) and stir the mixture for 30 min. Add water at 0 °C, dilute with EtOAc
and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts
over Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the
desired intermediate as yellow oil (1.519 g, 84%).
(iy)-l-[4-(l-hvdroxvethvl)-phenvll-3.3-dimethvlbutan-l-one: Dissolve l-[4-(l-
hydroxyethyl)-phenyl]-3,3-dimethyIbutan-l-one (1.519 g, 6.905 mmol) in diisopropyl
ether (20 mL). Add 4A molecular sieves powder (1.5 g), vinyl acetate (2 mL) and lipase
Candida Antarctica acrylic resin (150 mg). Stir the mixture at room temperature
overnight. Remove the solid residue by filtration. Concentrate the filtrate in vacuo and
purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc
(4:1) to give (i?)-l-(l-acetoxi-ethyl)-4-(3,3-dimethyl-butyryl)-benzene as colorless oil
(0.661 g, 36%) and (5)-l-[4-(l-hydroxyethyl)-phenyl]-3,3-dimethylbutan-l-one as a light
yellow oil (0.737 g, 49%).


Heat a mixture of 4'-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12
mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120 mL) for 14 h at
reflux. Cool to ambient temperature and wash sequentially with water (100 mL), 1M
aqueous HC1 (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the
organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1,
9:1) to provide the title compound as oil (5.191 g, 65%). GC-MS m/r. 213 (M+).
Preparations 3S3-3S4
The compounds of Preparations 353-354 may be prepared essentially as described
in Preparation 326 using 4'-methylpropiophenone (Preparation 353) and 4'-
methylbutyrophenone (Preparation 354). Yields are shown in the Table below.


3,4>-Dimethvlbutvrophenone: Add slowly isovaleryl chloride (3.0 g, 24.88 mmol) to an
ice-cold stirred solution of aluminum trichloride (4.976 g, 37.32 mmol) in anhydrous
toluene (60 mL). Stir the reaction mixture at ambient temperature overnight. Add slowly
ice-cold water and extract the mixture twice with EtOAc. Dry the combined organic
extracts over Na2SO4, filter and concentrate in vacuo to give the desired intermediate
(4.38 g, 100%) that was used without any further purification. GC-MS m/z: 176 (M+).
4-(3-Methyl-biitvrvD-benzvl bromide: Heat a mixture of 3,4'-dimethylbutyrophenone
(3 g, 17.02 mmoi), NBS (3.787 g, 16.18 mmol), and AIBN (70 mg, 0.425 mmol) in
carbon tetrachloride (80 mL) for 14 h at reflux. Cool to ambient temperature and filter
the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to
provide the title compound as oil (2.802 g, 65%). GC-MS m/z: 255 (M4).
Preparations 356-357
The compounds of Preparations 356-357 may be prepared essentially as described
in Preparation 329 using the appropriate acyl chloride. Overall yields and GC-MS data
are shown in the Table below.



[4^fert-ButvldimethvlsilvloxvmethvlVphenvll-Dvridin-3-yl-methanol: Dissolve 4-
(rerf-butyldimethylsilyloxymethyl)bromobenzene (1 g, 3.319 mmol, prepared by
following the procedure described in J. Am. Chem. Soc. 1995,117, 704-714) in
anhydrous THF (20 mL). Cool the solution to -78 °C, add rc-BuLi (4.149 mL, 6.638
mmol, 1.6M solution in hexane) and stir at this temperature for 1.5 h. Warm to -60°C,
stir for an additional 30 min and add 3-pyridine carboxaldehyde. Allow the reaction
mixture to warm gradually to room temperature and stir overnight. Add brine and extract
with EtOAc. Dry the organic phase over Na2SC>4, filter and concentrate in vacuo. Purify
the crude mixture by chromatography on silica gel eluting sequentially with hexane and
EtOAc to give the desired intermediate (380 mg, 35%). MS (ES+) m/z: 330 (M+H)+.
[4-(/gr/-Butvldimethvlsirvloxvmethvl)-phenvll-pyridin-3-vl-methanone: Add
manganese dioxide (1.44 g) to a stirred solution of [4-(fer?-butyldimethylsilyloxymethyl)-
phenyl]-pyridin-3-yl-methanol (360 mg, 0.303 mmol) in anhydrous 1,4-dioxane (25 mL).
Heat the mixture to 70 °C overnight. Cool the reaction mixture to room temperature,
filter through Celite® and wash with EtOAc. Concentrate the filtrate in vacuo. Purify the
crude mixture by chromatography on silica gel eluting sequentially with hexane and
hexane/EtOAc (1:1) to provide the desired intermediate (233 mg, 65%). GC-MS m/z:
327 (M*).
4-(Pyridine-3-car bony D-benzyl alcohol: Add tetrabutylammonium fluoride (1.37 mL,
1.37 mmol, 1M solution in THF) to a solution of [4-(rm-butyldimethylsilyloxymethyl)-
phenyl]-pyridin-3-yl-methanone (225 mg, 0.687 mmol) in anhydrous THF (10 mL) at 0
°C and stir at this temperature for 1 h. Concentrate the solvent in vacuo and purify the
crude mixture by chromatography on silica gel eluting with EtOAc to provide the desired
intermediate (85 mg, 58%). MS (ES+) m/z: 214 (M+H)+.

4-fPyridine-3-carbonvl)-benzyl methanesulfonate: Dissolve 4-(pyridine-3-carbonyl)-
benzyl alcohol (85 mg, 0.399 mmol) in dichloromethane (5 mL). Cool to 0 °C and add
triethylamine (0.056 mL, 0.438 mmol) and methanesulfonyl chloride (0.033 mL, 0.438
mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the
reaction mixture with dichloromethane and wash with saturated aqueous NaHCOj. Dry
the organic phase over Na2SC>4, filter and concentrate in vacuo to provide the title
compound as oil (115 mg, 100%). GC-MS m/z: 291 (M+).
Preparation 333
4-(Pyridine-4-carbonyl)-benzyl methanesulfonate

The compound of Preparation 333 may be prepared essentially as described in
Preparation 332 using 4-(/erf-butyldimethyIsilyloxymethyl)bromobenzene and 4-pyridine
carboxaldehyde (GC-MS m/z 291 (M)*).
Preparation 334
4-(4-Cyano-benzoyl)-benzyl bromide

4-(4-Methvl-henzovh-benzonitrile: Suspend 4-cyanobenzoyl chloride (2.0 g, 12 mmol)
in anhydrous toluene (30 mL). Add aluminum trichloride (2.4 g, 18 mmol) in three
portions and stir the reaction mixture at ambient temperature overnight. Cool to 0°C, add
carefully water and extract the mixture twice with EtOAc. Dry the combined organic
extracts over Na2SO4, filter and concentrate in vacuo to give a solid. Suspend the solid in

diethyl ether and filter to obtain the desired intermediate (1.30 g, 49%) that was used
without any further purification. GC-MS w/z: 221 (M+).
4-(4-Cyano-benzovlY-benzyl bromide: Heat a mixture of 4-(4-methyl-benzoyl)-
benzonitrile (300 mg, 1.356 mmol), NBS (386 mg, 2.169 mmol), and AIBN (22 mg,
0.136 mmol) in carbon tetrachloride (10 mL) for 14 h at reflux. Add additional NBS (121
mg) and AIBN (11 mg) and reflux the mixture for 3 h. Cool the reaction mixture to
ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the
crude mixture by chromatography on silica gel eluting sequentially with hexane and
hexane/EtOAc (9:1) to provide the title compound as a solid (286 mg, 70%). GC-MS
m/z: 300 (JVT)-
Preparation 335
4-(3-Cyano-benzoyl)-benzyl bromide

Br
The compound of Preparation 335 may be prepared essentially as described in
Preparation 334 using 3-cyanobenzoyl chloride (GC-MS m/z 300 (M*)).
Preparation 336
2-Methanesulfonyloxymethyl-5-(3-methyl-butyryl)-pyridine



2-(/er^BurvldimethyIsilvloxvmethylV5-(l-hydroxv-3-methvl-buryl)-pyridine:
Dissolve 5-bromo-2-(/ert-butyldimethylsilyloxymethyl)-pyridine (0.5 g, 1.654 mmol,
prepared by following the procedure described in J. Med. Chem. 1987, 30, 871-880) in
anhydrous THF (12 mL). Cool the solution to -78 °C, add H-BuLi (1.14 mL, 1.819
mmol, 1.6M solution in hexane) and stir at this temperature for 40 min. Add slowly
isovaleryl aldehyde (0.284 mL, 2.646 mmol) and stir the mixture for 5 h at -78 °C. Add
additional isovaleryl aldehyde (0.089 mL, 0.827 mmol) and stir the mixture for 1.5 h at -
78 °C. Add ammonium chloride at -78 °C and warm the mixture to room temperature.
Add EtOAc and extract the aqueous layer twice with EtOAc. Dry the combined organic
extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1) to give the
desired intermediate as oil (330 mg, 64%). GC-MS m/z: 309 (M*).
2-(fert-ButvIdimethvlsiIvloxvinethvlV5-f3-methvl-butvrvn-Dvridine: Add manganese
dioxide (1.32 g) to a stirred solution of 2-(ter?-butyldimethylsilyloxymethyl)-5-(l-
hydroxy-3-methyl-butyl)-pyridine (330 mg, 1.066 mmol) in anhydrous 1,4-dioxane (30
mL). Heat the mixture to 70 °C overnight. Cool the reaction mixture to room
temperature, filter through Celite® and wash with EtOAc. Concentrate the filtrate in
vacuo to provide the desired intermediate as oil (327 mg, 100%). GC-MS m/z: 307 (M*).
2-Hvdroxymethvl-5-(3-methvl-biitYrvO-pyridine: Add tetrabutylammonium fluoride
(2.13 mL, 2.13 mmol, 1M solution in THF) to a solution of2-(Jert-
butyldimethylsilyloxymethyl)-5-(3-methyl-butyryl)-pyridine (330 mg, 1.066 mmol) in
anhydrous THF (20 mL) at 0 °C and stir at this temperature for 1 h. Concentrate the
solvent in vacuo and purify the crude mixture by chromatography on silica gel eluting
with EtOAc to provide the desired intermediate (327 mg, 100%).
2-Methanesulfonvloxvmethvl-5-f3-methvl-butvrvIVpyridine: Dissolve 2-
hydroxymethyl-5-(3-methyl-butyryl)-pyridine (190 mg, 0.98 mmol) in dichloromethane
(10 mL). Cool to 0 °C and add triethylamine (0.151 mL, 1.08 mmol) and
methanesulfonyl chloride (0.083 mL, 1.08 mmol). Allow the mixture to warm to room

temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash
with saturated aqueous NaHC03. Dry the organic phase over Na2SO4, filter and
concentrate in vacuo to provide the title compound as oil (263 mg, 98%).
Preparation 337
5-Methanesulfonyloxymethyl-2-(3-methyl-butyryl)-pyridine

5-(fgrf-Butvldimethvlsirvloxvmethyl>-2-(3-methvl-butvrvl)-PVridine: Dissolve 2-
bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g, 6.583 mmol, prepared by
following the procedure described in J. Org. Chem. 2004, 69, 250-262) in anhydrous THF
(20 mL). Cool the solution to -78 °C, add H-BuLi (4.32 mL, 6.912 mmol, 1.6M solution
in hexane) and stir at this temperature for 40 min. Add slowly a solution of JV-methoxy-
JV-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL). Stir
the mixture for 2 h at -78 °C and then allow the mixture to warm to room temperature.
Add brine and extract the aqueous layer twice with EtOAc. Dry the combined organic
extracts over Na2SC>4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the
desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z: 307 (M*).
5-HvdroxymethyI-2-(3-methvl-bntYrvD-pvridine: Add tetrabutylammonium fluoride
(5.853 mL, 5.853 mmol, 1M solution in THF) to a solution of 5-(ferf-
butyldimethylsilyloxymethyl)-2-(3-methyl-butyryl)-pyridine (900 mg, 2.927 mmol) in
anhydrous THF (30 mL) at 0 °C and stir at this temperature for 2 h. Concentrate the
solvent in vacuo and purify the crude mixture by chromatography on silica gel eluting
with hexane and hexane/EtOAc (3:2) to provide the desired intermediate (478 mg, 84%).
MS (ES+) m/z: 194 (M+H)+.

5-MethanesulfonvIoxvmethyI-2-f3-methyl-butyryl)-pyridine: Dissolve 5-
hydroxymethyl-2-(3-methyl-butyryl)-pyridine (210 mg, 1.086 mmol) in dichloromethane
(5 mL). Cool to 0 °C and add triethylamine (0.167 mL, 1.195 mmol) and
methanesulfonyl chloride (0.093 mL, 1.195 mmol). Allow the mixture to warm to room
temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash
with saturated aqueous NaHCCb. Dry the organic phase over NaaSCXt, filter and
concentrate in vacuo to provide the title compound (256 mg, 87%). GC-MS m/z: 271
(M+).
Preparation 338
1 -(3-Chloro-propyl)-1,3-dihydro-indol-2-one

Reflux together oxindole (2.66 g, 20.0 mmol), l-bromo-3-chloropropane (2.56
mL, 26.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) in acetonitrile (300 mL)
under nitrogen for 16 h. Cool the suspension to room temperature and filter off the
precipitate. Concentrate the filtrate in vacuo and purify the crude mixture by
chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40
min) to give the title compound as an orange oil (1.65 g, 39%). MS (ES+) m/z: 210
(M+H)+.
Preparation 339
l-(2-Chloro-ethyl)-pyrrolidin-2-one


Add thionyl chloride (5 mL) to l-(2-hydroxy-ethyl)-pyrrolidin-2-one (1.12 mL,
10.0 mmol) dropwise then stir at room temperature for 10 min. Remove solvent in vacuo
to give the title compound as an orange oil. MS (ES+) m/z: 148 (M+H)+.
Preparation 340
l-(3-Bromo-propyl)-3-methyl-l,3-dihydro-benzoimidazol-2-one

Add portion wise 3-methyl-l,3-diliydro-benzoimidazol-2-one (400 mg, 27.0
mmol) to a suspension of sodium hydride (1.296 g, 32.4 mmol of 60% dispersion in oil)
in anhydrous THF (200 mL) under nitrogen over 15 min, then continue to stir for 30 min.
Add 1,3-dibromopropane (11.0 mL, 108 mmol) and stir overnight. Then heat at reflux for
3 days. Cool the suspension to room temperature, pour into brine (400 mL), extract with
diethyl ether (300 mL), dry over MgSO4 and concentrate in vacuo. Purify by
chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40
min) to give the title compound as a colourless oil (2.15 g, 30%).
Preparations 341-342
The Compound of Preparation 341 may be prepared essentially as described in
Preparation 340 using 3-methyl-l,3-dihydro-benzoimidazol-2-one and 1,4-
dibromobutane. The compound of Preparation 342 may be prepared essentially as
described in Preparation 340 using l-tert-butyl-imidazolidin-2-one and l-bromo-3-
chloropropane. Yields are shown in the Table below.


Preparation 343
l-(3-Bromo-propyl)-3-isopropenyl-l,3-dihydro-benzoimidazol-2-one

Add sodium hydride (600 mg, 16.5 mmol of 60% dispersion in oil) to a solution
of l-isopropenyl-l,3-dihydro-benzoimidazoI-2-one (1.311 g, 7.53 mmol) in anhydrous
DMF (10 mL) under nitrogen at room temperature and stir for 2 h. Add l-bromo-3-
chloropropane (900 \xL, 9.03 mmol) and stir for 3 days. Pour the suspension into water
(100 mL), extract with diethyl ether (2 x 50 mL). Wash the organic extract with brine
(100 mL), dry over MgSO4 and concentrate in vacuo to give the title compound
impurified with l-(3-chloro-propyl)-3-isopropenyl-l,3-dihydro-benzoimidazol-2-one
(2.03 g, 1:1 mixture). MS (ES+) m/z: 251 (M+H)+, 293 (M+H)+.
Preparation 344
5-(3-Chloropropyl)-3,3-dimethyl-l,3-dihydro-indol-2-one


5-(3-Chloropropionvl)-33-dimethyI-13-dihydro-indol-2-one: Under nitrogen
atmosphere, add chloropropionyl chloride (1.54 mL, 16.13 mmol) to a mixture of 3,3-
dimethyl-l,3-dihydro-indol-2-one (2.0 g, 12.41 mmol) and aluminium trichloride (10.26
g, 76.92 mmol) in carbon disulphide (70 mL). Heat under reflux for 3 h then allow to
cool. Decant off the solvent and replace it carefully with ice/water (200 mL). Allow the
resultant suspension to stir for 20 min before filtering off the product and washing with
water (80 mL). Dry in vacuo to obtain the desired intermediate as a pale brown solid
(3.08 g, 99%).
5-(3-Chloropropvl)-33-dimethvl-l atmosphere, add 5-(3-chloropropyl)-3,3-dimethyl-l,3-dihydro-indol-2-one (3.08 g, 12.24
mmol) to trifluoroacetic acid (9.4 mL, 122.4 mmol). Cool the resulting suspension to 0
°C and then add triethylsilane (4.5 mL, 28.2 mmol) dropwise over 2 min. Heat at 45 °C
for 30 min then stir at ambient temperature overnight. Pour the reaction mixture onto
ice/water (100 mL) and extract with EtOAc (2 x 100 mL). Dry the combined extracts
over MgSC>4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica ge5 eluting with hexane/EtOAc (1:0 to 4:1 gradient), to give the
title compound as a yellow-orange solid (2.12 g, 73%).
Preparation 345
3-/ert-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-
l/Z-benzofrflazepine

7-Chloro-6-fO-dimethvlthiocarbamovl>-9-fluoro-3-(2^,2-trifluoroacetvn-23.4,5-
tetrahydro-1/f-benzoti/lazepine: Heat 7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-
trifluoroacetyl)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine (0.56 g, 1.8 mmol) at reflux in
anhydrous 1,4-dioxane (18 mL) with triethylamine (1.01 mL, 7.2 mmol), A^iV-dimethyM-
aminopyridine (22 mg, 0.18 mmol) and dimethylthiocarbamoyl chloride (0.67 g, 5.4

mmol) for 16 h. Cool and wash the mixture with IN aqueous HC1, saturated aqueous
NaHCC>3 and brine. Concentrate in vacuo and purify by chromatography on silica gel
eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give the desired intermediate as a
yellow oil that solidifies on standing (0.69 g, 96%). MS (ES+) m/z: 399 (M+H)+.
7-Chloro-6-dimethvlcarbamovlthio-9-fluoro-3-(2JJ-trifluoroacetvlV2^,4^-
tetrahydro-l/f-benzo||azepine: Heat 7-chloro-6-(O-dimethylthiocarbamoyl)-9-fluoro-
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lW-benzo[rf]azepine (0.69 g, 1.73 mmol) in
diphenyl ether (6 mL) at 245 °C for 2.5 h. Cool the mixture and load onto a column of
silica gel. Wash diphenyl ether off with hexane and elute with hexane/EtOAc (1:0 to 3:2
gradient) to give the desired intermediate (0.44 g, 64%). MS (ES+) m/z: 399 (M+H)+.
3-te/f-ButoxYcarbonvI-7-chloro-6-dimethYlcarbamovlthio-9-fluoro-23,4,5-
tetrahydro-l//-benzol]azepine: Heat 7-chloro-6-dimethylcarbamoylthio-9-fluoro-3-
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lJH-benzo[rf)azepine (0.2 g, 0.5 mmol) in
methanol (50 mL) with potassium carbonate (0.28 g, 2 mmol) at reflux for 5 h. Cool the
mixture, add dropwise a solution of di-fer/-butyl-dicarbonate (0.22 g, 1.0 mmol) in
dichloromethane (20 mL) and stir 17 h. Evaporate the mixture onto silica gel and purify
by chromatography eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give the title
compound (0.12 g, 62%). MS (ES+) m/z: 303 (M+H-Boc)+.
Examples 608-611
Examples 608-611 may be prepared essentially as described in Example 350 by
using 3-/ert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-
benzo[tf)azepine and the appropriately substituted chloromethylheterocycle or
bromomethylheterocyde. MS (ES+) data are shown in the Table below.



Example 612
7-Chloro-6-([l,3,4]thiadiazoI-2-yl-methylthio)-2,3,4,5-tetrahydro-l//-benzo[cf]azepine
Hydrochloride

Stir 2-hydroxymethyl-[l,3,4]-thiadiazole (241 mg, 2.1 mmol) in thionylchloride
(15 mL) for 1 h and concentrate in vacuo. Treat this residue with the thiolate prepared
from 3-rert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-
benzo[]azepine (0.4 g, 1.04 mmol) and potassium hydroxide (1.37 g, 24.5 mmol) in
methanol (3.5 mL) according to General Procedure 7 to give 3-/err-butoxycarbonyl-7-
chloro-6-([l,3,4]thiadiazol-2-yl-methylthio)-2,3,4,5-tetrahydro-l//-benzo[ g, 70%). Treat an aliquot with trifluoroacetic acid to obtain the mass spectrum. MS
(ES+)Wz:312(M+H)+.
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-([l,3,4]thiadiazol-2-yl-methylthio)-2,3,4,5-tetrahydro-l//-

benzo[rf]azepine (300 mg, 0.73 mmol). Use a method similar to the General Procedure 2-
2 to give the title compound (208 mg, 82%). MS (ES+) m/z: 312 (M+H)+.
Example 613
7-Chloro-6-(thiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[£/]azepine Succinate

Use a method similar to General Procedure 7, using 3-tert-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-benzo[rf]azepineand 5-
chloromethylthiazole to give, after deprotection and salt formation by methods similar to
the General Procedures 1-5 and 2-1, the title compound as a white solid (700 mg, 80%
overall). HRMS (ES+) m/z: 311.0427 (M+H)+.
Example 614
7-Chloro-6-[2-(cyclohexylmethylamino)-thiazol-5-ylmethylthio]-2,3,4,5-tetrahydro-l//-
benzo[]azepine Succinate

Use a method similar to General Procedure 7 using 3-terr-butoxycarbonyl-6-
dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[J]azepineand 5-bromomethyl-2-
chlorothiazole to give 3-/er/-butoxycarbonyl-7-chloro-6-(2-chlorothiazol-5-ylmethylthio)-
2,3,4,5-tetrahydro-l//-benzo[]azepine as a yellow oil (0.9 g, 71%). Dissolve 3-ter/-
butoxycarbonyl-7-chloro-6-(2-chlorothiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (120 mg, 0.27 mmol) and cyclohexylmethylamine (1 mL, 7.7 mmol) in

absolute ethanol (1 mL) in a heavy walled Pyrex tube. Heat the reaction in an oil bath at
82 °C for 24 h. Cool the reaction mixture and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1). Use methods similar to
General Procedures 1-5 and 2-1 to deprotect and give the title compound as yellow oil (19
mg, 26% overall). MS (ES+) m/z: 422 (M+H)+.
Example 615
(-)-7-Chloro-6-[l-(thiazol-2-yl)-ethyIthio]-2,3,4,5-tetrahydro-177-benzo[rf]azepine
Succinate

Add potassium hydroxide (3.9 g, 70 mmol) to a solution of 3-tert-butoxycarbonyl-
7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-benzo[J]azepine (900 mg, 2.3
mmol) in methanol (25 mL) under a nitrogen atmosphere. Heat the mixture at 80 °C for
1.5 h. Cool the mixture to ambient temperature, then concentrate in vacuo to an oil.
Dissolve the oil in EtOAc (50mL) and wash with saturated aqueous ammonium chloride
(30 mL). Separate the organic layer and extract the aqueous layer with EtOAc (3 x 50
mL). Dry the combined organic extracts over Na2SC>4, filter and concentrate in vacuo to
an oil (735 mg). Dissolve the oil in anhydrous DMSO (20 mL), then add triethylamine
(1.9 mL, 14 mmol) and (±)-l-methanesulfonyloxy-l-thiazol-2-yl-ethyl (1-3 g, 6.3 mmol)
at ambient temperature under nitrogen. Heat the mixture at 40 °C for 1 h. Cool the
reaction to room temperature, then dilute the mixture with hexane/EtOAc (1:1, 50 mL)
and wash with aqueous 5% sodium chloride (3 x 50 mL). Separate the organic layer and
back extract the aqueous layer with EtOAc (3 x 50 mL). Combine the organic extracts
and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with
hexane/EtOAc (19:1 to 7:3 gradient) to obtain (±)-3-terr-butoxycarbonyl-7-chloro-6-[l-
(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine (779 mg, 79%). MS
(ES+) m/z: 425.0 (M+H)+.

Separate (±}-3-terf-butoxycarbonyl-7-chloro-6-[ 1 -(thiazol-2-yl)-ethylthio]-2,3,4,5-
tetrahydro-l//-benzo[rf]azepine (770 mg, 1.8 mmol) by normal phase chiral
chromatography [Chiralpak AD, 8 x 30 cm, eluting with heptane/3 A ethanol (9:1)].
Collect the 2nd eluting isomer of 3-/ert-butoxycarbonyl-7-chloro-6-[l-(thiazol-2-yl)-
ethylthio]-2,3,4,5-tetrahydro-l//-benzo[cf]azepine {348 mg, 99% ee [Chiralpak AD-H,
4.6 x 150 mm, eluant heptane/3A ethanol (9:1)]}.
Use a method similar to the General Procedure 1-5 to deprotect 3-terh
butoxycarbonyl-7-chloro-6-ll-(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-l#-
benzo[rf]azepine isomer 2. Purify by chromatography on silica gel eluting with
dichloromethane/2M ammonia in methanol (98:2 to 90:10 gradient) to give the free base
of the title compound. Use a method similar to the General Procedure 2-1 to obtain the
title compound (350 mg, 96%). MS (ES+) m/z: 325.0 (M+H)+. [af°D -160° (c 0.5,
MeOH).
Example 616
7-Chloro-3-methyl-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Succinate

Suspend 7-chloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[|azepine hydrochloride in saturated aqueous NaHCO3 and extract three times with
EtOAc. Dry the combined organic extracts over MgSC>4. Filter and concentrate in vacuo
to give the free base as a yellow oil. Combine the free base (0.2 g, 0.66 mmol), sodium
triacetoxyborohydride (0.78 g, 3.7 mmol), formaldehyde (37% solution in water, 0.2 mL,
2.7 mmol), and acetic acid (0.45 mL, 7.9 mmol), in 1,2-dichloroethane (5 mL). Stir at
room temperature for 12 h. Concentrate the crude reaction mixture in vacuo and partition
the residue between EtOAc/water. Separate the layers and extract the aqueous phase with
EtOAc (3 x 30 mL). Wash the combined organic extracts with 1M aqueous NaOH. Dry

over MgSC>4, filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with 2M ammonia in methanol/dichloromethane
(4:96).
Use a method similar to the General Procedure 2-1 to give the title compound as a
sticky glass (140 mg, 48%). HRMS (ES+) m/z: 319.1029 (M+H)+.
Examples 617 and 618
7-Chloro-6-(2^,2-trifluoro-l-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride Isomer 1 and 7-Chloro-6-(2,2,2-trifluoro-l-pyridin-2-yl-
ethylthio)-2,3,4,5-tetrahydro-l//-benzo[]azepine Hydrochloride Isomer 2

Separate the two enantiomers of (±)-7-chloro-6-(2,2,2-trifluoro-l-pyridin-2-yl-
ethylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine hydrochloride by normal phase chiral
chromatography (Chiralpak AD, 2 x 25 cm, eluting with heptane/ethanol (85:15) with
0.2% DMEA).
Subject the first eluting isomer to the General Procedure 1-4 to obtain 7-chloro-6-
(2,2,2-trifluoro-l-pyridin-2-yl-ethylthio)-2,3>4,5-tetrahydro-l//-benzo[^azepine
hydrochloride isomer 1 [99% ee (Chiralpak AD-H, 4.6 x 150 mm, eluting with
heptane/ethanol (85:15) with 0.2% DMEA, flow rate 0.6 mL/min)]. MS (ES+) m/z: 373.1
(M+H)+.
Subject the second eluting isomer to the General Procedure 1-4 to obtain 7-chloro-
6-(2,2,2-trifluoro-l-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-l//-benzofaT|azepine
hydrochloride isomer 2 [99% ee (Chiralpak AD-H, 4.6 x 150 mm, eluting with heptane/
ethanol (85:15) with 0.2% DMEA, flow rate 0.6 mL/min)]. MS (ES+) m/z 373.1 (M+H)+.

Example 619
(-)-7-Chloro-6-(l-pyridin-2-yl-propylthio)-2,3,4,5-tetrahydro-l//-benzo[flT|azepine
Hydrochloride

Separate the two enantiomers of (±)-7-chloro-6-(l-pyridin-2-yl-propylthio)-
2,3,4,5-tetrahydro-l//-benzo[cf)azepine hydrochloride by normal phase chiral
chromatography (Chiralcel OJ, 8 x 33 cm, editing with heptane/methanol/3A ethanol
(85:10:5) with 0.2% DMEA).
Subject the second eluting isomer to the General Procedure 1-4 to obtain the title
compound [93% ee (Chiralcel OJ, 4.6 x 250 mm, eluting with heptane/methanol/3A
ethanol (90:5:5) with 0.2% DMEA, flow rate 0.6 mL/min)]. MS (ES+) m/r. 333.1
(M+H)+. [ Example 620
(±)-7-Chloro-6-[l-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l/f-benzo[rfIazepine
Hydrochloride

Dissolve 3-ter/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[]azepme (415 mg, 1.08 mmol) in methanol (20 mL) and add
potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60 °C for 4 h. Cool the reaction
mixture to ambient temperature, add aqueous saturated ammonium chloride and
concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic
phase over anhydrous Na2SC>4 and concentrate in vacuo to give 3-/er/-butoxycarbonyl-7-

chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[cOazepine (0.34 g, 1.086 mmol).
Dissolve the crude 3-/erf-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydrolfl-
benzo[tf]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride
(65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of
(±)-l-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and
heat the solution at 45 °C overnight. Cool to ambient temperature, add water and extract
the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous
Na2SO4, filter and concentrate in vacua. Purify the crude mixture by chromatography on
silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-/crf-
butoxycarbonyl-7-chloro-6-[l-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[t/]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H-Boc)+.
Use a method similar to the General Procedure 1-4 to deprotect (±)-3-/ert-
butoxycarbonyl-7-chloro-6-[l-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[rflazepine (47 mg, 0.108 mmol) and give the title compound as a solid (39 mg,
99%). MS (ES+) m/z: 336 (M+H)+.
Examples 621-622
Examples 621-622 may be prepared essentially as described in Example 620 using
3-/err-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/7-
benzo[c/]azepine and the appropriate alkyl bromide. Overall yields and MS (ES+) data
are shown in the Table below.



Examples 623 and 624
7-Chloro-6-[l-(4-fluorophenyl)ethyIthio]-2,3,4,5-tetrahydro-l/f-benzo[rf|azepine
Succinate Isomer 1 and 7-chloro-6-[l-(4-fiuorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[cfjazepine Succinate Isomer 2

Separate the two enantiomers of (±)-3-/er/-butoxycarbonyl-7-chloro-6-[l-(4-
fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-lJ7-benzo[rf]azepine by chiral HPLC
(Chiralcel OJ-H 4.6 x 150 mm column, eluting with methanol at 0.6 mL/min).
Subject Isomer 1 OR = 7.3 min, ee > 99.9%) to the General Procedure 2-1 to afford
7-chloro-6-[ 1 -(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro- l//-benzo[cf|azepine
succinate isomer 1 as a white solid. MS (ES+) mlz 336 (M+H)+.
Subject Isomer 2 (tR = 12.9 min, ee = 99.9%) to the General Procedure 2-1 to
afford 7-chloro-6-[l-(4-fluorophenyl)ethylthio]-2>3,4,5-tetrahydro-l//-benzo[cf]azepine
succinate isomer 2 as a white solid. MS (ES+) mlz 336 (M+H)+.

Examples 625 and 626
7-Chloro-6-[l-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-lH-bcnzo[c/lazepine
Succinate Isomer 1 and 7-chloro-6-[l-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-
benzo[
Separate the two enantiomers of (±)-3-terf-butoxycarbonyl-7-chloro-6-[l-(3-
fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine by chiral HPLC
(Chiralcel OJ-H 4.6 x 150 mm column, eluting with methanol at 0.6 mL/min).
Subject Isomer I (tR = 5.4 min, ee > 99.9%) to the General Procedure 2-1 to afford
7-chloro-6-[l-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-l//-benzo[J)azepine
succinate isomer 1 as a white solid. MS (ES+) mlz 336 (M+H)+.
Subject Isomer 2 (tR = 11.2 min, ee = 99.7%) to the General Procedure 2-1 to
afford 7-chloro-6-[l-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-li7-benzo[rflazepine
succinate isomer 2 as a white solid. MS (ES+) mlz 336 (M+H)+.
Example 627
(S)-7-Chloro-6- {1 -[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio} -2,3,4,5-tetrahydro-1H-
benzo[d]azepine Hydrochloride

Heat the mixture of 3-tert-butoxycarbonyI-7-chloro-6-dimethyIcarbamoylthio-
2,3,4,5-tetrahydro-lH-benzo[d]azepine (310 mg, 0.807 mmol) and potassium hydroxide

(1.45 g, 25.83 mmol) in methanol (5 mL) at 50 °C for 3 h. Cool the reaction mixture to
room temperature and dilute with saturated aqueous NH4CI and EtOAc. Separate the
layers and extract the aqueous layer three times with EtOAc. Dry the combined organic
extracts over Na2SO,t, filter and concentrate in vacuo. Dissolve the crude 3-tert-
butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-lH-benzo[d]azepine in
anhydrous DMF (2 mL) and cool at 0 °C. Add sodium hydride (21 mg, 0.888 mmol) and
a solution of (R)-l-[4-(l-bromoethyl)-phenyl]-3,3-dimethylbutan-l-one {prepared by the
mixture of (S)-l-[4-(l-hydroxyethyl)-phenyl]-3,3-dimethylbutan-l-one (213 mg, 0.969
mmol), triphenylphosphine (296 mg, 1.130 mmol) and NBS (201 mg, 1.13 mmol) in
anhydrous THF (5 mL) at 0 °C and then room temperature}. Stir the mixture at 0 °C for
30 min and quench with water. Dilute with EtOAc and extract the aqueous layer three
times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with hexane/EtOAc (85:15) to give (S)-3-tert-butoxycarbonyl-7-chloro-6-{l-[4-(3,3-
dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-lH-benzo[d]azepine as yellow oil
(197 mg, 47%).
Use a method similar to the General Procedure 1-4, using (S)-3-tert-
butoxycarbonyl-7-chloro-6-{ 1 -[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio} -2,3,4,5-
tetrahydro-lH-benzo[d]azepine (197 mg, 0.382 mmol) to give the title compound as a
white solid (161 mg, 93%). MS (ES+) m/z: 416 (M+H)+; ee = 92%, tR = 11.27 min
(Chiralcel OJ, 4.6 x 250 mm, 45 °C , eluent: 20% isopropanol with 0.05% triethylamine
in SFC, flow rate 2 mL/min, UV detector at 234 nm).
Example 628
(S)-7-Chloro-6-(l-phenyl-ethylthio)-2,3,4,5-tetrahydro-17?-benzo[c/lazepine
Hydrochloride


Example 628 may be prepared essentially as described in Example 627 using 3-
/err-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine and (#)-( 1-bromo-ethyl)-benzene (64% yield, MS (ES+) m/z 318
(M+H)*).
Example 629
6-(4-Acetyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-l//-benzo[rf]azepineHydrochloride

Use a method similar to the General Procedure 7 to react 3-te/?-butoxycarbonyl-7-
chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-benzo[rfjazepine (200 mg, 0.521
mmot) with 4-acetylbenzyl bromide (555 mg, 2.605 mmol). Purify the crude mixture by
chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1,
4:1) to obtain 6-(4-acetyl-benzylthio)-3-rer/-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-
l//-benzo[rf|azepine (190 mg, 82%).
Use a method similar to the General Procedure 1-4 to deprotect 6-(4-acetyl-
benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l^/-benzo[rf]azepine(170
mg, 0.381 mmol) and give the title compound as a white solid (140 mg, 96%). MS (ES+)
m/z: 346 (M+H)+.
Examples 630-634
Examples 630-634 may be prepared essentially as described in Example 629 using
3-terNbutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lf/-

benzo[J]azepine and the appropriate benzyl bromide. Overall yields and MS (ES+) data
are shown in the Table below.

Example 635
7-Chloro-6-[4-(pyridine-3-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-l//-benzo[^|azepine
Hydrochloride

Dissolve 3-rerf-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[c/]azepine (150 mg, 0.39 mmol) in methanol (10 mL) and add

potassium hydroxide (0.7 g, 12.47 mmol). Heat at 60 °C for 4 h. Cool the reaction
mixture to ambient temperature, add aqueous saturated ammonium chloride and
concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic
phase over anhydrous Na2SC>4 and concentrate in vacuo to give 3-ter/-butoxycarbonyl-7-
chloro-6-mercapto-2,3,4,5-tetrahydro-l W-benzo[cf|azepine (0.12 g). Dissolve the crude
3-/erf-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[rf]azepine(0.12
g, 5.2 mmol) in anhydrous DMSO (6 mL) and add triethylamine (0.325 mL, 2.34 mmol)
and 4-(pyridine-3-carbonyl)-benzyl methanesulfonate (114 mg, 0.39 mmol). Heat the
solution at 40 °C overnight. Cool to ambient temperature, dilute the mixture with
hexane/EtOAc (1:1, 100 mL), and wash the organic solution sequentially with brine and
ice-cold water. Dry the organic layer over anhydrous Na2SO4, filter and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and
hexane/EtOAc (1:1) to give 3-/er/-butoxycarbonyl-7-chloro-6-[4-(pyridine-3-carbonyl)-
benzylthio]-2,3A5-tetrahydro-l//-benzo[J]azepine as 0\\ (123 mg, 64%).
Use a method similar to the General Procedure 1-4 to deprotect 3-/er/-
butoxycarbonyl-7-chloro-6-[4-(pyridine-3-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-l^-
benzo[rf]azepine (113 mg, 0.22 mmol) and give the title compound as a solid (105 mg,
99%). MS (ES+) mJz: 409 (M+H)+.
Examples 636-638
Examples 636-638 may be prepared essentially as described in Example 635 using
3-fer/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[J]azepine and the appropriate methanesulfonate. Overall yields and MS (ES+)
data are shown in the Table below.


Example 639
7-Chloro-6-[4-(3-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-l//-benzo[c/lazepine
Hydrochloride

Dissolve 3-ter/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-li/-benzo[ potassium hydroxide (0.935 g, 16.66 mmol). Heat at 60 °C for 4 h. Cool the reaction
mixture to ambient temperature, add aqueous saturated ammonium chloride and
concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic
phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-
chloro-6-mercapto-2,3>4,5-tetrahydro-l//-benzo[£/]azepine (0.16 g, 5.2 mmol). Dissolve

the crude 3-te/*r-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-l H-
benzo[*/]azepine (0.16 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine
(0.435 mL, 3.12 mmol) and 4-(3-cyano-benzoyl)benzyl bromide (289 mg, 0.96 mmol).
Heat the solution at 40 °C overnight. Cool to ambient temperature, dilute the mixture
with hexane/EtOAc (1:1, 100 mL), and wash the organic solution sequentially with brine
and ice-cold water. Dry the organic layer over anhydrous Na2SC>4, filter and concentrate
in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane
and hexane/EtOAc (9:1,4:1) to give 3-ferf-butoxycarbonyl-7-chloro-6-[4-(3-
cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-l//-benzo[c/]azepine as oil (212 mg, 77%).
Use a method similar to the General Procedure 1-4 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-[4-(3-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-l/f-
benzo[cf|azepine (200 mg, 0.37 mmol) and give the title compound as a solid (136 mg,
77%). MS (ES+) m/z: 433 (M+H)+.
Example 640
7-Chloro-6-[4-(4-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
Hydrochloride




Example 640 may be prepared essentially as described in Example 639 using 3-
/ert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine and 4-(4-cyano-benzoyl)benzyl bromide (49% yield, MS (ES+) m/z 433
(M+H)*).

Example 641
7-Chloro-6-(4-/ert-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Hydrochloride

Combine 7-chloro-6-(4-ter/-butylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-l//-
benzo []azepine (53 mg, 0.13 mmol) with 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-
diphosphetane-2,4-disulfide (Lawesson's reagent) (53 mg, 0.13 mmol) in anhydrous 1,4-
dioxane (1 mL) in a sealed tube and heat at 100 °C for 2 h. Cool the reaction mixture to
room temperature, concentrate in vacuo and purify the residue by SCX chromatography
to obtain 7-chloro-6-(4-ter/-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-\H-
benzo[ Phenyl 21.2 x 250 mm, 5 micron, 22 mL/min of 0.1% aqueous HC1 /acetonitrile (9:1 to
1:9) over 30 min, detector at 230 nm].
Use a method similar to the General Procedure 2-2 to obtain the title compound as
a yellow solid (36 mg, 58%). MS (ES+) mJz: 419 (M+H)+.
Example 642
7-Chloro-6-[4-(4-fluorobenzylthiocarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-l//-
benzo[cf]azepine Succinate


Combine 7-chloro-6-[4-(4-fluorobenzylcarbamoyl)-benzylthio]-2,3,4,5-
tetrahydro-l//-benzo[J]azepine (23 mg, 0.05 mmol) with 2,4-bis(4-methoxyphenyl)-l,3-
dithia-2,4-diphosphetane-2,4~disulfide (Lawesson's reagent) (23 mg, 0.05 mmol) in
anhydrous 1,4-dioxane (1 mL) in a sealed tube and heat at 100 °C for 2 h. Cool the
reaction mixture to room temperature, concentrate in vacuo and purify the residue by
SCX chromatography to obtain 7-chloro-6-[4-(4-fluorobenzylthiocarbamoyl)-benzylthio]-
2,3,4,5-tetrahydro-li/-benzo[rf]azepine as a yellow oil.
Use a method similar to the General Procedure 2-1 to obtain the title compound as
a white solid (10 mg, 42%). MS (ES+) m/z: 471 (M+H)+.
Example 643
7-Chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine Succinate
Use a method similar to General Procedure 7, using 3-/er/-butoxycarbonyl-7-
chIoro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-benzo[]azepine (2 g, 5.2 mmol)
and 2-chloro-5-(chloromethyl)pyridine (843 mg, 5.2 mmol) to give 3-tert-
butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine (2.2 g, 95%). MS (ES+) m/z: 439.1 (M+H)+.
Slurry palladium(II) acetate (434 mg, 1.9 mmol), BINAP (1.2 g, 1.9 mmol),
sodium-tert-butoxide (644 mg, 6.7 mmol), cyclohexylamine (1.4 g, 14.4 mmol) and 3-
/erNbutoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine (2.1 g, 4.8 mmol) in anhydrous toluene (70 mL). Degas the slurry under

house vacuum, then buble nitrogen. Heat the mixture to 95 °C for 16 h under a nitrogen
atmosphere. Cool the mixture to room temperature, dilute with EtOAc (50 mL) and filter
through Celite®. Concentrate the filtrate to an oil and purify by chromatography on silica
gel eluting with hexane/EtOAc (19:1 to 13:7 gradient) to obtain 3-tert-butoxycarbonyl-7-
chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine (800 mg, 33%). MS (ES+) m/z: 502.2 (M+H)+.
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-
tetrahydro-l//-benzo[rf|azepine (790 mg, 1.6 mmol). Purify by chromatography on silica
gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 95:5 gradient) to
give the free base of the title compound. Use a method similar to the General Procedure
2-1 to obtain the title compound (670 mg, 82%). MS (ES+) m/z: 402.1 (M+H)+.
Example 644
7-Chloro-6-(6-trifluoroethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-l//-
benzo[c/]azepine Succinate

Example 644 may be prepared essentially as described in Example 643 by using
3-/err-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-
l#-benzo[]azepine and 2,2,2-trifluoroethylamine (10% yield, MS (ES+) m/z 502.2
(M+H)4).

Example 645
7-Chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-
l//-benzo[*/]azepine Succinate

Add cyclohexylmethylamine (3 mL) to a flask containing 3-/erf-butoxycarbonyl-
7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-17/-benzo[]azepine
(340 mg, 0.8 mmol) and ammonium chloride (50 mg, 0.92 mmol). Heat the contents in a
sealed flask at 170 °C for 7 h. Cool the flask to room temperature, dilute with EtOAc (50
mL) and wash with water (20 mL). Collect the organic layer and concentrate in vacuo.
Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (19:1 to
4:1 gradient) to obtain 3-ter/-butoxycarbonyl-7-chloro-6-(6-cyclohexylmethylamino-
pyridin-3-ylmethyIthio)-2,3,4,5-tetrahydro-li/-benzo[c(]azepirie (160 mg, 40%).
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylthio)-2,3,4,5-
tetrahydro-li/-benzo[c/]azepine. Purify by chromatography on silica gel eluting with
dichloromethane/2M ammonia in methanol (99:1, 98:2, 96:4 gradient) to give the free
base of the title compound. Use a method similar to the General Procedure 2-1 to obtain
the title compound (115 mg, 70%). MS (ES+) m/r. 416.0 (M+H)+.
Example 646
7-Chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-li/-benzo[rf]azepine
Hydrochloride


Dissolve 3-terr-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-]//-benzo[c/Jazepine (200 mg, 0.52 mmol) in methanol (10 mL) and add
potassium hydroxide (0.934 g, 16.64 mmol). Heat at 60 °C for 4 h. Cool the reaction
mixture to ambient temperature, add aqueous saturated ammonium chloride and
concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic
phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-ter/-butoxycarbonyl-7-
chloro-6-mercapto-2,3,4,5-tetrahydro-l//-benzo[*/]azepine (0.163 g). Dissolve the crude
3-terf-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,54etrahydro-l//-benzo[rf]azepine
(0.163 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine (0.43 mL, 3.12
mmol) and 2,2-difluoro-2-phenylethyl trifluoromethanesulfonate (151 mg, 0.52 mmol).
Heat the solution at 40 °C overnight. Cool to ambient temperature, add water and extract
the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous
Na2SC>4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1 and 4:1) to give 3-fer/-
butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine as oil (132 mg, 56%).
Use a method similar to the General Procedure 1-4 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-l//-
benzofrfjazepine (132 mg, 0.29 mmol) and give the title compound as a solid (111 mg,
98%). MS (ES+) m/z: 354 (M+H)+.

Example 647
7-Chloro-6-(2,2-difluoro-2-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-l//-
benzo[rfjazepine Hydrochloride

Example 647 may be prepared essentially as described in Example 646 using 3-
/er/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[t/]azepine and 2,2-difluoro-2-pyridin-2-yl-ethyl trifluoromethanesulfonate
(prepared by following the procedure described in J. Med. Chem. 2003,46,461-473)
(66% yield, MS (ES+) m/z 355 (M+H)*).
Example 648
7-Chloro-6-[3-(2-oxo-2,3-dihydro-indol-l-yl)-propylthio]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Add potassium hydroxide (899 mg, 16.64 mmol) in one portion to a solution of 3-
/er/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the raction to 50 °C
under nitrogen for 24 h, then cool to room temperature and add l-(3-chloro-propyl)-l,3-
dihydro-indol-2-one (217 mg, 1.04 mmol). Stir the reaction at room temperature for 4
days. Remove solvents in vacuo, add dichloromethane (20 mL) and water (20 mL).
Remove the organic layer and dry using an ISCO® phase separator then concentrate in
vacuo to give 3-/err-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-l-yl)-

propylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as orange powder. MS (ES+) m/z:
509 (M+Na)+.
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-l-yl)-
propylthio]-2,3,4,5-tetrahydro-l//-benzo[rf|azepine (0.52 mmol) in dichloromethane (10
mL), then add TFA (2 mL) dropwise and stir for 2 h. Remove solvents in vacuo, then
free base using an SCX column, eluting with 7M ammonia in methanol. Purify using
UV-guided reverse phase HPLC [Supelco Discovery C18 column (21.2 x 100 mm, 5um
packing), 20 mL/min flow rate, eluting with water/acetonitrile/acetic acid gradient over
15 min, fraction collection triggered using UV detector (220 and 254 nm)] followed by
SCX column, eluting with 7M ammonia in methanol, then Mass-guided reverse phase
HPLC [Supelco Discovery C18 column (21.2 x 100 mm, 5|im packing), 25 mL/min flow
rate, eluting with water/acetonitrile/acetic acid gradient over 12 min, fraction collection
triggered by Electrospray MS] and SCX column. Concentrate in vacuo, then use a
method similar to the General Procedure 2-1 and freeze dry to give the title compound as
a light pink solid (51 mg, 19%). MS (ES+) m/z: 387 (M+H)+.
Examples 649-650
Examples 649-650 may be prepared essentially as described in Example 648 using
3-rert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-
benzo[rf]azepine and the appropriately substituted alkyl chloride. Overall yields and MS
(ES+) data are shown in the Table below.


Example 651
7-Chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-l-yl)-propyIthio]-2,3,4,5-
tetrahydro-l//-benzo[rf|azepine Succinate

Add potassium hydroxide (170 mg, 3.03 mmol) in one portion to a solution of 3-
fert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lif-
benzo[c/]azepine (187 mg, 0.49 mmol) in methanol (10 mL). Heat the reaction at reflux
under nitrogen overnight. Then add further portion of KOH (867 mg, 15.45 mmol) and
heat at reflux for 3 h. Then cool to room temperature and add l-(3-bromo-propyl)-l,3-
dihydro-3,3-dimethyl-indol-2-one (274 mg, 0.97 mmol, prepared by following the
procedure described in Perkin 1 2000, 769-774). Stir the reaction at room temperature
overnight. Remove solvents in vacuo, add water and extract with diethyl ether (2 x 50
mL). Combine the organic extracts, wash with water (2 x 50 mL) and brine (50 mL).
Dry over MgSC>4 and concentrate in vacuo. Purify by chromatography on silica gel
eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 3-terf-
butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-l-yl)-propylthio]-
2,3,4,5-tetrahydro-l//-benzo[*/]azepine as a colourless oil (330 mg), 50% contaminated
with l-(3-methoxypropyl)-l,3-dihydro-3,3-dimethyl-indol-2-one. MS (ES+) m/z: 537
(M+Na)+.
Dissolve 3-tert-butoxycarbonyl-7-chIoro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-
indol-l-yl)-propylthio]-2,3,4,5-tetrahydro-lH-benzo[d]azepine (240 mg, 0.52 mmol) in
dichloromethane (10 mL), then add TFA (1 mL) dropwise and stir at room temperature
overnight. Remove solvents in vacuo to give a straw coloured oil (580 mg), then free
base using an SCX column, eluting with 7M ammonia in methanol. Concentrate in

vacuo, then use a method similar to the General Procedure 2-1 and freeze dry to give the
title compound as a solid (196 mg, 82%). MS (ES+) m/z: 415 (M+H)+.
Examples 652-654
Examples 652-654 may be prepared essentially as described in Example 651 using
3-ter/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li/-
benzo[|azepine and the appropriate alkyl bromide. Examples 655-657 may be prepared
essentially as described in Example 651 using the appropriate alkyl chloride. Overall
yields and MS (ES+) data are shown in the Table below.



Example 658
7-Chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-l-yl)-propylthio]-2,3,4,5-tetrahydro-
l//-benzo[flf]azepine Succinate

Add potassium hydroxide (933 mg, 16.6 mmol) in one portion to a solution of 3-
/er?-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction at reflux
under nitrogen 4 h. Then cool to room temperature and add l-(3-bromo-propyl)-3-
isopropenyl-l,3-dihydro-benzoimidazol-2-one (142 mg, 0.52 mmol). Stir the reaction at
room temperature overnight. Remove solvents in vacuo, extract into diethyl ether (2 x 50
mL), wash with water (2 x 50 mL) and brine (50 mL). Dry over MgSO4, filtrate and
concentrate in vacuo to give 3-terNbutoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-
benzoimidazol-l-yl)-propylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as an oil (209
mg, 76%). MS (ES+) mfz: 550 (M+Na)+.
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-
l-yl)-propylthio]-2,3,4,5-tetrahydro-l#-benzo[rf|azepine (209 mg, 0.396 mmol) in

dichloromethane (10 mL), then add TFA (0.5 mL) dropwise and stir at room temperature
overnight. Remove solvents in vacuo then free base using an SCX column, eluting with
7M ammonia in methanol. Concentrate in vacuo, then use a method similar to the
General Procedure 2-1 and freeze dry to give the title compound as a solid (140 mg,
70%). MS (ES+) m/z: 388 (M+H)+.
Example 659
7-Chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-l/^-indol-5-yl)-propylthio]-2,3,4,5-
tetrahydro-1 //-benzo[rf]azepine Succinate

Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol) to a
stirred solution of 3-/er/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-
tetrahydro-l//-benzo[t/]azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under
reflux for 2 h then add further potassium hydroxide (159 mg, 2.83 mmol) and continue
heating under reflux for another 6 h. Cool the reaction mixture and add dropwise via
cannula a solution of 5-(3-chloropropyl)-3,3-dimethyl-l,3-dihydro-indol-2-one (245 mg,
1.03 mmol) in methanol (10 mL). Stir at ambient temperature overnight then heat at 50
°C for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to the reaction mixture and then
heat under reflux for 5 h. Concentrate in vacuo and partition the residue between water
(100 mL) and EtOAc (50 mL). Extract the aqueous phase with EtOAc (2 x 50 mL).
Wash the combined extracts with brine (50 mL), dry over MgSCu, filter and concentrate
in vacuo to obtain the crude mixture as a yellow oil. Dilute this oil with dichloromethane
then re-concentrate in vacuo and repeat until a solid remains. Dry the solid in a vacuum
oven to give 3-/erf-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-l//-
indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a yellow solid (481 mg)
that was used without further purification. MS (ES+) m/z: 537 (M+Na)+.

Add trifluoroacetic acid (0.2 mL, 2.6 mmol) to a solution of 3-tert-
butoxycarbonyl-7-chloro-6-f3-(3,3-dimethyl-2-oxo-2,3-dihydro-l//-indol-5-yl)-
propylthio]-2,3,4,5-tetrahydro-l#-benzo[rf]azepine (257 mg, 0.5 mmol) in
dichloromethane (5 mL) then stir at ambient temperature over the weekend. Concentrate
in vacuo. Dissolve the residue in methanol and load onto an SCX column. Elute with
methanol followed by 7M ammonia in methanol. Collect the basic fraction and
concentrate in vacuo. Purify the residue by prep-LCMS [Supelco Discovery C18 column
(21.2 x 100 mm, 5pm packing), 25 mL/min flow rate, eluting with a water/acetonitrile
gradient containing acetic acid as modifier over 12 min, fraction collection triggered by
Electrospray MS] to give 7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-l//'-indol-5-yl)-
propylthio]-2,3,4,5-tetrahydro-l//-benzo|>/]azepine as a white solid (101 mg, 25% over 2
steps). MS (ES+) m/z: 415 (M+H)+.
Dissolve 7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-l//-indol-5-yl)-
propylthio]-2,3,4,5-tetrahydro-li/-benzo[ diethyl ether (3 mL) and methanol (2 mL). Add succinic acid (28.7 mg, 0.24 mmol) and
allow the resultant suspension to stir at ambient temperature for 2 h. Concentrate in
vacuo and dry the residue in a vacuum oven to afford the title compound as a white solid.
MS (ES+) m/z: 415 (M+H)+.
Example 660
7-Chloro-6-(A^-phenylcarbamoyl-methylthio)-2,3,4,5-tetrahydro-l/f-benzo[d]azepine
Succinate




Add potassium hydroxide (890 mg, 15 mmol) in one portion to a solution of 3-
/ert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l/f-
benzo[
under nitrogen 3 h. Then cool to room temperature, add 2-chloro-ALphenyl-acetamide
(79 mg, 0.47 mmol) and stir overnight. Remove solvents in vacuo, extract into diethyl
ether (2 x 50 mL), wash with water (2 x 50 mL) and brine (50 mL). Dry over MgSO4,
filtrate and concentrate in vacuo to give 3-terr-butoxycarbonyl-7-chloro-6-(/V-
phenylcarbamoyl-methylthio)-2,3,4,5-tetrahydro-l//-benzo[rf]azepine as a clear oil (210
mg, 100%). MS (ES+) m/z: 460 (M+Na)+.
Dissolve 3-fm-butoxycarrx>nyl-7-chloro-6-(N-phenylcarbamoyl-methylthio)-
2,3,4,5-tetrahydro-l//-benzo[|azepine(210 mg, 0.47 mmol) in dichloromethane (10 mL)
then add TFA (0.5 mL) dropwise and stir at room temperature for 3 days. Remove
solvents in vacuo then free base using an SCX column, eluting with 7M ammonia in
methanol. Concentrate in vacuo, then use a method similar to the General Procedure 2-1
and freeze dry to give the title compound as a solid (150 mg, 69%). MS (ES+) m/z: 347
(M+H)+.
Example 661
7-Chloro-6-(3-methylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-l//-benzo[rflazepine
Succinate

3-tert-Butoxvcarbonvl-7-chloro-6-(3-carboxv-propvIthio'>-2J.4.5-tetrahvdro-l.ff-
benzoltfiazepinc: Add potassium hydroxide (700 mg, 12.5 mmol) in one portion to a
solution of 3-/e/-/-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-
l//-benzo[rf]azepine (150 mg, 0.39 mmol) in methanol (10 mL). Heat the reaction at
reflux under nitrogen 4 h. Then cool to room temperature, add 4-bromo-butyric acid (65
mg, 0.39 mmol) and stir for 3 days. Remove solvents in vacuo, neutralize with

ammonium chloride (200 mL) and extract into EtOAc (2 x 50 mL). Dry over MgSO4,
filtrate and concentrate in vacuo to give a clear oil (125 mg). Dissolve the oil in
anhydrous DMF (10 mL) and add sodium hydride (30 mg, 0.78 mmol of 60% dispersion
in oil) under nitrogen. Stir for 30 min. Add 4-bromo-butyric acid (65 mg, 0.39 mmol)
and stir for 30 min. Pour into water (50 mL) and extract with diethyl ether (2 x 50 mL).
Wash the combined organic extracts with brine (50 mL) and dry over MgSO4.
Concentrate the filtrate in vccuo to give the desired intermediate as a solid (146 mg,
94%). MS (ES+) m/z: 398 (M+H)+.
3-fe/f-ButoxvcarbonvI-7-chloro-6-(3-methvlcarbamovl-propylthio)-23,4,5-
tetrahvdro-l//-benzo[ tetramethyluronium tetrafluoroborate (123 mg, 0383 mmol) portion wise to a solution of
3-rcr/-butoxycarbonyl-7-chloro-6-(3-carboxy-propylthio)-2,3,4,5-tetrahydro-l//-
benzo[]azepine (146 mg, 0365 mmol) and methylamine (182 (iL, 0.365 mmol) in
anhydrous DMF (5 mL) under nitrogen at 0 °C. Stir for 15 min then add
diisopropylethylamine (127 uL, 0.73 mmol) in anhydrous DMF (1 mL) and continue to
stir at 0 °C for 1 h. Warm to room temperature and continue to stir overnight. Pour into
water (50 mL) and extract with EtOAc (3 x 20 mL). Wash the combined organic extracts
with saturated aqueous NaHCCh (50 mL) and brine (50 mL). Dry over MgSC>4, filtrate
and concentrate in vacuo to give a pale yellow oil (74 mg). MS (ES+) m/z: 398 (M+H)+.
Purify using Mass-guided reverse phase HPLC [Supelco Discovery C18 column (21.2 x
100 mm, 5pm packing), 25 mL/min flow rate, eluting with water/acetonitrile/acetic acid
gradient over 12 min, fraction collection triggered by Electrospray MS]. Concentrate in
vacuo to give the desired intermediate as a colourless oil (30 mg, 20%). MS (ES+) m/z:
435 (M+Na)+.
7-Chloro-6-(3-methvlcarbamovl-propvlthiot-2,3,4,5-tetrahvdro-lg-benzof Succinate: Dissolve 3-rcrt-butoxycarbonyl-7-chloro-6-(3-methylcarbamoyl-propylthio)-
2,3,4,5-tetrahydro-l//-benzo[rf]azepine (30 mg, 0.07 mmol) in dichloromethane (10 mL)
then add TFA (0.5 mL) dropwise and stir at room temperature for 3 days. Remove
solvents in vacuo then free base using an SCX column, eluting with 7M ammonia in

methanol. Concentrate in vacuo, then use a method similar to the General Procedure 2-1
and freeze dry to give the title compound as a solid (21 mg, 72%). MS (ES+) m/z: 313
(M+H)+.
Example 662
7-Chloro-6-( 1 -cyano-1 -methyl-ethylthio)-2,3,4,5-tetrahydro-1 //-benzo[c/Jazepine
Succinate

3--23,4,5-tetrahvdro-lH-
benzofrflazepine: Add potassium hydroxide (10.8 g, 192 mmol) to a solution of 3-ter/-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[c/|azepine (3 g, 7.8 mmol) in degassed methanol (150 mL) under a nitrogen
atmosphere. Heat the mixture at 80 °C for 6 h. Cool the mixture to ambient temperature,
then concentrate in vacuo to an oil. Dissolve the oil in EtOAc (50mL), wash with
aqueous saturated ammonium chloride (30 mL). Separate the organic layer and extract
the aqueous layer with EtOAc (3 x 50 mL). Dry the combined organic extracts over
Na2SO4, filter and concentrate in vacuo to an oil (2.4 g). Dissolve the oil in anhydrous
DMF (50 mL). Slowly add sodium hydride (470 mg, 11.7 mmol) portionwise over 5 min
followed by 2-bromopropionitrile (1 mL, 11.7 mmol). Stir the mixture under nitrogen at
ambient temperature for 16 h. Dilute the mixture slowly with EtOAc (100 mL) and wash
with cold aqueous saturated ammonium chloride (50 mL). Separate the organic layer and
extract the aqueous layer with EtOAc (3 x 50 mL). Combine the organic extracts and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with hexane/EtOAc (19:1 to 3:1 gradient) to obtain the desired intermediate (2.5 g, 89%).
MS (ES+) m/z: 267.2 (M-Boc)+.

3-fe/^-Butoxvcarbonvl-7-chloro-6-(l-cvano-l-methvI-ethvIthioV23.4,5-tetrahydro-
1/7-benzokflazepine: Slowly add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(l-
cyano-ethylthio)-2,3,4,5-tetrahydro-l//-benzo[J]azepine (2.5 g, 6.8 mmol) in anhydrous
THF (20 mL) to a slurry of sodium hydride (1.4 g, 34 mmol) in anhydrous THF (50 mL)
at 0 °C under a nitrogen atmosphere. Stir the slurry for 5 min, then add iodomethane
(12.7 mL, 204 mmol) to the slurry while maintaining the temperature below 30 °C. Stir
the mixture for 3 h at ambient temperature then quench with methanol (10 mL) and
concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting
with hexane/EtOAc (19:1 to 9:1 gradient) to obtain the desired intermediate (2 g, 79%).
MS (ES+) m/z: 281.2 (M+H-Boc)+.
7-Chloro-6-(l-cvano-l-methvl-ethYlthio)-23»4.5-tetrahvdro-lfl-benzofrflazepine
Succinate: Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-( 1 -cyano-1 -methyl-ethy lthio)-2,3,4,5 -tetrahydro-1H-
benzo[*/]azepine (1.4 g, 3.5 mmol). Purify by chromatography on silica gel eluting with
dichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to give the free base
of the title compound. Use a method similar to the General Procedure 2-1 to obtain the
title compound (992 mg, 71%). MS (ES+) m/z: 281.2 (M+H)+.

Example 663
7-Chloro-6-(l-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-l//-benzo[rf|azepine
Succinate

OH
*O

Add potassium hydroxide (5.4 g, 96.2 mmol) to a solution of 3-terl-
butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-l//-
benzo[tf]azepme (1.5 g, 4.7 mmol) in degassed methanol (75 mL) under a nitrogen
atmosphere. Heat the mixture at 80 °C for 6 h. Cool the mixture to ambient temperature,

then concentrate in vacuo to an oil. Dissolve the oil in EtOAc (50mL) and wash with
saturated aqueous ammonium chloride (30 mL). Separate the organic layer and extract
the aqueous layer with EtOAc (3 x 50 mL). Dry the combined organic extracts over
Na2SO4, filter and concentrate in vacuo to an oil (1.4 g). Dissolve the oil in anhydrous
DMF (25 mL), then slowly add sodium hydride (282 mg, 7.1 mmol) and
bromoacetonitrile (470 u.1, 7.1 mmol). Stir the mixture under nitrogen at ambient
temperature for 16 h. Dilute the mixture slowly with EtOAc (100 mL) and wash with
cold aqueous saturated ammonium chloride (40 mL). Separate the organic layer and
extract the aqueous layer with EtOAc (3 x 50 mL). Combine the organic extracts and
concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with
hexane/EtOAc (9:1 to 7:3 gradient) to obtain 3-/er/-butoxycarbonyl-7-chloro-6-(l-cyano-
methylthio)-2,3,4,5-tetrahydro-l//-benzo[^azepine (1.34 g, 81%). MS (ES+) m/z: 253.2
(M-Boc)+.
Add sodium bis(trimethylsilyl)amide (5.4 mL, 5.4 mmol, 1M solution in THF) at
room temperature under nitrogen to a solution of 3-/ert-butoxycarbonyl-7-chloro-6-(l-
cyano-methylthio)-2,3,4,5-tetrahydro-l//-benzo[e(]azepine (380 mg, 1.1 mmol) in
anhydrous toluene (4 mL). Stir the solution for 10 min, then add quickly 1,2-
dibromoethane (2.8 mL, 32.4 mmol) followed by anhydrous DMF (4 mL). An
exothermic reaction was observed and the reaction temperature increased to 38 °C. Stir
the mixture for 15 min at ambient temperature, then quench with methanol (2 mL).
Concentrate in vacuo and purify by chromatography on silica gel eluting with
hexane/EtOAc (9:1) to obtain 3-terf-butoxycarbonyl-7-chloro-6-(l-cyano-
cyclopropylthio)-2,3,4,5-tetrahydro-l//-benzo[flf]azepine (259 mg).
Use a method similar to the General Procedure 1-5 to deprotect 3-tert-
butoxycarbonyl-7-chloro-6-(l-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-l//-
benzo[^/]azepine. Purify by reverse phase chromatography [Column: Symmetry C18, 19
x 300 mm, flow rate 30 mL/min, eluting with water with 0.1% TFA/acetonitrile (19:1 to
1:1 gradient)] followed by SCX chromatography to obtain the free base of the title

compound. Use a method similar to the General Procedure 2-1 to obtain the title
compound (120 mg, 28% yield over 3 steps). MS (ES+) m/z: 279.2 (M+H)+.
Example 664
6-(4-terf-Butylcarbamoyl-benzylthio)-7-chloro-9-fluoro-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine Succinate

Use a method similar to Example 456 to react 3-terf-butoxycarbonyl-7-chloro-6-
dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro- l//-benzo[rf]azepine with 4-
chloromethyl-Af-(tert-butyl)-benzamide.
Use methods similar to the General Procedures 1-5 and 2-1 to give the title
compound as a white solid. MS (ES+) m/z: 421 (M+H)+.
Example 665
7-Chloro-6-[4-(3,3-dimethylbutyryl)-benzylthio]-9-fluoro-2,3,4,5-tetrahydro-li/-
benzo[rf]azepine Succinate

Use a method similar to Example 435 to react 3-tert-butoxycarbonyl-7-chloro-6-
dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-lfl-benzo[£/]azepinewith l-(4-
bromomethy lpheny l)-3,3 -dimethy lbutan-1 -one.

Use methods similar to the General Procedures 1-5 and 2-2 to give the title
compound as a white solid. MS (ES+) m/z: 420 (M+H)+.
Preparation 346
4-(2,2-Dimethyl-propane-1 -sulfonyl)-

l-(2,2-Dimethvl-propvlthio)-4-methvl-benzene: Dissolve 4-methyl-benzenethiol (1.5
g, 12.08 mmol) in anhydrous DMF (6 mL). Cool the solution to 0°C, add sodium hydride
(435 mg, 17.21 mmol, 95%) and stir the mixture under nitrogen atmosphere for 15 min.
Add l-iodo-2,2-dimethylpropane (1.93 mL, 14.5 mmol), stir the mixture for 1 h at 0°C,
warm to room temperature and stir overnight. Add water and extract the aqueous phase
twice with EtOAc. Wash the combined organic extracts twice with iced-water, dry over
Na2SC>4, filter and concentrate in vacua to give the desired intermediate (1.476 g, 63%
yield).
l-(2,2-Dimethvl-propane-l-sulfonvl>-4-methvl-benzene: Dissolve 1-(2,2-dimethyl-
propylthio)-4-methyl-benzene (1.476 g, 7.6 mmol) in trifluoroacetic acid (9.5 mL). Add
dropwise hydrogen peroxide (9.9 mL, 30% in water), cool the mixture to 0°C and stir 15
min at this temperature and 45 min at room temperature. Concentrate the mixture in
vacuo, dilute with saturated aqueous NaHCO3 and extract the aqueous phase twice with

EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo
to give the desired intermediate (1.548 g, 90%).
1-Bromomethvl-4-(2,2-dimethvl-propane-l-sulfonyO-benzene: Use a method similar
to the Preparation 213 (Step 2), using l-(2,2-dimethyl-propane-l-sulfonyl)-4-methyl-
benzene (560 mg, 2.47 mmol) to give the desired intermediate.
Af-(di- sodium hydride (60 mg, 2.39 mmol) to a solution of di-ter/-butyl-iminodicarboxylate
(519 mg, 2.39 mmol) in anhydrous DMF (2mL) at room temperature under nitrogen and
stir for 15 min. Then add a solution of l-bromomethyl-4-(2,2-dimethyl-propane-l-
sulfonyl)-benzene (731 mg, 2.39 mmol) in anhydrous DMF (3 mL) and stir for 1.5 h.
Add water and extract the aqueous phase twice with EtOAc. Wash the combined organic
extracts with iced-water. Dry the organic layer over Na2SC>4, filter and concentrate in
vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (88:12) to
obtain the desired intermediate (460 mg, 44% over 2 steps).
4-(2,2-Dimethvl-propane-l-sulfonvlVbenzvlamine: Add 4N hydrogen chloride in
dioxane (2 mL) to a solution of N-(di-tert-butoxycarbonyl)-4-(2,2-dimethyl-propane-l-
sulfonyl)-benzylamine (460 mg, 1.04 mmol) in dichloromethane (20 mL) and stir
overnight. Concentrate in vacuo, suspend the solid obtained in EtOAc, add saturated
aqueous NaHCCh and stir until both phases are clear. Extract the aqueous phase three
times with dichoromethane EtOAc. Dry the combined organic extracts over Na2SO,»,
filter and concentrate in vacuo to obtain the title compound as an oil that was used
without any further purification (166 mg, 71% yield). MS (ES+) m/z: 242 (M+H)+.
The compounds of Preparations 347-348 may be prepared essentially as described
in Preparation 346 using l-iodo-3,3,3-trifluoropropane (Preparation 347) or 1,1,1-
trifluoro-3-iodobutane (Preparation 348). MS (ES+) data are shown in the Table below.



4-tert-Butvlthiomethvl-benzonitriIe: Add sodium hydride (359 mg, 14.21 mtnol) to a
solution of 2-methyl-2-propanethiol (900 mg, 9.98 mmol) in anhydrous DMF (15 mL)
under nitrogen. Stir the mixture for 15 min, add 4-bromomethyl-benzonitrile (2.348 g,
11.97 mmol) and stir the resulting mixture overnight at room temperature. Add water and
extract the aqueous phase twice with EtOAc. Wash the combined organic extracts twice
with iced-water, dry over Na2SC>4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc 92:8 to give the desired
intermediate (1.42 g, 69% yield).
4-(2-Methyl-propane-2-sulfonvlmethvD-benzonitriIe: Dissolve 4-ter/-butylthiomethyl-
benzonitrile (1.42 g, 6.9 mmol) in trifluoroacetic acid (9 mL). Add dropwise hydrogen
peroxide (9 mL, 30% in water), cool the mixture to 0°C and stir 15 min at this
temperature and 45 min at room temperature. Concentrate the mixture in vacuo, dilute
with saturated aqueous NaHCO3 and extract the aqueous phase twice with EtOAc. Dry
the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the
desired intermediate (1.46 g, 89%).

4-(2-Mcthvl-propane-2-sulfonylniethvl)-benzvlamine: Dissolve 4-(2-methyl-propane-
2-sulfonylmethyl)-benzonitrile (300 mg, 1.26 mmol) in methanol (50 mL). Add
concentrated HC1 (10 drops), 10% Pd/C (Degussa type E101, 60 mg) and submit the
mixture to hydrogenation at atmospheric pressure for 1 h. Filter over Celite® and wash
with methanol. Concentrate the filtrate in vacuo to give the hydrochloride salt of the title
compound as a solid that was washed with diethyl ether (366 mg, 87%). Partition the
solid between saturated NaHCC>3 and EtOAc and extract the aqueous phase twice with
EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo
to give the title compound (195 mg, 74%). MS (ES+) m/z: 242 (M+H)+.
The compound of Preparation 350 may be prepared essentially as described in
Preparation 349 using 4-(2-bromo-ethyl)-benzonitrile. MS (ES+) data are shown in the
Table below.

6-Cyclohexvlethvnyl-nicotinonitrile: Add cyclohexylacetylene (1.54 mL, 11.6 mmol),
dichlorobis(triphenylphosphine)palladium (200 mg, 0.28 mmol), copper iodide (100 mg,

0.53 mmol), and triethylamine (2.0 mL, 14.3 mmol) to a solution of 6-
chloronicotinonitrile (1.38 g, 9.9 mmol) in DMF (4 mL). Heat the mixture in a sealed
flask for 3 h at 100 °C. Cool the mixture to room temperature, dilute with 1:1
hexane/EtOAc (100 mL) and wash with an aqueous 10% sodium chloride solution (3 x 30
mL). Collect the organic layer, concentrate in vacuo, and purify the residue by silica gel
chromatography (90 g silica, hexane / EtOAc 95/5 to 85/15 gradient) to obtain the desired
intermediate (1.75 g, 83%)
3-terf-Butoxvcarbonyl-aminomethyl-6-42-cvcloliexvl-ethyl)-pvridine: Add 6-
cyclohexylethynyl-nicotinonitrile (1.75 g, 8.3 mmol), 10% Pd/c (Degussatype E101,
50% water by wt) (1.0 g), methanol (100 mL), and di-f-butyl dicarbonate (2.3 g, 10.4
mmol) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 30 psi
with hydrogen, and stir the mixture for 3 h (monitor the reaction by TLC). Purge the
vessel with nitrogen, filter the mixture through Celite® and wash the cake with
dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo. Purify
the residue by silica gel chromatography (90 g silica, hexane / EtOAc, 95/5 to 50/50
gradient) to obtain the desired intermediate (1.05 mg, 40%). MS (ES+) tn/z: 319.2
(M+H)+.
3-Aminomethyl-6-(2-cvclohexyl-ethyl)-pvridine: Add trifluoroacetic acid (2.0 mL) to
a solution of 3-tert-butoxycarbonyl-aminomethyl-6-(2-cyclohexyl-ethyl)-pyridine (1.05
g, 3.3 mmol) in methanol (20 mL). Stir the solution for 1 h at room temperature under a
nitrogen atmosphere. Concentrate the solution in vacuo and purify the residue via SCX
chromatography to obtain the desired intermediate (670 mg, 93 %). MS (ES+) m/z: 219.2
(M+H)+.
Preparation 352
2-Aminomethyl-5-(2-cyclohexyl-ethyl)-pyridine


The title compound may be prepared essentially as described in Preparation 351
by using 5-chloro-pyridine-2-carbonitrile (24% yield, MS (ES) m/z 219.2 (M+H)+.
Example 666
7-Chloro-6-[4-(2,2-dimethyl-propane-l-sulfonyl)-benzylamino]-2,3,4,5-tetrahydro-l//-
benzo[rf]azepine (Z,)-Tartrate

Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-
trifluoroaceryl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-benzo[rf]azepine
(158 mg, 0.37 mmol) with 4-(2,2-dimethyl-propane-l-sulfonyl)-benzylamine (166 mg,
0.73 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.074 mmol),
BINAP (92 mg, 0.148 mmol) and cesium carbonate (169 mg, 0.518 mmol) in anhydrous
toluene (15 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc
(8:2) and then by reversed HPLC [Zorbax Bonus RP, 5 DM 21.2 x 100 mm, eluting with
water/acetonitrile (0.05% TFA in each), UV detector (230 nm)] to give 7-chloro-6-[4-
(2,2-dimethyl-propane-l-sulfonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
tetrahydro-l#-benzo[]azepine as an oil (153 mg, 80%). MS (ES+) m/z: 517 (M+H)+.
Use methods similar to the General Procedures 1-2 and 2-6 to give the title
compound as a white solid. MS (ES+) m/z: 421 (M+H)+.

Examples 667-672 may be prepared essentially as described in Example 666 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[J]azepine and the appropriate amine. Examples 673-674 may be prepared
essentially as described in Example 666 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-
trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li/-benzo[cf]azepine and the appropriate
amine but the succinate salt was prepared as described in General Procedure 2-1. MS
(ES+) data are shown in the Table below.



Examples 675-676 may be prepared essentially as described in Example 604 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l//-
benzo[]azepine and the appropriate amine but the (L)-tartrate salt was prepared as
described in General Procedure 2-6. MS (ES+) data are shown in the Table below.

Examples 677-684 may be prepared essentially as described in Example 563 by
using 3-rerr-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-
tetrahydro-l/f-benzo[rf]azepine and the appropriate amine. Examples 685-689 may be
prepared essentially as described in Example 563 by using 3-ter/-butoxycarbonyl-6-(4-
carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-l/f-benzo[rf]azepine and the
appropriate amine. MS (ES+) data are shown in the Table below.




The compounds of the present invention are relatively selective for the 5-HT2c
receptor. The compounds of the present invention are particularly relatively selective for
the 5-HT2c receptor in comparison to other 5-HT receptor subtypes and specifically the

5-HT2A and 5-HT2B receptors. This selectivity is demonstrated in the following agonist
activity assays and receptor binding assays.
Agonist Activity Assays (G alpha q-GTPy[35Sl Binding Assays)
The 5-HT2 receptors are functionally coupled to specific G-proteins. Agonist
activation of 5-HT2 G-protein-coupled receptors results in the release of GDP from the a-
subunit (G alpha q or G alpha i) of the G-protein and the subsequent binding of GTP.
The binding of the stable analog GTPy[35S] is an indicator of receptor activation (i.e.
agonist activity).
The G alpha q-GTPy[35S] binding assay is used to determine the in vitro potency
(EC50) and maximal efficacy (Emax, normalized to the 5-HT response) of a test compound
at the 5-HT2A, 5-HT2B, and 5-HT2c receptors. The area under the dose response curve
(AUC) is also determined for each receptor subtype and used to measure the test
compound's selectivity for the 5-HT2C receptor over the 5-HT2Aand 5-HT2B receptors,
expressed as Selectivity Ratios (AUC 2C/2A and AUC 2C/2B, respectively). The
Selectivity Ratios allow the assessment of selectivity based on both potency and efficacy.
A selectivity measure that incorporates both potency and efficacy at the 5-HT2C receptor,
as compared to the 5-HT2Aand 5-HT2B-receptors, is considered important due to the
adverse events associated with 5-HT2A and 5-HT2B agonist activity (see introduction).
Membrane Preparation: Grow AVI2 cells stably transfected with the human 5-HT2A,
5-HT2B, or 5-HT2C receptors in suspension, harvest by centrifugation, wash the cell pellet
with phosphate buffered saline, pH 7.4, pellet the cells again, remove the supernatant,
freeze the cell pellet on dry ice and store at -70°C. Thaw stock cell pellet and resuspend
in 50mM Tris, pH 7.4, aliquot into 1-2 mL volumes and refreeze at -70°C for subsequent
assays. (As is appreciated in the art, optimal cell quantities used per aliquot will vary
with the individual transfected cell line used. In one embodiment, 5-HT2A and 5-HT2C
transfected cells are typically used at about 6 x 108 cells per aliquot, while 5-HT2B cells
are typically used at about 7.5 x 10 cells per aliquot).

On the day of assay, thaw membranes, wash the membranes with assay buffer (50
mM Tris-HC! (pH 7.4), 10 mM MgCl2, 100 mM NaCl, and 0.2 mM EDTA), resuspend in
assay buffer and incubate for 10 min. at 37°C to hydrolyze any residual endogenous 5-
HT. Wash the membranes again with assay buffer, and resuspend in assay buffer at a
concentration to provide aliquots of about l-4xl06 cell equivalents per well (typically
about 1-2 x 106 cell equivalents for assays with 5-HT2A or 5-HT2C receptor assays, and
about 3-4 x 106 cell equivalents for assays with 5-HT2B receptor assays). Homogenize the
cells with a tissue grinder and use the homogenate directly in the assay as described
below.
G alpha q-GTPy[35S] Binding Assays: The immunoadsorption scintillation
proximity assay (ISPA) of [35S]-GTPyS binding to G alpha q is modified from published
conditions (DeLapp et al, JPET 289 (1999) 946-955). Dissolve test compounds in DMSO
and dilute in assay buffer to provide a range of concentrations to generate a concentration
response curve. In wells of a 96 well microtiter plate, mix diluted test compound, GDP
(0.1 uM final concentration), and [35S]-GTPyS (between 0.5 and 1.0 nM final
concentration). Add an aliquot of membranes to the incubation mixture and mix the
plates to initiate agonist stimulation of the nucleotide exchange (200 \i\ final volume).
Incubate the microtiter plates for 30 min. at room temperature. Quench the incubation
with IGEPAL® CA-630 detergent (0.27% final concentration). Add affinity purified
polyclonal rabbit anti-G alpha q antibody (about 1-2 u,g per well), and anti-rabbit Ig
scintillation proximity assay beads (Amersham; about 1.25 mg per well; 300 p\ final
volume). Seal the plates and incubate the mixture for 3 h at room temperature.
Centrifuge the microtiter plates briefly to pellet beads. Quantitate the GTPy[35S] binding
by microtiter plate scintillation spectrometry (Wallac Trilux MicroBeta™ scintillation
counter).
Data Analysis: For each concentration response curve for a test compound at a
given receptor, analyze the data with GraphPad Prism™ software (v3.02; GraphPad
Software, San Diego, CA) running on a personal computer with MicroSoft Windows

OS®, using nonlinear regression analysis curve fitting to determine the EC50 and Emax
(normalized to 5-HT control curves). Determine the Area Under the agonist
concentration-response Curve (AUC) with GraphPad Prism™ by the trapezoidal method.
To calculate the Selectivity Ratios, first, determine the AUC for the test
compound for each receptor subtype as described above. Second, normalize the AUC's
at each receptor subtype relative to the AUC determined for 5-HT at that receptor. The
normalized AUC for a test compound at a given receptor is therefore expressed as a
percentage of the AUC determined for 5-HT at that receptor. For example:
5HT2A Normalized AUC = a = (AUC,M, 1^,^^ at 5HT?A receptor) X 100%
(AUC5-HT at 5HT2A receptor)
5HT2B Normalized AUC = b =( AUC,M,M(mnn..nri at 5HT7p receptor) X 100%
(AUCS-HT at 5HT2B receptor)
5HT2C Normalized AUC = c = fAUC^,.,,.^.^ at 5HT>r receptor) X 100%
(AUCS-HT at 5HT2C receptor)
Third, calculate the Selectivity Ratios for the test compound as follows:
Selectivity Ratio for 5-HT2C receptor/5-HTM receptor (AUC 2C/2A) = c/a
Selectivity Ratio for 5-HT2C receptor/5-HT2B receptor (AUC 2C/2B) = c/b
For reference purposes, the AUC 2C/2A and AUC 2C/2B for 5-HT are each 1.0.
Likewise, the ratios for mCPP (me/a-chlorophenylpiperazine) are tested and are found to
be 2.1 and 2.1 respectively.
Representative compounds of the present invention are tested in the G alpha q-
GTPy[35S] assays for the 5-HT2A, 5-HT2B, and 5-HT2C receptors essentially as described
above and are found to be a highly potent and selective agonists of the 5-HT2C receptor,
with ECso's typically less than or equal to 200 nM, and AUC 2C/2A and AUC 2C/2B
ratios greater than 1.5. Preferred compounds are those with EC50's less than or equal to
100 nM, and AUC 2C/2A and AUC 2C/2B ratios greater than or equal to 2.0. More
preferred are those with EC50's less than or equal to 50 nM, and AUC 2C/2A and AUC
2C/2B ratios greater than or equal to 3.0.

Ligand Binding Assays
The ligand binding affinity of the compounds of the present invention to the
5-HT2C receptor subtype is measured essentially as described by Wainscott (Wainscott, et
al, Journal of Pharmacology and Experimental Therapeutics, 276:720-727 (1996)).
Data is analyzed by nonlinear regression analysis on the concentration response curves
using the four parameter logistic equation described by DeLean (DeLean, et al..
Molecular Pharmacology. 21, 5-16 (1982)). IC5Q values are converted to Kj values using
theCheng-Prusoff equation (Cheng, etaL, Biochem. Pharmacol., 22, 3099-3108 (1973)).
Representative compounds of the present invention are tested essentially as
described above and are found to have excellent affinity for the 5-HT2c receptor, with
Kj's typically less than or equal to about 200 nM. Preferred compounds are those with
Kj's of less than or equal to about 100 nM. More preferred are those with Kj's less than
or equal to 50 nM.
Affinities for other receptor subtypes can readily be determined by slight
modification of the above described radioligand receptor binding assay using cells
transfected with the desired receptor in place of cells transfected with the 5-HT2C receptor
subtype and using an appropriate radioligand. The binding affinities for representative
compounds of the present invention for a variety of receptors are determined in such
assays and the compounds are found to have surprisingly higher affinity for the 5-HT2C
receptor. Affinity for the 5-HT2C receptor is found to be significantly higher than for
other 5-HT receptor subtypes, and notably higher than the 5-HT2A and 5-HT2B receptor
subtypes. Preferred compounds are those with IC5o's equal to or greater than 300 nM for
the alpha 1 and alpha 2 adrenergic receptors and equal to or greater than 500 nM for Di
and D2 dopaminergic receptors. More preferred compounds are those with ICso's equal to
or greater than 1000 nM for the alpha 1 and alpha 2 adrenergic receptors and the Di and
D2 dopaminergic receptors. Still more preferred are those compounds with ICso's equal
to or greater than 3000 nM for the alpha 1 and alpha 2 adrenergic receptors and the Di
and D2 dopaminergic receptors.

For the above in vitro assays, exemplified compounds are assayed and found to
have either an EC50 or a Ki value of equal to or less than 50 nM, and to have AUC 2C/2A
and AUC 2C/2B ratios of greater than or equal to 2.0. Exemplified compounds are
assayed and found to have alpha 1 and alpha 2 adrenergic receptor ICso's equal to or
greater than 300 nM, and Di and D2 dopaminergic receptor ICso's equal to or greater than
500 nM.
Rat feeding assays
The ability of the compounds of the present invention to treat obesity is
demonstrated by testing in acute and chronic rat feeding assays.
Animals: Obtain male Long-Evans rats (Harlan Sprague-Dawley, Indianapolis, IN) that
are approximately one hundred-days old and have been maintained on a calorie rich diet
since weaning (TD 95217, 40% calories from fat; Teklad, Madison, WI). House the rats
individually with a 12 h:12 h lighfcdark cycle (lights on from about 22:00 h to about 10:00
h) and maintain rats on the same diet (TD 95217) with free access to water, for about 1-2
weeks to acclimate the rats to the environment. Dose rats orally with vehicle (10% acacia
with 0.15% saccharin in water) once daily for at least 1 day (typically 1-2 days) to
acclimate the rats to the procedures. Randomize the rats into groups so each group has
similar mean body weights.
Calorimetric Acute Feeding Assay: At approximately 8:00 h on the day of assay, weigh
each rat and transfer to individual chambers of an open circuit calorimetry system
(Oxymax, Columbus Instruments International Corporation; Columbus, OH), with free
access to food (pre-weighed) and water, and begin measuring VO2 and VCO2. At
approximately 10:00 h, dose rats orally with vehicle or test compound, return them to
their calorimetry chambers, and continue measuring VO2 and VCO2 at regular time
intervals (approximately hourly). At approximately 8:00 h the following day, measure rat
body weight and the remaining food, assuming the difference in weight of food is equal to
the mass of food consumed. Calculate the 24 h energy expenditure (EE) and respiratory

quotient (RQ) essentially as described in Chen, Y. and Heiman, M. L., Regulatory
Peptide, 92:113-119 (2000). EE during light photoperiod is indicative of the resting
metabolic rate and RQ is indicative of the fuel source the animal utilizes (pure
carbohydrate metabolism gives an RQ of about 1.0, pure fat metabolism gives an RQ of
about 0.7, mixed carbohydrate and fat metabolism gives intermediate values for RQ).
Calculate EE as the product of calorific value (CV) and VO2 per body weight (kg); where
CV = 3.815 + 1.232+RQ, and RQ is the ratio of CO2 produced (VCO2) to O2 consumed
(VO2). Caloric intake is calculated as (mass of 24 h food intake in grams) x
(physiological fuel value of the diet in kilocalorie/g) per kg of body weight.
Acute Feeding Assay with a selective 5-HT2C receptor antagonist: The above
calorimetric acute feeding assay is conducted with the following modifications. Open
circuit calorimetry systems are not used and only the 24 h periodic food intake and body
weight are measured. Three groups of rats are used with the first group receiving a
subcutaneous dose of saline (0.5 mL) about 15 minutes prior to the oral dose of vehicle,
the second group receiving a subcutaneous dose of saline (0.5 mL) about 15 minutes prior
to the oral dose of test compound in vehicle, and the third group receiving a subcutaneous
injection of a selective 5-HT2c receptor antagonist, 6-chloro-5-methyl-N-{2-[(2-
methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-dihydroindole (3 mg/Kg, in
35% cyclodextrin, 0.5 mL), about 15 min. prior to the oral dose of test compound in
vehicle.
Chronic Feeding Assay: At between approximately 8:00 h and 10:00 h on day one of the
assay, weigh and orally dose each rat with vehicle or test compound and return the animal
to its home cage, with free access to food (pre-weighed) and water. For each of days 2-
15, at between approximately 8:00 h and 10:00 h, measure rat body weight and the weight
of food consumed in the last 24 h period, and administer daily oral dose of test compound
or vehicle. On days —2 and 15 measure total fat mass and lean mass by nuclear magnetic
resonance (NMR) using an EchoMRI™ system (Echo Medical Systems, Houston Texas).
(See Frank C. Tinsley, Gersh Z. Taicher, and Mark L. Heiman, "Evaluation of a New

Quantitative Magnetic Resonance (QMR) Method for Mouse Whole Body Composition
Analysis", Obesity Research, submitted May 1, 2003.)
Representative compounds of the present invention are tested in acute and chronic
feeding assays essentially as described above. In the acute assays, the compounds are
found to significantly reduce 24 h food intake, which effect is blocked by pre-
administration of the 5-HT2c receptor antagonist. The compounds also are found to dose-
dependently reduce RQ without significantly changing the energy expenditure during the
light photo-period. Thus the compounds are found to reduce caloric intake and increase
the proportion of foel deriving from fat utilization, without significantly changing the
resting metabolic rate. In the chronic assay, the compounds are found to significantly
decrease cumulative food intake and cumulative body weight change in a dose-dependent
manner compared to control animals. The decrease in body weight is found to be due to
loss of adipose tissue while lean body mass is not changed.
The ability of the 5-HT2c receptor agonists of the present invention to treat
obsessive/compulsive disorder is demonstrated by testing in a variety of in vivo assays as
follows:
Marble burying assay
Marble burying in mice has been used to model anxiety disorders including
obsessive-compulsive disorders (OCD) due to ethological study of the behavior (e.g.
Gyertyan I. "Analysis of the marble burying response: Marbles serve to measure digging
rather than evoke burying", Behavioural Pharmacology 6: 24-31, (1995)) and due to the
pharmacological effects of clinical standards (c.f., Njung'E K. Handley SL. "Evaluation
of marble-burying behavior as a model of anxiety", Pharmacology, Biochemistry &
Behavior. 38: 63-67, (1991)); Borsini F., Podhorna J., and Marazziti, D. "Do animal
models of anxiety predict anxiolytic effects of antidepressants?", Psychopharmacology
163: 121-141, (2002)). Thus, drugs used in the treatment of generalized anxiety in
humans (e.g. benzodiazepines) as well as compounds used to treat OCD (e.g. SSRIs like
fluoxetine) decrease burying.

House experimentally-naive male, NIH Swiss mice (Harlan Sprague-Dawley,
Indianapolis, IN) weighing between 28-35 g in groups of 12 for at least three days prior to
testing in a vivarium with 12 h light and dark cycles. Conduct experiments during the
light cycle in a dimly lit experimental testing room. Dose mice with vehicle or test
compound and, after a specified pretreatment interval (generally 30 min.), place each
mouse individually on a rotorod (Ugo Basile 7650) operating at a speed of 6
revolutions/min. and observe for falling. After 2 min. on the rotorod, place the mice
individually in a 17 x 28 x 12 cm high plastic tub with 5 mm sawdust shavings on the
floor that are covered with 20 blue marbles (1.5 cm diameter) placed in the center. After
30 min., count the number of marbles buried (2/3 covered with sawdust). Assess the test
compound's effect on marble burying with Dunnett's test and the effect on rotorod
performance by Fisher's exact test.
Clinically effective standard compounds suppress marble burying at doses that are
devoid of motor-impairing effects as measured on the rotorod. The in vivo efficacy of
5HT2C compounds at the 5HT2C receptor is confirmed by the prevention of effects of the
5HT2C agonists on marble burying by co-administration of the 5HT2C receptor antagonist,
6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-
dihydroindole.
Representative compounds of the present invention are assayed in the marble
burying assay essentially as described and are surprisingly found to reduce burying
behavior in the test mice. The reduction of burying behavior is found to be blocked by
co-administration of the 5-HT2C antagonist. In contrast to the compounds of the present
invention, the anxiolytic compound chlordiazepoxide and the antipsychotic compound
chlorpromazine decrease marble burying only at doses that also disrupt rotorod
performance.

Nestlet Shredding
Mice naturally will construct nests of material available in their living
environment. Since this behavior is obsessive in nature, it has been used to model OCD
(Xia Li, Denise Morrow and Jeffrey M. Witkin, "Decreases in nestlet shredding of mice
by serotonin uptake inhibitors: comparison with marble burying", Psychopharmacology,
submitted July 14, 2003). House experimentally-naive male, NIH Swiss mice (Harlan
Sprague-Dawley, Indianapolis, IN) weighing between 28-35 g in groups of 12 for at least
three days prior to testing in a vivarium with a 12 h light/dark cycle. Conduct
experiments during the light cycle in an experimental room with normal overhead
fluorescent lighting. Dose mice with vehicle or test compound and after a specified
pretreatment interval (generally 30 min.), place the mice individually in a 17 x 28 x 12 cm
high plastic tub with about 5 mm sawdust shavings on the floor along with a pre-weighed
multi-ply gauze pad (51 mm square). After 30 min., weigh the remainder of the gauze
pad not removed by the mouse. Determine the weight of the gauze used for nestlet
construction by subtraction. Compare the results for test compound treated mice to the
results for vehicle control treated mice with Dunnett's test.
Clinically effective OCD treatment standard compounds suppress nestlet
shredding at doses that are devoid of motor-impairing effects as measured by the rotorod
test. The in vivo efficacy of 5HT2C compounds at the 5HT2C receptor is confirmed by the
prevention of effects of the 5HT2C agonists on nestlet shredding by co-administration of
the 5HT2C receptor antagonist, 6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-
oxy)pyridin-5-yl]aminocarbonyl}-2,3-dihydroindole.
Representative compounds of the present invention are assayed essentially as
described above and are surprisingly found to suppress nestlet shredding at doses that are
devoid of motor-impairing effects as measured by the rotorod test.
In contrast to the compounds of the present invention, the anxiolytic
chlordiazepoxide and the psychomotor stimulant d-amphetamine decreases nestlet
shredding only at doses that produce motoric side effects (depression or stimulation,
respectively).

Schedule-Induced Polydipsia
Food-deprived rats exposed to intermittent presentations of food will drink
amounts of water that are far in excess of their normal daily intake and in excess of their
intake when given all of their food at one time (Falk JL. "Production of polydipsia in
normal rats by an intermittent food schedule", Science 133: 195-196, (1961)). This
excessive behavior is persistent and has been used to model OCD.
Maintain Wistar rats on a food restricted diet (to maintain 85% free feeding
weight), but with free access to water. Train the rats in a behavioral testing chamber to
press a lever to receive a food pellet under a fixed interval schedule, such that the rats are
rewarded with a 45 mg food pellet the first time they press a lever after a 120 second
interval has elapsed. The fixed interval is then reset to 120 seconds and the process
repeated. Thus, during a 90 min. test session, the rats can earn a maximum of 45 pellets.
The behavioral chamber is also equipped with a water bottle that is weighed before and
after the session to determine the amount of water consumed.
Administer test compounds on Tuesdays and Fridays. Determine control day
performances on Thursdays. Administer compounds either orally at 60 min. before the
beginning of a test session, or subcutaneously at 20 min. before the beginning of a test
session. Compare the rates of lever pressing and water consumption for each animal's
performance during sessions after test compound treatment with that animal's
performance during control sessions, expressed as a percent of the control rate. Average
the individual percent of control rates for each dose and calculate the standard error of the
mean.
Clinically effective OCD treatment standard compounds (e.g. chlomipramine,
fluoxetine) suppress schedule-induced polydipsia without producing notable changes in
motor patterns, food intake, or behavior the following day. The in vivo efficacy of 5HT2c
compounds at the 5HT2C receptor is confirmed by the prevention of effects of the 5HT2c
agonists on excessive drinking by co-administration of the 5HT2C receptor antagonist, 6-

chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-
dihydroindole.
Representative compounds of the present invention are assayed in the schedule-
induced polydipsia assay essentially as described above and are surprisingly found to
suppress schedule-induced polydipsia without producing notable changes in motor
patterns, food intake, or behavior the following day. The behavior suppression is blocked
by co-administration of the 5-HT2C antagonist.
In contrast to the compounds of the present invention, the psychomotor stimulant
d-amphetamine decreases excessive drinking only at behaviorally stimulating doses and
these effects are not prevented by the 5HT2C receptor antagonist.
While it is possible to administer compounds employed in the methods of this
invention directly without any formulation, the compounds are usually administered in
the form of pharmaceutical compositions comprising a pharmaceutically acceptable
excipient and at least one compound of Formula I or a pharmaceutically acceptable salt
thereof. These compositions can be administered by a variety of routes including oral,
rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The
compounds employed in the methods of this invention are effective as both injectable and
oral compositions. Such compositions are prepared in a manner well known in the
pharmaceutical art. See, e.g. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
In making the compositions employed in the present invention the active
ingredient is usually mixed with at least one excipient, diluted by at least one excipient, or
enclosed within such a carrier which can be in the form of a capsule, sachet, paper or
other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus,
the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid
medium), ointments containing for example up to 10% by weight of the active compound,

soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile
packaged powders.
In preparing a formulation, it may be necessary to mill the compound to provide
the appropriate particle size prior to combining with the other ingredients. If the active
compound is substantially insoluble, it ordinarily is milled to a particle size of less than
200 mesh. If the active compound is substantially water soluble, the particle size is
normally adjusted by milling to provide a substantially uniform distribution in the
formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and
methyl cellulose. The formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending
agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening
agents; and flavoring agents. The compositions of the invention can be formulated so as
to provide quick, sustained or delayed release of the active ingredient after administration
to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage
containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of
the active ingredient. The term "unit dosage form" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the desired therapeutic
effect, in association with a suitable pharmaceutical excipient.
The compounds are generally effective over a wide dosage range. For examples,
dosages per day normally fall within the range of about 0.01 to about 30 mg/kg. In the
treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or
divided dose, is especially preferred. However, it will be understood that the amount of

the compound actually administered will be determined by a physician, in the light of the
relevant circumstances, including the condition to be treated, the chosen route of
administration, the actual compound or compounds administered, the age, weight, and
response of the individual patient, and the severity of the patient's symptoms, and
therefore the above dosage ranges are not intended to limit the scope of the invention in
any way. In some instances dosage levels below the lower limit of the aforesaid range
may be more than adequate, while in other cases still larger doses may be employed.
Another preferred formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such transdermal
patches may be used to provide continuous or discontinuous infusion of the
compounds of the present invention in controlled amounts. The construction and use
of transdermal patches for the delivery of pharmaceutical agents is well known in the
art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by
reference. Such patches may be constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical agents.
Under some circumstances, it will be desirable or necessary to introduce the
pharmaceutical composition to the brain, either directly or indirectly. Direct
techniques usually involve placement of a drug delivery catheter into the host's
ventricular system to bypass the blood-brain barrier. One such implantable delivery
system, used for the transport of biological factors to specific anatomical regions of
the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein
incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating
the compositions to provide for drug latentiation by the conversion of hydrophilic
drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through
blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the
drug to render the drug more lipid soluble and amenable to transportation across the
blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced

by intra-arterial infusion of hypertonic solutions which can transiently open the
blood-brain barrier.
The type of formulation employed for the administration of the compounds
employed in the methods of the present invention may be dictated by the particular
compound employed, the type of pharmacokinetic profile desired from the route of
administration, and the state of the patient.

We claim:
1. A compound which is 7-Chloro-6-[4-(t-butyl-sulfonylmethyl)-benzylarnino]-2,3,4.5-
tetrahydro-1 H-benzo[d]azepine
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound according to Claim 1, or a
pharmaceutically acceptable salt thereof, as an active ingredient in association with a
pharmaceutically acceptable carrier, diluent or excipient.


The present invention provides 6-substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepines of
Formula I as selective 5-HT2C receptor agonists for the treatment of 5-HT2C associated
disorders including obesity, obsessive/compulsive disorder, depression, and anxiety: I where:
R6 is -C=C-R10, -O-R12, -S-R14, or -NR24R25; and other substituents are as defined in the
specification


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02479-kolnp-2006-abstract.pdf

02479-kolnp-2006-assignment.pdf

02479-kolnp-2006-claims.pdf

02479-kolnp-2006-correspondence others.pdf

02479-kolnp-2006-description(complete).pdf

02479-kolnp-2006-form-1.pdf

02479-kolnp-2006-form-2.pdf

02479-kolnp-2006-form-26.pdf

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02479-kolnp-2006-international search authority report.pdf

02479-kolnp-2006-pct others.pdf

2479-KOLNP-2006-(29-03-2012)-CORRESPONDENCE.pdf

2479-KOLNP-2006-(29-03-2012)-FORM-27.pdf

2479-KOLNP-2006-ABSTRACT 1.1.pdf

2479-KOLNP-2006-ABSTRACT.pdf

2479-KOLNP-2006-ASSIGNMENT-1.1.pdf

2479-KOLNP-2006-CANCELLED PAGES.pdf

2479-KOLNP-2006-CLAIMS.pdf

2479-KOLNP-2006-CORRESPONDENCE-1.1.pdf

2479-kolnp-2006-correspondence-1.2.pdf

2479-KOLNP-2006-CORRESPONDENCE.pdf

2479-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED 1.1.pdf

2479-kolnp-2006-examination report.pdf

2479-KOLNP-2006-FORM 1 1.1.pdf

2479-KOLNP-2006-FORM 1.pdf

2479-KOLNP-2006-FORM 13-1.1.pdf

2479-kolnp-2006-form 13-1.2.pdf

2479-KOLNP-2006-FORM 13.pdf

2479-kolnp-2006-form 18-1.1.pdf

2479-kolnp-2006-form 18.pdf

2479-KOLNP-2006-FORM 2 1.1.pdf

2479-KOLNP-2006-FORM 2.pdf

2479-kolnp-2006-form 26.pdf

2479-kolnp-2006-form 3-1.1.pdf

2479-KOLNP-2006-FORM 3.pdf

2479-kolnp-2006-form 5.pdf

2479-kolnp-2006-granted-abstract.pdf

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2479-kolnp-2006-granted-description (complete).pdf

2479-kolnp-2006-granted-form 1.pdf

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2479-kolnp-2006-granted-specification.pdf

2479-kolnp-2006-others-1.1.pdf

2479-KOLNP-2006-OTHERS.pdf

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2479-KOLNP-2006-PCT PRIORITY DOCUMENT NOTIFICATION.pdf

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2479-kolnp-2006-reply to examination report-1.1.pdf

2479-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

abstract-02479-kolnp-2006.jpg


Patent Number 247943
Indian Patent Application Number 2479/KOLNP/2006
PG Journal Number 23/2011
Publication Date 10-Jun-2011
Grant Date 06-Jun-2011
Date of Filing 31-Aug-2006
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY COPORATE CENTER, CITY OF INDIANAPOLIS, IN
Inventors:
# Inventor's Name Inventor's Address
1 JOHN GORDON ALLEN 5255 VIA CAPOTE NEWBURY PARK,CALIFORNIA 91320
2 MICHAEL PHILIP COHEN 8141 BOWLINE COURT INDIANAPOLIS, INDIANA 46236
3 CHRISTOPHER STANLEY GALKA 13690 NORTH STONE HAVEN DRIVE CARMEL, INDIANA 46033
4 SARAH LYNNE HELLMAN 7620 KIMCOE LANE INDIANAPOLIS, INDIANA 46254
5 MARIA ANGELES MARTINEZGRAU LILLY S.A. AVENIDA DE LA INDUSTRIA 30, 28108 ALCOBENDAS(MADRID)
6 MATTHEW ROBERT REINHARD 8301 SCARSDALE COURT,INDIANAPOLIS, INDIANA 46256
7 MICHAEL JOHN RODRIGUEZ 7649 GORDONSHIRE COURT, INDIANAPOLIS, INDIANA 46278
8 ROGER RYAN ROTHHZAAR 5282 WEST 775 SOUTH REELSVILLE, INDIANA 46171
9 MICHAEL WADE TIDWELL 665 DOWNING DRIVE GREENWOOD,INDIANA 46171
10 FRANTZ VICTOR 4855 NORTH TUXEDO STREET,INDIANAPOLIS, INDIANA 46205
11 ANDREW CAERWYN WILLIAMS ELI LILLY ANY COMPANY LIMITED KINGSCLERE OAD, BASINGSTOKE, HAMPSHIRE RG21 6XA
12 DEYI ZHANG 1372 KIRKLEES DRIVE CARMEL,INDIANA 46032
13 STEVEN ARMEN BOYD 5665 SAINT VRAIN ROAD LONGMONT,COLORADO 80503-9061
14 RICHARD GERARD CONWAY 3315 BEECH DRIVE CARMEL, INDIANA 46033
15 ARUNDHATI S.DEO 2342 HILLSIDE AVENUE ST.PAUL,MINNESOTA 55108
16 WAI-MAN LEE 2128 24th AVENUE,LONGMONT,COLORADO 80501
17 CHRISTOPHER STEPHEN SIEDEM 4215 REDMONT DRIVE LONGMONT,COLORADO 80503
18 AJAY SINGH 2028 SOUTH EVANSTON COURT AURORA,COLORADO 80014
19 MICHAEL P.MAZANETZ ELI LILLY AND COMPANY LIMITED, KINGSCLERE ROAD, BASINGSTOKE, HAMPSHIRE, RG21 6XA
20 KARIN BRINER 7649 PINESPRINGS EAST DRIVE INDIANAPOLIS, INDIANAN 46256
PCT International Classification Number C07D 223/16
PCT International Application Number PCT/US2005/005418
PCT International Filing date 2005-02-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/547,681 2004-02-25 U.S.A.