HETEROCYCLIC CYCLOPENTYL TETRAHYDROISOQUINOLINE AND TETRAHYDROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

MODULATEURS TETRAHYDROISOQUINOLINE ET TETRAHYDROPYRIDOPYRIDINE CYCLOPENTYLES HETEROCYCLIQUES DE L'ACTIVITE DES RECEPTEURS DE CHIMIOKINE

English Abstract

The present invention is directed to compounds of formula (I), wherein R1, R2,
R3, R4, R5, R6, R7, R8, R9, X, n and the broken lines are as defined herein
which are useful as modulators of chemokine receptor activity. In particular,
these compounds are useful as modulators of the chemokine receptor CCR-2.

French Abstract

L'invention concerne des composés de formule (I), dans laquelle R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, n et la ligne pointillée sont tels que définis dans la description. Ces composés sont utilisés en tant que modulateurs de l'activité des récepteurs de chimiokine. Plus particulièrement, ces composés sont utiles en tant que modulateurs du récepteur CCR-2 de chimiokine.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I:
<IMG>
Wherein:
X is selected from the group consisting of:
C, N, O, S and SO2;
Y is N or C;
R1 is selected from the group consisting of:
hydrogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-S-C1-6alkyl,
-(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), hydroxy, heterocycle,
-CN, -NR12R12, -NR12COR13, -NR12SO2R14, -COR11, -CONR12R12, and phenyl,
where R11 is independently selected from the group consisting of: hydroxy,
hydrogen, C
1-6 alkyl, -O-C1-6alkyl, benzyl, phenyl and C3-6 cycloalkyl where the alkyl,
phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with
1-3
substituents where the substituents are independently selected from the group
consisting of: halo, hydroxy, C1-3alkyl, C1-3alkoxy, -CO2H, -CO2-C1-6 alkyl,
and trifluoromethyl, and
169

where R12 is selected from the group consisting of: hydrogen, C1-6 alkyl,
benzyl, phenyl
and
C3-6 cycloalkyl where the alkyl, phenyl, benzyl and cycloalkyl groups can be
unsubstituted or substituted with 1-3 substituents where the substituents are~
independently selected from the group consisting of: halo, hydroxy, C1-3alkyl,
C1-3alkoxy, -CO2H, -CO2-C1-6 alkyl, and trifluoromethyl, and
where R13 is selected from the group consisting of: hydrogen, C1-6 alkyl, -O-
C1-6alkyl,
benzyl, phenyl and C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and
cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents
where
the substituents are independently selected from the group consisting of:
halo,
hydroxy, C1-3alkyl, C1-3alkoxy, -CO2H, -CO2-C1-6 alkyl, and trifluoromethyl,
and~~
where R14 is selected from the group consisting of: hydroxy, C1-6 alkyl, -O-C1-
6alkyl,
benzyl, phenyl and C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and
cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents
where
said substituents are independently selected from the group consisting of:
halo,
hydroxy, C1-3alkyl, C1-3alkoxy, -CO2H, -CO2-C1-6 alkyl, and trifluoromethyl,
and
where said alkyl and said cycloalkyl, are unsubstituted or substituted with 1-
7 substituents
where said substituents are independently selected from the group consisting
of:
(a) ~halo,
(b) ~hydroxy,
(c) ~-O-C1-3alkyl,
(d) ~trifluoromethyl,
(f) ~C1-3alkyl,
(g) ~-O-C1-3alkyl,
(h) ~-COR11,
(i) ~-SO2R14,
170

(j) -NHCOCH3,
(k) -NHSO2CH3,
(l) -heterocycle,
(m) =O and
(n) -CN,
and where said phenyl and heterocycle are unsubstituted or substituted with 1-
3
substituents where said substituents are independently selected from the group
consisting
of: halo, hydroxy, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
R2 is selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C1-3alkyl, where the alkyl is unsubstituted or substituted with 1-6
substituents independently selected from fluoro and hydroxy,
(e) -NR12R12,
(f) -COR11,
(g) -CONR12R12,
(h) -NR12COR13,
(i) -OCONR12R12,
(j) -NR12CONR12R12,
(k) -heterocycle,
(l) -CN,
(m) -NR12-SO2-NR12R12,
(n) -NR12-SO2-R14,
(o) -SO2-NR12R12, and
(p) =O, where R2 is connected to the ring via a double bond;
171

R3 is oxygen or is absent when Y is N;
R3 is selected from when Y is C:
(a) ~hydrogen,
(b) ~hydroxy,
(c) ~halo,
(d) ~C1-3alkyl, where said alkyl is unsubstituted or substituted with 1-6
substituents independently selected from: fluoro, hydroxy, and -COR11,
(e) ~NR12R12,
(f) ~-COR11,
(g) ~-CONR12R12,
(h) ~-NR12COR13,
(i) ~-OCONR12R12,
(j) ~-NR12CONR12R12,
(k) ~-heterocycle,
(l) ~-CN,
(m) ~-NR12-SO2-NR12R12,
(n) ~-NR12-SO2-R14,
(o) ~-SO2-NR12R12 and
(p) ~nitro,
R4 is selected from the group consisting of:
(a) ~hydrogen,
(b) ~C1-6alkyl,
(c) ~trifluoromethyl,
(d) ~trifluoromethoxy,
(e) ~chloro,
(f) ~fluoro,
(g) ~bromo, and
172

(h) ~phenyl;
R5 is selected from the group consisting of:
(a) C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6
fluoro
and optionally substituted with hydroxyl,
(b) -O-C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6

fluoro,
(c) -CO-C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6
fluoro,
(d) -S-C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6

fluoro,
(e) -pyridyl, which may be unsubstituted or substituted with one or more
~
substituents selected from the group consisting of: halo, trifluoromethyl,
C1-4alkyl, and COR11,
(f) fluoro,
(g) chloro,
(h) bromo,
(i) -C4-6cycloalkyl,
(j) -O-C4-6cycloalkyl,
(k) phenyl, which may be unsubstituted or substituted with one or more
substituents selected from the group consisting of: halo, trifluoromethyl,
C1-4alkyl, and COR11,
(l) -O-phenyl, which may be unsubstituted or substituted with one or more

substituents selected from the group consisting of: halo, trifluoromethyl,
C1-4alkyl, and COR11,
(m) -C3-6cycloalkyl, where alkyl may be unsubstituted or substituted with 1-
6
fluoro,
(n) -O-C3-6cycloalkyl, where alkyl may be unsubstituted or substituted with
1-6 fluoro,
173

(o)-heterocycle,
(p)-CN, and
(q)-COR11;
R6 is selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) trifluoromethyl,
(d) fluoro,
(e) chloro, and
(f) bromo;
R7 is selected from:
hydrogen, (C0-6alkyl)-phenyl, (C0-6alkyl)-heterocycle, (C0-6alkyl)-C3-
7cycloalkyl,
(C0-6alkyl)-COR11, (C0-6alkyl)-(alkene)-COR11, (C0-6alkyl)-SO3H, (C0-
6alkyl)-W-C0-4alkyl, (C0-6alkyl)-CONR12-phenyl, (C0-6alkyl)-CONR15-V-
COR11, and nothing (when X is O, S, or SO2), where V is C1-6alkyl or phenyl,
where W is selected from the group consisting of: a single bond, -O-, -S-, -SO-
, -
SO2-, -CO-, -CO2-, -CONR12- and -NR12-
where the R15 can be hydrogen, C1-4alkyl, or where R15 is joined via a 1-5
carbon tether to one of the carbons of V to form a ring,
where the C0-6alkyl is unsubstituted or substituted with 1-5 substituents,
where
said substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -C0-6alkyl
(d) -O-C1-3alkyl,
(e) trifluoromethyl, and
(f) -C0-2alkyl-phenyl,
174

where said phenyl, heterocycle, cycloalkyl, and C0-4alkyl is unsubstituted or
substituted with 1-5 substituents where said substituents are independently
selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) -O-C1-3alkyl,
(f) -C0-3-COR11,
(g) -CN,
(h) _NR12R12,
(i) -CONR12R12, and
(j) -C0-3-heterocycle,
or where the phenyl and heterocycle may be fused to another heterocycle, which
itself may be unsubstituted or substituted with 1-2 substituents independently
selected from hydroxy, halo, -COR11, and-C1-3alkyl,
and where alkene is unsubstituted or substituted with 1-3 substituents which
are
independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) C1-3alkyl,
(d) phenyl, and
(e) heterocycle;
R8 is selected from the group consisting of:
(a) hydrogen,
(b) nothing when X is either O, S, SO2 or N or when a double bond joins the
carbons to which R7 and R10 are attached,
175

(c)hydroxy,
(d)C1-6alkyl,
(e)C1-6alkyl-hydroxy,
(f)-O-C1-3alkyl,
(g)-COR11,
(h)-CONR12R12, and
(i)-CN;
or where R7 and R8 are joined together to form a ring which is selected from
the group
consisting of:
(a) 1H-indene,
(b) 2,3-dihydro-1H-indene,
(c) 2,3-dihydro-benzofuran,
(d) 1,3-dihydro-isobenzofuran,
(e) 2,3-dihydro-benzothiofuran,
(f) 1,3-dihydro-isobenzothiofuran,
(g) 6H-cyclopenta[d]isoxazol-3-ol
(h) cyclopentane, and
(i) cyclohexane,
where said ring formed may be unsubstituted or substituted with 1-5
substituents
independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) -O-C1-3alkyl,
(f) -C0-3-COR11,
(g) -CN,
(h) _NR12R12,
176

(i) -CONR12R12, and
(j) -C0-3-heterocycle,
or where R7 and R9 or R8 and R10 may be joined together to form a ring which
is phenyl or
heterocycle,
wherein said ring is unsubstituted or substituted with 1-7 substituents where
said
substituents are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) -O-C1-3alkyl,
(f) -COR11,
(g) -CN,
(h) -NR12R12, and
(i) -CONR12R12;
R9 and R10 are independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) C1-6alkyl,
(d) C1-6alkyl-COR11,
(e) C1-6alkyl-hydroxy,
(f) -O-C1-3alkyl,
(g) =O, when R9 or R10 is connected to the ring via a double bond
(h) halo;
n is selected from 0, 1 and 2;
the dashed line represents a single or a double bond;
177

and pharmaceutically acceptable salts thereof and individual diastereomers
thereof.
2. A compound of claim 1 having formula Ia:
<IMG>
wherein R1, R2, R3, R5, R9, Y, and n are defined as in Claim 1,
and wherein R16 and R17 are independently selected from the group consisting
of:
(a) hydrogen,
(b) halo,
(c) trifluoromethyl,
(d) hydroxy,
(e) C1-3alkyl,
(f) -O-C1-3alkyl,
(g) -C0-3-CO2H,
(h) -C0-3-CO2C1-3alkyl,
(i) -CN, and
(j) -C0-3-heterocycle,
or where the R16 and R17 are joined together to form a heterocycle which is
fused to the phenyl ring, and which itself may be unsubstituted or
substituted with 1-2 substituents independently selected from hydroxy,
halo, -COR11, and -C1-3alkyl;
178

and pharmaceutically acceptable salts and individual diastereomers thereof.
3. A compound of Claim 1 having the formula Ib:
<IMG>
wherein the dashed line represents a single or a double bond and R1, R2, R3,
R5, R9, R16, R17
Y, and n are as defined in Claim 1;
and pharmaceutically acceptable salts and individual diastereomers thereof.
4. A compound of Claim 1 having formula Ic:
<IMG>
wherein R1, R2, R3, R5, R9, R16, R17, Y, and n are as defined in Claim 1,
and where H is a heterocycle;
and pharmaceutically acceptable salts and individual diastereomers thereof.
5. A compound of Claim 1 having formula Id:
179

<IMG>
wherein R1, R2, R3, R5, R9, R11, Y, W, and n are defined in Claim 1
and where said C1-4 carbon chain may be unsubstituted, or substituted with 1-4
substituents which are independently selected from the group consisting of:
(a) halo,
(b) hydroxy,
(c) -C0-6alkyl
(d) -O-C1-3alkyl,
(e) trifluoromethyl, and
(f) -C0-2alkyl-phenyl,
or where aid C1-4 carbon chain may be included within a C3-7cycloalkyl ring,

and pharmaceutically acceptable salts and individual diastereomers thereof.
6. A compound of Claim 1 having formula Ie:
<IMG>
wherein R1, R2, R3, R5, R9, R16, R17, X, Y, and n are defined in Claim 1, and
180

where the dotted lines can represent either a single or double bond, and
where 0 can be 1 or 2, and
where A, B, and D, can independently be selected from C, N, O, or S, to make a
phenyl
ring (when X, A, B, D, are all C, and 0=2) or to make a heterocycle when at
least one of
X, A, B, D are N, O, or S and not C,
and pharmaceutically acceptable salts and individual diastereomers thereof.
7. A compound of Claim 1 having formula If:
<IMG>
wherein R1, R2, R3, R5, R7, R9, R10, Y, and n are defined in Claim 1, and X is
either
N, or O (in which case R7 is nothing).
and pharmaceutically acceptable salts and individual diastereomers thereof.
8. A compound of Claim 1 having formula Ig:
<IMG>
181

Ig
wherein R1, R5, R9, R16, R17, and Y are defined in Claim 1,
or where the R16 and R17 are joined together to form a heterocycle which is
fused
to the phenyl ring, and which itself may be unsubstituted or substituted
with 1-2 substituents independently selected from the group consisting of
hydroxy, halo, -COR11 and-C1-3alkyl;
and pharmaceutically acceptable salts and individual diastereomers thereof.
9. A compound of Claim 1 having formula Ih:
<IMG>
wherein the dashed line represents a single or a double bond and R1, R5, R9,
R16, R17, and Y
are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
10. A compound of Claim 1 having formula Ii:
<IMG>
182

wherein R1, R5, R9, R16, R17, and Y are defined herein,
and where H is a heterocycle;
and pharmaceutically acceptable salts and individual diastereomers thereof.
A compound of Claim 1 having formula Ij:
<IMG>
wherein R1, R5, R9, R11, Y, and W are defined herein
and where the C1-4 carbon chain may be unsubstituted, or substituted with 1-4
substituents which are independently selected from the group consisting of:
(a)halo,
(b)hydroxy,
(c)-C0-6alkyl
(d)-O-C1-3alkyl,
(e)trifluoromethyl, and
(f)-C0-2alkyl-phenyl,
and pharmaceutically acceptable salts and individual stereoisomers thereof.
11. A compound of Claim 1 having formula Ik:
183

<IMG>
wherein R1, R5, R9, R10, and Y are defined herein,
and pharmaceutically acceptable salts and individual diastereomers thereof.
12. A compound of Claim 1 wherein R1 is selected from the group consisting
of:
-C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, and
-(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl),
where the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7
substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -O-C1-3alkyl,
(d) trifluoromethyl,
(f) C1-3alkyl,
(g) -O-C1-3alkyl,
(h) -COR11,
(i) -CN,
(j) -NR12R12, and
(k) -CONR12R12.
13. A compound of Claim 1 wherein R1 is selected from the group consisting
of:
184

(1) -C1-6alkyl, which is unsubstituted or substituted with 1-6 substituents
where the
substituents are independently selected from the group consisting of:
(a) halo,
(b) hydroxy,
(c) -O-C1-3alkyl,
(d) trifluoromethyl, and
(e) -COR11,
(2) -C0-6alkyl-O-C1-6alkyl-, which is unsubstituted or substituted with 1-6
substituents where the substituents are independently selected from the group
consisting of:
(a) halo,
(b) trifluoromethyl, and
(c) -COR11,
(3) and -(C3-5cycloalkyl)-(C0-6alkyl), which is unsubstituted or substituted
with 1-7
substituents where the substituents are independently selected from the group
consisting of:
(a) halo,
(b) hydroxy,
(c) -O-C1-3alkyl,
(d) trifluoromethyl, and
(e) -COR11.
14. A compound of Claim 13 wherein R l is selected from the group
consisting of:
(a) C1-6alkyl,
(b) C1-6alkyl substituted with hydroxy and
(c) C1-6alkyl substituted with 1-6 fluoro.
185

15. A compound of Claim 14 wherein R1 is selected from the group
consisting of:
(a) -CH(CH3)2,
(b) -CH(OH)CH3, and
(c) -CH2CF3.
16. A pharmaceutical composition which comprises an inert carrier and a
compound of Claim 1.
17. A method for modulation of chemokine receptor activity in a mammal
which comprises the administration of an effective amount of the compound of
Claim 1.
18. A method for treating, ameliorating, controlling or reducing the risk of
an
inflammatory and immunoregulatory disorder or disease which comprises the
administration to a
patient of an effective amount of the compound of Claim 1.
19. A method for treating, ameliorating, controlling or reducing the risk of
rheumatoid arthritis which comprises the administration to a patient of an
effective amount of the
compound of Claim 1.
186

Description

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
TITLE OF THE INVENTION
HETEROCYLIC CYCLOPENTYL TETRAHYDROISOQUINOLINE AND
TETRAHYDROPYR>DOPYR1DINE MODULATORS OF CHEMOKINE RECEPTOR
ACTNITY
BACKGROUND OF THE INVENTION
The chemokines are a family of small (70-120 amino acids), proinflammatory
cytokines, with potent chemotactic activities. Chemokines are chemotactic
cytokines that are
released by a wide variety of cells to attract various cells, such as
monocytes, macrophages, T
cells, eosinophils, basophils and neutrophils to sites of inflammation
(reviewed in Schall,
C okine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). These
molecules
were originally defined by four conserved cysteines and divided into two
subfamilies based on
the arrangement of the first cysteine pair. In the CXC-chemokine family, which
includes IL-8,
GROa, NAP-2 and IP-10, these two cysteines are separated by a single amino
acid, while in the
CC-chemokine family, which includes RANTES, MCP-1, MCP-2, MCP-3, MIP-la, MIP-
113 and
eotaxin, these two residues are adjacent.
The a-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-
2
(NAP-2) and melanoma growth stimulatory activity protein (MGSA) are
chemotactic primarily
for neutrophils, whereas (3-chemokines, such as RANTES, M>I'-la, MIP-1(3,
monocyte
chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for
macrophages,
monocytes, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-
666 (1996)).
The chemokines are secreted by a wide variety of cell types and bind to
specific
G-protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. Sci.,
15, 159-165
(1994)) present on leukocytes and other cells. These chemokine receptors form
a sub-family of
GPCRs, which, at present, consists of fifteen characterized members and a
number of orphans.
Unlike receptors for promiscuous chemoattractants such as CSa, fMLP, PAF, and
LTB4,
chemokine receptors are more selectively expressed on subsets of leukocytes.
Thus, generation
of specific chemokines provides a mechanism for recruitment of particular
leukocyte subsets.
On binding their cognate ligands, chemokine receptors transduce an
intracellular
signal though the associated trimeric G protein, resulting in a rapid increase
in intracellular
calcium concentration. There are at least seven human chemokine receptors that
bind or respond
to (3-chemokines with the following characteristic pattern: CCR-1 (or "CKR-1"
or "CC-CKR-
1") [MIP-la, MIP-1(3, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.,
270, 22123-
22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or
"CKR-

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
2A"/"CKR-2A" or "CC-CKR-2A"/"CC-CKR-2A") [MCP-1, MCP-2, MCP-3, MCP-4]; CCR-3
(or "CKR-3" or "CC-CKR-3") [Eotaxin, Eotaxin 2, RANTES, MCP-2, MCP-3]
(Rollins, et al.,
Blood, 90, 908-928 (1997)); CCR-4 (or "CKR-4" or "CC-CKR-4") [MIP-la, RANTES,
MCP-1]
(Rollins, et al., Blood, 90, 908-928 (1997)); CCR-5 (or "CKR-5" or "CC-CKR-5")
[MIP-la,
RANTES, MIP-1(3] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the
Duffy blood-
group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 269, 7835-
7838 (1994)).
The (3-chemokines include eotaxin, MIP ("macrophage inflammatory protein"),
MCP
("monocyte chemoattractant protein") and RANTES ("regulation-upon-activation,
normal T
expressed and secreted") among other chemokines.
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-
4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of
inflammatory and immunoregulatory disorders and diseases, including asthma,
rhinitis and
allergic diseases, as well as autoimmune pathologies such as rheumatoid
arthritis and
atherosclerosis. Humans who are homozygous for the 32-basepair deletion in the
CCR-5 gene
appear to have less susceptibility to rheumatoid arthritis (Gomez, et al.,
Arthritis & Rheumatism,
42, 989-992 (1999)). A review of the role of eosinophils in allergic
inflammation is provided by
Kita, H., et al., J. Exp. Med. 183, 2421-2426 (1996). A general review of the
role of chemokines
in allergic inflammation is provided by Lustger, A.D., New England J. Med.,
338(7), 426-445
(1998).
A subset of chemokines are potent chemoattractants for monocytes and
macrophages. The best characterized of these is MCP-1 (monocyte
chemoattractant protein-1),
whose primary receptor is CCR2. MCP-1 is produced in a variety of cell types
in response to
inflammatory stimuli in various species, including rodents and humans, and
stimulates
chemotaxis in monocytes and a subset of lymphocytes. In particular, MCP-1
production
correlates with monocyte and macrophage infiltration at inflammatory sites.
Deletion of either
MCP-1 or CCR2 by homologous recombination in mice results in marked
attenuation of
monocyte recruitment in response to thioglycollate injection and Listeria
monocytogenes
infection (Lu et al., J. Exp. Med., 187, 601-608 (1998); Kurihara et al. J.
Exn Med., 186, 1757-
1762 (1997); Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Kuziel et
al. Proc. Natl. Acad.
Sci., 94, 12053-12058 (1997)). Furthermore, these animals show reduced
monocyte infiltration
into granulomatous lesions induced by the injection of schistosomal or
mycobacterial antigens
(Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Warmington et al. Am
J. Path., 154, 1407-
1416 (1999)). These data suggest that MCP-1-induced CCR2 activation plays a
major role in
monocyte recruitment to inflammatory sites, and that antagonism of this
activity will produce a
2

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
sufficient suppression of the immune response to produce therapeutic benefits
in
immunoinflammatory and autoimmune diseases.
Accordingly, agents which modulate chemokine receptors such as the CCR-2
receptor would be useful in such disorders and diseases.
In addition, the recruitment of monocytes to inflammatory lesions in the
vascular
wall is a major component of the pathogenesis of atherogenic plaque formation.
MCP-1 is
produced and secreted by endothelial cells and intimal smooth muscle cells
after injury to the
vascular wall in hypercholesterolemic conditions. Monocytes recruited to the
site of injury
infiltrate the vascular wall and differentiate to foam cells in response to
the released MCP-1.
Several groups have now demonstrated that aortic lesion size, macrophage
content and necrosis
are attenuated in MCP-1 -/- or CCR2 -/- mice backcrossed to APO-E -/-, LDL-R -
/- or Apo B
transgenic mice maintained on high fat diets (Boring et al. Nature, 394, 894-
897 (1998); Gosling
et al. J. Clin. Invest., 103, 773-778 (1999)). Thus, CCR2 antagonists may
inhibit atherosclerotic
lesion formation and pathological progression by impairing monocyte
recruitment and
differentiation in the arterial wall.
SUMMARY OF THE INVENTION
The present invention is further directed to compounds which are modulators of
chemokine receptor activity and are useful in the prevention or treatment of
certain inflammatory
and immunoregulatory disorders and diseases, allergic diseases, atopic
conditions including
allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as
autoimmune pathologies such
as rheumatoid arthritis and atherosclerosis. The invention is also directed to
pharmaceutical
compositions comprising these compounds and the use of these compounds and
compositions in
the prevention or treatment of such diseases in which chemokine receptors are
involved.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of the formula I:
3

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Rs
R'
R8 _X ~ O Rs
~ n Rs
R1o . N f
n ~R1
Ra
R' R.,
Formula I
X is selected from:
C, N, O, S and SOz;
Y is selected from N or C.
R1 is selected from:
hydrogen, -C1_6alkyl, -CO_6alkyl-O-C1_galkyl, -Cp_6alkyl-S-C1_6alkyl,
-(CO_6alkyl)-(C3_~cycloalkyl)-(CO_6alkyl), hydroxy, heterocycle,
_CN~ _~g12R12~ _yzCORl3, -NR'zSOZRI4, -COR11, -CONR'zR'z, and phenyl,
where R11 is independently selected from: hydroxy, hydrogen,
C1_6 alkyl, -O-C,_6alkyl, benzyl, phenyl, C3_6 cycloalkyl where the alkyl,
phenyl,
benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3
substituents where the substituents are independently selected from: halo,
hydroxy, C1_3alkyl, C1_3alkoxy, -C02H, -C02-C1_6 alkyl, and trifluoromethyl,
and
where R12 is selected from: hydrogen, C1_6 alkyl, benzyl, phenyl,
C3_6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be
unsubstituted or substituted with 1-3 substituents where the substituents are
independently selected from: halo, hydroxy, C1_3alkyl, C1_3alkoxy, -C02H, -
C02-C1_6 alkyl, and trifluoromethyl, and
4

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
where R'3 is selected from: hydrogen, C1-( alkyl, -O-C~_6alkyl, benzyl,
phenyl, C3-
cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be
unsubstituted or substituted with 1-3 substituents where the substituents are
independently selected from: halo, hydroxy, C1_3alkyl, C1_3alkoxy, -C02H, -
C02-C1_6 alkyl, and trifluoromethyl, and
where R'4 is selected from: hydroxy, C1_6 alkyl, -O-C~_6alkyl, benzyl, phenyl,
C3-
cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be
unsubstituted or substituted with 1-3 substituents where the substituents are
independently selected from: halo, hydroxy, C1-3alkyl, C1-3alkoxy, -C02H, -
C02-C1_6 alkyl, and trifluoromethyl, and
where the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7
substituents
where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -O-C1-3alkyl,
(d) trifluoromethyl,
(f) C1-3alkyl,
(g) -O-C1_3alkyl,
(h) -COR11,
(i) -S02R14,
(j) -NHCOCH3,
(k) -NHS02CH3,
(1) -heterocycle,
(m) =O,
(n) -CN,
and where the phenyl and heterocycle are unsubstituted or substituted with 1-3
substituents where the substituents are independently selected from: halo,
hydroxy, C1_
3alkyl, C1_3alkoxy and trifluoromethyl;
5

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
R2 is selected
from:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C1_3alkyl, where the alkyl is unsubstituted
or substituted with 1-6
substituents independently selected from:
fluoro, and hydroxy,
(e) _~12R12~
(f) -COR11,
(g) -CONR 12R 12~
(h) -NR12COR13,
(i) -OCONR12R12~
_~12CONR12R12,
(k) -heterocycle,
(I) -CN,
(m) _NR 12-S02-NR 12R 12~
(n) -NR12_Sp2_R14~
(o) -S02-NR12R12, and
(p) =O, where R2 is connected to the ring via a double bond;
R3 is oxygen or is absent when Y is N;
R3 is selected from the following list when Y is C:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C1_3alkyl, where the alkyl is unsubstituted or substituted with 1-6
substituents independently selected from: fluoro, hydroxy, and -COR",
(e) -NR12R12~
(f) -COR 11,
6

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(g) -CONR12R12~
(h) -NR12COR13,
(i) -OCONR 12R 12~
) _~12CONR12R12~
(k) -heterocycle,
(1) -CN,
(m) _~12_Sp2_~12R12~
(n) _~12_SO2_R14~
(o) -S02-NR12R12 and
(p) nitro~
R4 is selected
from:
(a) hydrogen,
(b) C 1 _6alkyl,
(c) trifluoromethyl,
(d) trifluoromethoxy,
(e) chloro,
(f) fluoro,
(g) bromo, and
(h) phenyl;
RS is selected from:
(a) C1-(alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro
and optionally substituted with hydroxyl,
(b) -O-C1-(alkyl, where alkyl may be unsubstituted or substituted with 1-6
fluoro,
(c) -CO-C1_6alkyl, where alkyl may be unsubstituted or substituted with 1-6
fluoro,
7

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(d) -S-C1_6alkyl, where alkyl may be unsubstituted or substituted with 1-6
fluoro,
(e) -pyridyl, which may be unsubstituted or substituted
with one or more
substituents selected from the group consisting
of: halo, trifluoromethyl,
C1_4alkyl, and COR11,
(f) fluoro,
(g) chloro,
(h) bromo,
(i) -C4-(cycloalkyl,
(j) -O-C4-6cycloalkyl,
(k) phenyl, which may be unsubstituted or substituted
with one or more
substituents selected from the group consisting
of : halo, trifluoromethyl,
C~_4alkyl, and COR11,
(1) -O-phenyl, which may be unsubstituted or substituted
with one or more
substituents selected from the group consisting
of : halo, trifluoromethyl,
C~_4alkyl, and COR11,
(m) -C3_6cycloalkyl, where alkyl may be unsubstituted
or substituted with 1-6
fluoro,
(n) -O-C3_6cycloalkyl, where alkyl may be unsubstituted
or substituted with 1-
6 fluoro,
(o) -heterocycle,
(p) -CN, and
(q) -COR11;
R6 is selected from:
(a) hydrogen,
(b) C1-(alkyl, and
(c) trifluoromethyl
(d) fluoro
8

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(e) chloro, and
(f) bromo;
R~ is selected from:
nothing (when X = O), hydrogen, (Cp_6alkyl)-phenyl, (Cp-(alkyl)-heterocycle,
(Cp_
(alkyl)-C3_~cycloalkyl , (Cp_6alkyl)-COR", (Cp-(alkyl)-(alkene)-COR", (Cp_
6alkyl)-S03H, (Cp_6alkyl)-W-Cp_4alkyl, (Cp_6alkyl)-CONR'2-phenyl, (Cp_
6alkyl)-CONR'S-V-COR", and nothing (when X is O, S, or S02), where V is
selected from C,_6alkyl or phenyl, and
where W is selected from: a single bond, -O-, -S-, -SO-, -S02-, -CO-, -C02-, -
CONR'2- and -NR12-, and
where the R'S can be hydrogen, C,_4alkyl, or where R'S is joined via a 1-5
carbon
tether to one of the carbons of V to form a ring, and
where the Cp_6alkyl is unsubstituted or substituted with 1-5 substituents,
where
the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -Cp_6alkyl
(d) -O-C1_3alkyl,
(e) trifluoromethyl, and
(f) -Co_2alkyl-phenyl,
and where the phenyl, heterocycle, cycloalkyl, and Cp_4alkyl is unsubstituted
or
substituted with 1-5 substituents where the substituents are independently
selected
from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1_3alkyl,
9

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(e) -O-C1-3alkyl,
-Co-3-COR 11,
(g) -CN,
(h) -NR12R12~
(i) -CONR 12R 12, and
(j) -Co-3-heterocycle,
or where the
phenyl and heterocycle
may be fused
to another heterocycle,
which
itself may be unsubstituted or substituted with
1-2 substituents
independently selected from hydroxy, halo, -COR11,
and -C1_3alkyl~
10and where alkene
is unsubstituted
or substituted
with 1-3 substituents
which are
independently
selected from:
(a) halo,
(b) trifluoromethyl,
(c) C~_3alkyl,
15(d) phenyl, and
(e) heterocycle;
Rg is selected
from:
(a) hydrogen,
20(b) nothing when X is either O, S, SOZ or N or when
a double bond joins the
carbons to which R' and R' are attached,
(c) hydroxy,
(d) C1-(alkyl,
(e) C1-6alkyl-hydroxy,
25(f) -O-C1_3alkyl,
(g) -COR11,
(h) -CONR12R12, and
(i ) -CN;

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
or where R~ and R8 may be joined together to form a ring which is selected
from:
(a) 1H-indene,
(b) 2,3-dihydro-1H-indene,
(c) 2,3-dihydro-benzofuran,
(d) 1,3-dihydro-isobenzofuran,
(e) 2,3-dihydro-benzothiofuran,
(f) 1,3-dihydro-isobenzothiofuran,
(g) 6H-cyclopenta[d]isoxazol-3-0l
(h) cyclopentane, and
(i) cyclohexane,
where the ring formed may be unsubstituted or substituted with 1-5
substituents
independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1_3alkyl,
(e) -O-C1_3alkyl,
-Co-s-COR 11,
(g) -CN,
(h) -NR12R12~
(i) -CONR12R12, and
(j) -C°_3-heterocycle,
or where R~ and R9 or Rg and R'° may be joined together to form a ring
which is phenyl or
heterocycle,
wherein the ring is unsubstituted or substituted with 1-7 substituents where
the
substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
11

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(d) C1-3alkyl,
(e) -O-C1_3alkyl,
(f) -COR11,
(g) -CN,
(h) -NR12R12,
and
(i) -CONR12R12;
R9 and R10 are independently selected from:
(a) hydrogen,
(b) hydroxy,
(c) C1-(alkyl,
(d) C1-(alkyl-COR'1,
(e) C1-(alkyl-hydroxy,
(f) -O-C1_3alkyl,
(g) =O, when R9 or R10 is connected to the ring via a double bond
(h) halo;
n is selected from 0, 1 and 2;
the dashed line represents a single or a double bond;
and pharmaceutically acceptable salts thereof and individual diastereomers
thereof.
Another embodiment of the present invention includes compounds of formula Ia:
R16
' 9
R
R1~~
O
Rs
n R1
~Y
R2 R3
12

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Ia
wherein R1, R2, R3, R5, R9, Y, and n are defined herein,
and wherein R16 and R1~ are independently selected from:
(a) hydrogen,
(b) halo,
(c) trifluoromethyl,
(d) hydroxy,
(e) C1_3alkyl,
(f) -O-C1-3alkyl,
(g) -Co-3-C02H~
(h) -Co_3-C02C1_3alkyl,
(i) -CN, and
(j) -Co_3-heterocycle,
or where the R~~ and R" are joined together to form a heterocycle which is
fused
to the phenyl ring, and which itself may be unsubstituted or substituted
with 1-2 substituents independently selected from hydroxy, halo, -CORD 1,
and -C 1 _3alkyl
and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embodiment of the present invention also includes compounds of formula
Ib:
Rs
Ri ~ ~ ,
_ O
5
~ R
R n
Ri Y~
R2 R3
13

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Ib
wherein the dashed line represents a single or a double bond and R1, R2, R3,
RS, R9, R16, R17
Y, and n are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
A still further embodiment of the present invention includes compounds of
formula Ic:
Ris Rs
i
R1~~H
O
Rs
n ~N
'R1 Y~
R2 R3
Ic
wherein R1, R2, R3, R5, R9, R16, R17, Y, and n are defined herein,
and where H is a heterocycle;
and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embidiment of the present invention include compounds of formula Id:
Rs
O
i~C~W
R1\ 1-4 I O
N N \ R5
n R1 ~ YJ
R2 R3
Id
wherein R1, R2, R3, R5, R9, R11, Y, W, and n are defined herein
14

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
and where the C~_4 carbon chain may be unsubstituted, or substituted with 1-4
substituents which are independently selected from:
(a) halo,
(b) hydroxy,
(c) -Cp_6alkyl
(d) -O-C1_3alkyl,
(e) trifluoromethyl, and
(f) -Co_Zalkyl-phenyl,
or where the C1_4 carbon chain may be included within a C3_~cycloalkyl ring,
and pharmaceutically acceptable salts and individual diastereomers thereof.
A further embodiment of the present invention includes compounds of formula
Ie:
R9
R16 ~A~X
~ O
17
R p- N N ~ R
R
° n 1
R2 R3
Ie
wherein R1, R2, R3, R5, R9, RI~, R1', X, Y, and n are defined herein, and
where the dotted lines can represent either a single or double bond, and
where o can be 1 or 2, and
where A, B, and D, can independently be selected from C, N, O, or S, to make a
phenyl
ring (when X, A, B, D, are all C, and o = 2) or to make a heterocycle when at
least one of
X, A, B, D are N, O, or S and not C,
and pharmaceutically acceptable salts and individual diastereomers thereof.
A still further embodiment of the present invention includes compounds of
formula If:

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
R9
R ~X
O
N ~ R5
Rio n _N
R1 Y~
R2 R3
If
wherein R1, R2, R3, R5, R7, R9, RI°, Y, and n are defined herein, and X
is either
N, or O (in which case R' is nothing).
and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embodiment of the present invention includes compounds of formula Ig:
R1s
R~ ~ O
N \ R5
_ 2 R1
Y
Ig
wherein R1, R5, R9, R16, R1~, and Y are defined herein,
or where the R'6 and R" are joined together to form a heterocycle which is
fused
to the phenyl ring, and which itself may be unsubstituted or substituted
with 1-2 substituents independently selected from hydroxy, halo, -COR",
and -Cl_3alkyl~
and pharmaceutically acceptable salts and individual diastereomers thereof.
16

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
A further embodiment of the present invention includes compounds of formula
Ih:
R9
R1s ,
O
- N R5
1~ N \
R
R' I Y J
Ih
wherein the dashed line represents a single or a double bond and R1, R5, R~,
R16, R17, and Y
are defined herein;
and pharmaceutically acceptable salts and individual diastereomers thereof.
An additional embodiment of the present invention includes compounds of
formula Ii:
R1s Rs
i
R1~~H
O
R5
1 _2 R1 N
Ii
wherein R1, R5, R9, R16, R17, and Y are defined herein,
and where H is a heterocycle;
and pharmaceutically acceptable salts and individual diastereomers thereof.
A still further embodiment of the present invention includes compounds of
formula Ij:
17

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
R9
O
i~C~-W
R 1-4 1 O
R5
1-2 R1
Y
Ij
wherein R1, R5, R9, R11, Y, and W are defined herein
and where the C~_4 carbon chain may be unsubstituted, or substituted with 1-4
substituents which are independently selected from:
(a) halo,
(b) hydroxy,
(c) -CO_6alkyl
(d) -O-C1-3alkyl,
(e) trifluoromethyl,
and
(f) -C°_Zalkyl-phenyl,
and pharmaceutically acceptable salts and individual stereoisomers thereof.
Another embodiment of the present invention includes compounds of formula Ik:
R9
O
R5
Ri o ~ 2 R~ N
Y
Formula Ik
wherein R1, R5, R9, R'°, and Y are defined herein,
and pharmaceutically acceptable salts and individual diastereomers thereof.
In a still further embodiment of the present invention X is C, O or N.
18

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
In another embodiment of the present invention X is C or O.
In another embodiment of the present invention R1 is selected from:
-C1_6alkyl, -CO_6alkyl-O-C1_6alkyl, and
-(CO_6alkyl)-(C3_~cycloalkyl)-(CO_6alkyl),
where the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7
substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -O-C 1 _3alkyl,
(d) trifluoromethyl,
(f) C1_3alkyl,
(g) -O-C1_3alkyl,
(h) -COR11,
(i) -CN,
(j) -NR12R12, and
(k) -CONR 12R 12,
In another aspect of the present invention R1 is selected from:
(1) -C1_6alkyl, which is unsubstituted or substituted with 1-6 substituents
where the
substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -O-C1_3alkyl,
(d) trifluoromethyl, and
(e) -CORD ~,
(2) -CO_6alkyl-O-C1_6alkyl-, which is unsubstituted or substituted with 1-6
substituents where the substituents are independently selected from:
19

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(a) halo,
(b) trifluoromethyl, and
(c) -CORIy
(3) -(C3_5cycloalkyl)-(CO_6alkyl), which is unsubstituted or substituted with
1-7
substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -O-C1_3alkyl,
(d) trifluoromethyl, and
(e) -COR11.
In still another aspect of the present invention R1 is selected from:
(a) C1_6alkyl,
(b) C 1 _6alkyl substituted with hydroxy
(c) C1_6alkyl substituted with 1-6 fluoro.
In a still further aspect of the present invention R1 is selected from:
(a) -CH(CH3)2,
(b) -CH(OH)CH3, and
(c) -CHZCF3.
In another aspect of the present invention R2 is selected from:
(a) hydroxy
(b) hydrogen
(c) =O, where RZ is connected to the ring via a double bond.
In another aspect of the present invention R2 is hydrogen.

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
In a still further aspect of the present invention when Y is N, R3 is nothing
or O (to give a N-
oxide)
In a further aspect of the present invention when Y is N, R3 is nothing.
In a still further aspect of the present invention when Y is C, R3 is selected
from:
(a) hydrogen
(b) halo
(c) hydroxy
(d) C1_3alkyl, where the alkyl is unsubstituted or substituted with 1-6
substituents independently selected from: fluoro, and hydroxy,
(e) -COR11,
(f) -CONR 12R 12,
(g) -heterocycle,
(h) -NR12-S02-NR12R12~
(i) -NR12_S02_R14~
-S 02-NR 12R 12,
(k) -vitro, and
(1) -y2Ri2~
In another aspect of the present invention when Y is C, R3 is hydrogen.
In another aspect of the present invention R4 is hydrogen.
In another aspect of the present invention RS is selected from:
(a) C1_6alkyl substituted with 1-6 fluoro,
(b) -O-C1_6alkyl substituted with 1-6 fluoro,
(c) chloro,
(d) bromo, and
(e) phenyl.
21

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
In another aspect of the present invention RS is selected from:
(a) trifluoromethyl,
(b) trifluoromethoxy,
(c) chloro,
(d) bromo, and
(e) phenyl.
In another aspect of the present invention RS is trifluoromethyl.
In another aspect of the present invention R6 is hydrogen
In another aspect of the present invention R~ is phenyl, heterocycle,
C3_~cycloalkyl, C,_6alkyl, -
CORI ~, and -CONH-V-CORI ~,
where V is selected from C1_6alkyl or phenyl, and
where the phenyl,
heterocycle, C3_~cycloalkyl,
and C1_6alkyl
is unsubstituted
or
substit uted with 1-5 substituents where the substituents
are independently selected
from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1_3alkyl,
(e) -O-C1-3alkyl,
(f) -COR11,
(g) -CN,
(h) -heterocycle, and
(i) -CONR12R12.
22

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
In still another aspect of the present invention (when X is not O) that R~ is
phenyl,
heterocycle, C~_4alkyl, -COR", and -CONH-V-COR",
where V is selected from C,_6alkyl or phenyl, and
where the phenyl, heterocycle, and CI_4alkyl is unsubstituted or substituted
with 1-
3 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) C1_3alkyl,
(d) -O-C1_3alkyl,
(e) -COR l l ,and
(f) -heterocycle
In still another aspect of the present invention (when X is C), R~ is selected
from:
(a) ~N,N ~) ~N
J
HN~N iN
(b) para-fluorophenyl,(k) N
~N
(c) 3-carboxyphenyl, (1) N -
jN
(d) 3-carboxy-4- (m) H
N ~O
l
fluoropheny ~
,
N-S
(e) phenyl, (n) N ,N
,NJ
23

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(f) -COZCHZCH3, (o) ~N
N
iN~
(g) -COZH (p) N =N
iN~N
(h) -CONHCH3 (q) O
~~
~
N
C02H
H
(i) -hydroxy (r) O
~~N~C02CH3
H
In another aspect of the present invention when X is C, Rg is selected from:
(a) hydrogen,
(b) hydroxy,
(c) -CN, and
(d) -F
In another aspect of the present invention R' and R$ may be joined together to
form a ring which
is selected from:
(a) 1H-indene,
(b) 2,3-dihydro-1H-indene,
where the ring formed may be unsubstituted or substituted with 1-3
substituents
independently selected from:
(a) halo,
(b) hydroxy,
(c) C1_3alkyl,
(d) -O-C1_3alkyl,
(e) -COR11, and
(f) -heterocycle.
24

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
In another aspect of the present invention R9 and R10 are independently
selected from:
(a) hydrogen,
(b) hydroxy,
(c) -CH3,
(d) -O-CH3, and
(e) =O (where R9 and/or R~° are joined to the ring via a double bond).
In yet another aspect of the present invention n = 1 or 2.
Representative compounds of the present invention include those presented in
the
Examples and pharmaceutically acceptable salts and individual diastereomers
thereof.
The compounds of the instant invention have at least two asymmetric centers at
the 1- and 3-positions of the cyclopentyl ring. Additional asymmetric centers
may be present
depending upon the nature of the various substituents on the molecule. Each
such asymmetric
center will independently produce two optical isomers and it is intended that
all of the possible
optical isomers and diastereomers in mixtures and as pure or partially
purified compounds are
included within the ambit of this invention. The absolute configurations of
one aspect of the
compounds of this invention, where the substituents on the cyclopentyl ring
(amide and amine
units) are cis, as depicted:
R9
R ~X~~ n ~ R6
R ~ R5
Rio~n N
R1 YJwRa
R2 R3
The absolute configurations of a still further aspect of the compounds of this
invention are those of the orientation as depicted:

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
R9
8 ~X~) n 0 Rs
R ~/ ~ R5
R10' l- In N
YJwR4
R2 R3
wherein the carbon bearing the amine substituent is designated as being of the
(R) absolute
configuration and the carbon bearing the amide subunit can be designated as
being of either the
(S) or (R) absolute configuration depending on the priority for R1. For
example if R is isopropyl
then the absolute stereochemistry at the carbon bearing the amide subunit
would be (S) since the
amide and amine units are preferred to have the cis arrangement on the
cyclopentyl ring.
The independent syntheses of diastereomers and enantiomers or their
chromatographic separations may be achieved as known in the art by appropriate
modification of
the methodology disclosed herein. Their absolute stereochemistry may be
determined by the x-
ray crystallography of crystalline products or crystalline intermediates which
are derivatized, if
necessary, with a reagent containing an asymmetric center of known absolute
configuration.
As appreciated by those of skill in the art, halo or halogen as used herein
are
intended to include chloro, fluoro, bromo and iodo.
As used herein, "alkyl" is intended to mean linear, branched and cyclic
structures
having no double or triple bonds. Thus C1_6alkyl is defined to identify the
group as having 1, 2,
3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C1_6alkyl
specifically includes
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl
and hexyl. "Cycloalkyl"
is an alkyl, part or all of which which forms a ring of three or more atoms.
CO or COalkyl is
defined to identify the presence of a direct covalent bond.
The term "heterocycle" as used herein is intended to include the following
groups:
benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,
26

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl,
imidazolyl,
indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,
isoquinolyl, isothiazolyl,
isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl,
pyrazinyl, pyrazolyl,
pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,
quinazolinyl, quinolyl,
quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,
thiazolyl, thienyl,
triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,
piperidinyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,
dihydroimidazolyl,
dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,
dihydrooxazolyl,
dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
dihydropyrrolyl,
dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,
dihydrothienyl,
dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl,
and
tetrahydrothienyl, and N-oxides thereof.
The phrase "pharmaceutically acceptable" is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms which are, within the
scope of sound
medical judgment, suitable for use in contact with the tissues of human beings
and animals
without excessive toxicity, irritation, allergic response, or other problem or
complication,
commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives
wherein
the parent compound is modified by making acid or base salts thereof. Examples
of
pharmaceutically acceptable salts include, but are not limited to, mineral or
organic acid salts of
basic residues such as amines; alkali or organic salts of acidic residues such
as carboxylic acids;
and the like. The pharmaceutically acceptable salts include the conventional
non-toxic salts or
the quaternary ammonium salts of the parent compound formed, for example, from
non-toxic
inorganic or organic acids. For example, such conventional non-toxic salts
include those derived
from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric
and the like; and the salts prepared from organic acids such as acetic,
propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic,
hydroxymaleic,
27

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be prepared
from the parent compound which contains a basic or acidic moiety by
conventional chemical
methods. Generally, such salts can be prepared by reacting the free acid or
base forms of these
compounds with a stoichiometric amount of the appropriate base or acid in
water or in an organic
solvent, or in a mixture of the two; generally, nonaqueous media such as
ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are used. Suitable salts are found, e.g.
in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985,
p. 1418.
Exemplifying the invention is the use of the compounds disclosed in the
Examples and herein.
Specific compounds within the present invention include a compound which
selected from the group consisting of: the title compounds of the Examples;
and pharmaceutically acceptable salts thereof and individual diastereomers
thereof.
The subject compounds are useful in a method of modulating chemokine receptor
activity in a patient in need of such modulation comprising the administration
of an effective
amount of the compound.
The present invention is directed to the use of the foregoing compounds as
modulators of chemokine receptor activity. In particular, these compounds are
useful as
modulators of the chemokine receptors, in particular CCR-2.
The utility of the compounds in accordance with the present invention as
modulators of chemokine receptor activity may be demonstrated by methodology
known in the
art, such as the assay for chemokine binding as disclosed by Van Riper, et
al., J. Ex~. Med., 177,
851-856 (1993) which may be readily adapted for measurement of CCR-2 binding.
Receptor affinity in a CCR-2 binding assay was determined by measuring
inhibition of ~ZSI-MCP-1 to the endogenous CCR-2 receptor on various cell
types including
monocytes, THP-1 cells, or after heterologous expression of the cloned
receptor in eukaryotic
cells. The cells were suspended in binding buffer (50 mM HEPES, pH 7.2, 5 mM
MgCl2, 1 mM
CaCl2, and 0.50% BSA) with and added to test compound or DMSO and ~ZSI-MCP-1
at room
temperature for 1 h to allow binding. The cells were then collected on GFB
filters, washed with
25 mM HEPES buffer containing 500 mM NaCI and cell bound l2sl-MCP-1 was
quantified.
In a chemotaxis assay chemotaxis was performed using T cell depleted PBMC
isolated from venous whole or leukophoresed blood and purified by Ficoll-
Hypaque
centrifugation followed by rosetting with neuraminidase-treated sheep
erythrocytes. Once
isolated, the cells were washed with HBSS containing 0.1 mg/ml BSA and
suspended at 1x10'
28

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
cells/ml. Cells were fluorescently labeled in the dark with 2 p,M Calcien-AM
(Molecular
Probes), for 30 min at 37° C. Labeled cells were washed twice and
suspended at 5x 106 cells/ml in
RPMI 1640 with L-glutamine (without phenol red) containing 0.1 mg/ml BSA. MCP-
1
(Peprotech) at 10 ng/ml diluted in same medium or medium alone were added to
the bottom
wells (27 ~l). Monocytes (150,000 cells) were added to the topside of the
filter (30 p1) following
a 15 min preincubation with DMSO or with various concentrations of test
compound. An equal
concentration of test compound or DMSO was added to the bottom well to prevent
dilution by
diffusion. Following a 60 min incubation at 37° C, 5 °Io COZ,
the filter was removed and the
topside was washed with HBSS containing 0.1 mg/ml BSA to remove cells that had
not migrated
into the filter. Spontaneous migration (chemokinesis) was determined in the
absence of
chemoattractant
In particular, the compounds of the following examples had activity in binding
to
the CCR-2 receptor in the aforementioned assays, generally with an IC50 of
less than about 1
pM. Such a result is indicative of the intrinsic activity of the compounds in
use as modulators of
chemokine receptor activity.
Mammalian chemokine receptors provide a target for interfering with or
promoting eosinophil and/or lymphocyte function in a mammal, such as a human.
Compounds
which inhibit or promote chemokine receptor function, are particularly useful
for modulating
eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly,
compounds which
inhibit or promote chemokine receptor function would be useful in treating,
preventing,
ameliorating, controlling or reducing the risk of a wide variety of
inflammatory and
immunoregulatory disorders and diseases, allergic diseases, atopic conditions
including allergic
rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune
pathologies such as
rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one or more functions of a
mammalian chemokine receptor (e.g., a human chemokine receptor) may be
administered to
inhibit (i.e., reduce or prevent) inflammation. As a result, one or more
inflammatory processes,
such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes,
histamine) or
inflammatory mediator release, is inhibited.
In addition to primates, such as humans, a variety of other mammals can be
treated according to the method of the present invention. For instance,
mammals including, but
not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or
other bovine, ovine,
equine, canine, feline, rodent or murine species can be treated. However, the
method can also be
practiced in other species, such as avian species (e.g., chickens).
29

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Diseases and conditions associated with inflammation and infection can be
treated
using the compounds of the present invention. In one embodiment, the disease
or condition is
one in which the actions of lymphocytes are to be inhibited or promoted, in
order to modulate the
inflammatory response.
Diseases or conditions of humans or other species which can be treated with
inhibitors of chemokine receptor function, include, but are not limited to:
inflammatory or
allergic diseases and conditions, including respiratory allergic diseases such
as asthma,
particularly bronchial asthma, allergic rhinitis, hypersensitivity lung
diseases, hypersensitivity
pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic
eosinophilic
pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD)
(e.g., idiopathic
pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic
lupus erythematosus,
ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis
or
dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug
allergies (e.g., to
penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such
as rheumatoid
arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus
erythematosus, myasthenia gravis,
juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's
disease; graft
rejection (e.g., in transplantation), including allograft rejection or graft-
versus-host disease;
inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis;
spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated
psoriasis) and
inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis,
allergic contact
dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and
hypersensitivity vasculitis);
eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte
infiltration of the skin or
organs. Other diseases or conditions in which undesirable inflammatory
responses are to be
inhibited can be treated, including, but not limited to, reperfusion injury,
atherosclerosis, certain
hematologic malignancies, cytokine-induced toxicity (e.g., septic shock,
endotoxic shock),
polymyositis, dermatomyositis.
Diseases or conditions of humans or other species which can be treated with
modulators of chemokine receptor function, include, but are not limited to:
immunosuppression,
such as that in individuals with immunodeficiency syndromes such as A>DS or
other viral
infections, individuals undergoing radiation therapy, chemotherapy, therapy
for autoimmune
disease or drug therapy (e.g., corticosteroid therapy), which causes
immunosuppression;
immunosuppression due to congenital deficiency in receptor function or other
causes; and
infections diseases, such as parasitic diseases, including, but not limited to
helminth infections,
such as nematodes (round worms), (Trichuriasis, Enterobiasis, Ascariasis,
Hookworm,
Strongyloidiasis, Trichinosis, filariasis), trematodes (flukes)
(Schistosomiasis, Clonorchiasis),

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis),
visceral worms,
visceral larva migraines (e.g., Toxocara), eosinophilic gastroenteritis (e.g.,
Anisaki sp.,
Phocanema sp.), and cutaneous larva migraines (Ancylostona braziliense,
Ancylostoma
caninum). In addition, treatment of the aforementioned inflammatory, allergic
and autoimmune
diseases can also be contemplated for promoters of chemokine receptor function
if one
contemplates the delivery of sufficient compound to cause the loss of receptor
expression on
cells through the induction of chemokine receptor internalization or delivery
of compound in a
manner that results in the misdirection of the migration of cells.
The compounds of the present invention are accordingly useful in treating,
preventing, ameliorating, controlling or reducing the risk of a wide variety
of inflammatory and
immunoregulatory disorders and diseases, allergic conditions, atopic
conditions, as well as
autoimmune pathologies. In a specific embodiment, the present invention is
directed to the use
of the subject compounds for treating, preventing, ameliorating, controlling
or reducing the risk
of autoimmune diseases, such as rheumatoid arthritis or psoriatic arthritis.
In another aspect, the instant invention may be used to evaluate putative
specific
agonists or antagonists of chemokine receptors, including CCR-2. Accordingly,
the present
invention is directed to the use of these compounds in the preparation and
execution of screening
assays for compounds that modulate the activity of chemokine receptors. For
example, the
compounds of this invention are useful for isolating receptor mutants, which
are excellent
screening tools for more potent compounds. Furthermore, the compounds of this
invention are
useful in establishing or determining the binding site of other compounds to
chemokine
receptors, e.g., by competitive inhibition. The compounds of the instant
invention are also useful
for the evaluation of putative specific modulators of the chemokine receptors,
including CCR-2.
As appreciated in the art, thorough evaluation of specific agonists and
antagonists of the above
chemokine receptors has been hampered by the lack of availability of non-
peptidyl
(metabolically resistant) compounds with high binding affinity for these
receptors. Thus the
compounds of this invention are commercial products to be sold for these
purposes.
The present invention is further directed to a method for the manufacture of a
medicament for modulating chemokine receptor activity in humans and animals
comprising
combining a compound of the present invention with a pharmaceutical carrier or
diluent.
The present invention is further directed to the use of the present compounds
in
treating, preventing, ameliorating, controlling or reducing the risk of
infection by a retrovirus, in
particular, herpes virus or the human immunodeficiency virus (HIV) and the
treatment of, and
delaying of the onset of consequent pathological conditions such as AIDS.
Treating AIDS or
preventing or treating infection by HIV is defined as including, but not
limited to, treating a wide
31

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
range of states.of HIV infection: A>DS, ARC (AmS related complex), both
symptomatic and
asymptomatic, and actual or potential exposure to HIV. For example, the
compounds of this
invention are useful in treating infection by HIV after suspected past
exposure to HIV by, e.g.,
blood transfusion, organ transplant, exchange of body fluids, bites,
accidental needle stick, or
exposure to patient blood during surgery.
In an aspect of the present invention, a subject compound may be used in a
method of inhibiting the binding of a chemokine to a chemokine receptor, such
as CCR-2, of a
target cell, which comprises contacting the target cell with an amount of the
compound which is
effective at inhibiting the binding of the chemokine to the chemokine
receptor.
The subject treated in the methods above is a mammal, for instance a human
being, male or female, in whom modulation of chemokine receptor activity is
desired.
"Modulation" as used herein is intended to encompass antagonism, agonism,
partial antagonism,
inverse agonism and/or partial agonism. In an aspect of the present invention,
modulation refers
to antagonism of chemokine receptor activity. The term "therapeutically
effective amount"
means the amount of the subject compound that will elicit the biological or
medical response of a
tissue, system, animal or human that is being sought by the researcher,
veterinarian, medical
doctor or other clinician.
The term "composition" as used herein is intended to encompass a product
comprising the specified ingredients in the specified amounts, as well as any
product which
results, directly or indirectly, from combination of the specified ingredients
in the specified
amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or
excipient must be
compatible with the other ingredients of the formulation and not deleterious
to the recipient
thereof.
The terms "administration off' and or "administering a" compound should be
understood to mean providing a compound of the invention to the individual in
need of
treatment.
As used herein, the term "treatment" refers both to the treatment and to the
prevention or prophylactic therapy of the aforementioned conditions.
The term ""substituted" in reference to substitution on alkyl, cycloalkyl,
phenyl,
heterocycle, or some other chemical group is intended to include mono- and
poly-substitution by
a named substituent to the extent such single and multiple substitution is
chemically allowed in
any of the named chemical groups.
It is understood that the definition of a substituent at a particular location
in a
molecule is independent of its definition at other locations in the molecule.
Thus, for example,
when R3 = alkyl substituted with 1-5 of R12 (defined elsewhere), each R12 is
independently
32

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
selected from the possible values thereof; i.e., each R12 can be the same as
or different from any
other R 12.
The term "optionally substituted" is intended to include both substituted and
unsubstituted. Thus, for example, optionally substituted aryl could represent
a pentafluorophenyl
or a phenyl ring.
Combined therapy to modulate chemokine receptor activity for thereby treating,
preventing, ameliorating, controlling or reducing the risk of inflammatory and
immunoregulatory
disorders and diseases, including asthma and allergic diseases, as well as
autoimmune
pathologies such as rheumatoid arthritis and atherosclerosis, and those
pathologies noted above
is illustrated by the combination of the compounds of this invention and other
compounds which
are known for such utilities.
For example, in treating, preventing, ameliorating, controlling or reducing
the risk
of inflammation, the present compounds may be used in conjunction with an
antiinflammatory
or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such
as an inhibitor of 5-
lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2
inhibitor, an interleukin
inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an
inhibitor of nitric oxide or
an inhibitor of the synthesis of nitric oxide, a non-steroidal
antiinflammatory agent, or a
cytokine-suppressing antiinflammatory agent, for example with a compound such
as
acetaminophen, aspirin, codeine, embrel, fentanyl, ibuprofen, indomethacin,
ketorolac,
morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,
sunlindac, tenidap,
and the like. Similarly, the instant compounds may be administered with a pain
reliever; a
potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or
magnesium hydroxide;
a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,
oxymetazoline,
ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-
ephedrine; an
antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or
dextramethorphan; a
diuretic; and a sedating or non-sedating antihistamine.
Likewise, compounds of the present invention may be used in combination with
other drugs that are used in the treatment/prevention/suppression or
amelioration of the diseases
or conditions for which compounds of the present invention are useful. Such
other drugs may be
administered, by a route and in an amount commonly used therefor,
contemporaneously or
sequentially with a compound of the present invention. When a compound of the
present
invention is used contemporaneously with one or more other drugs, a
pharmaceutical
composition containing such other drugs in addition to the compound of the
present invention is
typically employed. Accordingly, the pharmaceutical compositions of the
present invention
33

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
include those that also contain one or more other active ingredients, in
addition to a compound of
the present invention.
Examples of other active ingredients that may be combined with a compound of
the present invention, either administered separately or in the same
pharmaceutical compositions,
include, but are not limited to: (a) VLA-4 antagonists such as those described
in US 5,510,332,
W095/15973, W096/01644, W096/06108, W096/20216, W096/22966, W096/31206,
W096/40781, W097/03094, W097/02289, WO 98/42656, W098/53814, W098/53817,
W098/53818, W098/54207, and W098/58902; (b) steroids such as beclomethasone,
methylprednisolone, betamethasone, prednisone, dexamethasone, and
hydrocortisone; (c)
immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506
type
immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as
bromopheniramine,
chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,
diphenhydramine,
diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine,
trimeprazine,
azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,
terfenadine,
loratadine, desloratadine, cetirizine, fexofenadine, descarboethoxyloratadine,
and the like; (e)
non-steroidal anti-asthmatics such as (32-agonists (terbutaline,
metaproterenol, fenoterol,
isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn
sodium, atropine,
ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast,
pranlukast, iralukast,
pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-
1005); (f) non-
steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives
(alminoprofen,
benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,
flurbiprofen, ibuprofen,
indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,
pranoprofen, suprofen,
tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin,
acemetacin, alclofenac,
clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,
ibufenac, isoxepac,
oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic
acid derivatives
(flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and
tolfenamic acid),
biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams
(isoxicam, piroxicam,
sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine)
and the pyrazolones
(apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone,
phenylbutazone); (g)
cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type
IV (PDE-IV); (i)
other antagonists of the chemokine receptors, especially CCR-1, CCR-2, CCR-3,
CXCR-3 and
CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors
(lovastatin,
simvastatin and pravastatin, fluvastatin, atorvastatin, rosuvastatin, and
other statins), sequestrants
(cholestyramine and colestipol), cholesterol absorption inhibitors
(ezetimibe), nicotinic acid,
fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and
benzafibrate), and probucol;
34

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(k) anti-diabetic agents such as insulin, sulfonylureas, biguanides
(metformin), a-glucosidase
inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (1)
preparations of interferon
beta (interferon beta-la, interferon beta-1(3); (m) other compounds such as 5-
aminosalicylic acid
and prodrugs thereof, antimetabolites such as azathioprine and 6-
mercaptopurine, and cytotoxic
cancer chemotherapeutic agents.
The weight ratio of the compound of the present invention to the second active
ingredient may be varied and will depend upon the effective dose of each
ingredient. Generally,
an effective dose of each will be used. Thus, for example, when a compound of
the present
invention is combined with an NSA)D the weight ratio of the compound of the
present invention
to the NSA>D will generally range from about 1000:1 to about 1:1000, or from
about 200:1 to
about 1:200. Combinations of a compound of the present invention and other
active ingredients
will generally also be within the aforementioned range, but in each case, an
effective dose of
each active ingredient should be used.
In such combinations the compound of the present invention and other active
agents may be administered separately or in conjunction. In addition, the
administration of one
element may be prior to, concurrent to, or subsequent to the administration of
other agent(s).
The compounds of the present invention may be administered by oral, parenteral
(e.g., intramuscular, intraperitoneal,-intravenous, ICV, intracisternal
injection or infusion,
subcutaneous injection, or implant), by inhalation spray, nasal, vaginal,
rectal, sublingual, or
topical routes of administration and may be formulated, alone or together, in
suitable dosage unit
formulations containing conventional non-toxic pharmaceutically acceptable
carriers, adjuvants
and vehicles appropriate for each route of administration. In addition to the
treatment of warm-
blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats,
monkeys, etc., the
compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of
this
invention may conveniently be presented in dosage unit form and may be
prepared by any of the
methods well known in the art of pharmacy. All methods include the step of
bringing the active
ingredient into association with the carrier which constitutes one or more
accessory ingredients.
In general, the pharmaceutical compositions are prepared by uniformly and
intimately bringing
the active ingredient into association with a liquid Garner or a finely
divided solid carrier or both,
and then, if necessary, shaping the product into the desired formulation. In
the pharmaceutical
composition the active object compound is included in an amount sufficient to
produce the
desired effect upon the process or condition of diseases. As used herein, the
term "composition"
is intended to encompass a product comprising the specified ingredients in the
specified

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
amounts, as well as any product which results, directly or indirectly, from
combination of the
specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a
form suitable for oral use, for example, as tablets, troches, lozenges,
aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules, or syrups
or elixirs.
Compositions intended for oral use may be prepared according to any method
known to the art
for the manufacture of pharmaceutical compositions and such compositions may
contain one or
more agents selected from the group consisting of sweetening agents, flavoring
agents, coloring
agents and preserving agents in order to provide pharmaceutically elegant and
palatable
preparations. Tablets contain the active ingredient in admixture with non-
toxic pharmaceutically
acceptable excipients which are suitable for the manufacture of tablets. These
excipients may be
for example, inert diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating agents, for
example, corn starch,
or alginic acid; binding agents, for example starch, gelatin or acacia, and
lubricating agents, for
example magnesium stearate, stearic acid or talc. The tablets may be uncoated
or they may be
coated by known techniques to delay disintegration and absorption in the
gastrointestinal tract
and thereby provide a sustained action over a longer period. For example, a
time delay material
such as glyceryl monostearate or glyceryl distearate may be employed. They may
also be coated
by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and
4,265,874 to form
osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules
wherein
the active ingredient is mixed with an inert solid diluent, for example,
calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed
with water or an oil medium, for example peanut oil, liquid paraffin, or olive
oil.
Aqueous suspensions contain the active materials in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such excipients are
suspending agents, for
example sodium carboxymethylcellulose, methylcellulose, hydroxy-
propylmethylcellulose,
sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting
agents may be a naturally-occurring phosphatide, for example lecithin, or
condensation products
of an alkylene oxide with fatty acids, for example polyoxyethylene stearate,
or condensation
products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethylene-
oxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions may also contain one
or more
36

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more
coloring agents,
one or more flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin:
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil,
or in a mineral oil such
as liquid paraffin. The oily suspensions may contain a thickening agent, for
example beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring
agents may be added to provide a palatable oral preparation. These
compositions may be
preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in admixture
with a dispersing
or wetting agent, suspending agent and one or more preservatives. Suitable
dispersing or wetting
agents and suspending agents are exemplified by those already mentioned above.
Additional
excipients, for example sweetening, flavoring and coloring agents, may also be
present.
The pharmaceutical compositions of the invention may also be in the form of
oil-
in-water emulsions. The oily phase may be a vegetable oil, for example olive
oil or arachis oil,
or a mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents
may be naturally- occurring gums, for example gum acacia or gum tragacanth,
naturally-
occurnng phosphatides, for example soy bean, lecithin, and esters or partial
esters derived from
fatty acids and hexitol anhydrides, for example sorbitan monooleate, and
condensation products
of the said partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also
contain a demulcent,
a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable
aqueous or oleagenous suspension. This suspension may be formulated according
to the known
art using those suitable dispersing or wetting agents and suspending agents
which have been
mentioned above. The sterile injectable preparation may also be a sterile
injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in
1,3-butane diol. Among the acceptable vehicles and solvents that may be
employed are water,
Ringer's solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils are
conventionally employed as a solvent or suspending medium. For this purpose
any bland fixed
oil may be employed including synthetic mono- or diglycerides. In addition,
fatty acids such as
oleic acid find use in the preparation of injectables.
37

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The compounds of the present invention may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be
prepared by
mixing the drug with a suitable non-irritating excipient which is solid at
ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the rectum to
release the drug.
Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc.,
containing the compounds of the present invention are employed. (For purposes
of this
application, topical application shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further
comprise other therapeutically active compounds as noted herein which are
usually applied in the
treatment of the above mentioned pathological conditions.
In treating, preventing, ameliorating, controlling or reducing the risk of
conditions which require chemokine receptor modulation an appropriate dosage
level will
generally be about 0.01 to 500 mg per kg patient body weight per day which can
be administered
in single or multiple doses. The dosage level will be about 0.1 to about 250
mg/kg per day; or
about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about
0.01 to 250 mg/kg
per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day.
Within this range
the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral
administration, the
compositions may be provided in the form of tablets containing 1.0 to 1000
milligrams of the
active ingredient, 2.0 to 500, 3.0 to 200, or 1, 5, 10, 15, 20, 25, 30, 50,
75, 100, 125, 150, 175,
200, 250, 300, 400, 500, 600, 750, 800, 900 and/or 1000 milligrams of the
active ingredient for
the symptomatic adjustment of the dosage to the patient to be treated. The
compounds may be
administered on a regimen of 1 to 4 times per day, preferably once or twice
per day.
It will be understood, however, that the specific dose level and frequency of
dosage for any particular patient may be varied and will depend upon a variety
of factors
including the activity of the specific compound employed, the metabolic
stability and length of
action of that compound, the age, body weight, general health, sex, diet, mode
and time of
administration, rate of excretion, drug combination, the severity of the
particular condition, and
the host undergoing therapy.
Several methods for preparing the compounds of this invention are illustrated
in
the following Schemes and Examples. Starting materials are commercially
available, made by
known procedures, or prepared as illustrated herein.
38

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
One of the principal routes used for preparation of compounds within the scope
of
the instant invention which bear a 1,1,3-trisubstituted cyclopentane framework
1-5 is depicted in
Scheme 1. According to this route, keto acids 1-1 (preparation described in
Schemes 2A, 2B, 2C,
and 2D) is coupled to amines 1-2 (preparation described in Schemes 3A-G). This
can be
accomplished in various ways, including by first converting the acid to its
acid chloride with a
reagent such as oxalyl chloride, and then combining with amine 1-2 in the
presence of a base
such as triethylamine. Reductive amination of 1-3 with an amine 1-4 using, for
example,
NaB(OAc)3H or NaBH3CN as the reducing agent gives chemokine receptor
modulators 1-5. The
compounds 1-9, which can be synthesized according to the chemistry described
in Scheme 1
represent stereoisomeric mixtures (Eliel, E. E., Wilen, S. H., Stereochemistry
of Organic
Compounds, John Wiley & Sons, Inc., New York). In particular, compounds 1-5
are often
obtained as a mixture of cis and trans isomers. When 1-1 is a single
stereoisomer (1-la) only 2
possible isomers of 1-5 can result (cis and traps); these can be separated by
a variety of methods,
including by preparative TLC, flash chromatography, MPLC, or by HPLC using a
column with a
chiral stationary phase. When 1-1 is racemic, a total of 4 possible isomers of
1-5 can be
obtained. Again, these may be separated by HPLC using a column with a chiral
stationary phase,
or by a combination of the methods above. The synthesis of racemic 1-1 is
detailed in Scheme
2A, while syntheses of the chiral 1-la are described in Schemes 2B and 2C.
Furthermore, compounds 1-5 can themselves be modified to give new chemokine
receptor
modulators 1-5.1. For example, an ester functional group within a compound 1-5
can be
hydrolyzed to the corresponding carboxylic acid, which also can be a chemokine
receptor
modulator.
SCHEME 1
39

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O Rs
O 1 ) oxalyl chloride O Rs
N
O , O~H. 2) Rs s R~ I ~ a
Y R
1-1 'R HN I \ R , Et3N R2 R3
Y~R4 '1-3
i
R2 R3 1-2
O Rs ~ R
O N I ~ Rs 8 R NaB(OAc)3H
i + R X
R Y~R4 Rio~NH
1-3 R2 R3
1-4
Rs
R3
R4-x~ ~ O R6 5 Further modifications
Rs ~N N ~ R 1-5.1
R~ ~ ~ such as ester hydrolysis,
~Y R4 etc.
1-5 R2 Rs
As depicted in Scheme 1A, the keto-ester 1-6 could be reductively aminated
with
amine 1-4 to form the amino ester 1-7 under a variety of conditions, including
sodium
triacetoxyborohydride or sodium cyanoborohydride. Alkylation of the ester 1-7
with an
alkylating agent such as an alkyl chloride, bromide or iodide in the presence
of an appropriate
base such as lithium bis(trimethylsilyl)amide, affords the intermediate esters
1-8. These esters
formed in the above mentioned transformations represent in general a mixture
of 1,3-cis- and
1,3-traps- diastereoisomers, which could be separated into respective
diastereoisomeric pairs
using column chromatography. A similar diastereoisomeric separation could be
also
accomplished later, after the esters 1-8 were hydrolytically cleaved to yield
the respective acids
1-9. This hydrolysis was readily accomplished under usual conditions,
including lithium, sodium
or potassium hydroxide, at ambient to elevated temperatures, depending on the
nature of the ester
group and substituent R~. These diastereoisomers could be separated by
crystallization from a
variety of solvents, taking advantage of the finding, that the cis-
diastereoisomeric acids are less
soluble, when compared to their traps- epimers.

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The compounds of formula 1-5 are then formed from the acids 1-9 and
tetrahydroisoquinoline derivatives 1-2 under standard amide-bond forming
reaction conditions,
including carbodiimide reagents, such as DCC, EDC and catalysts such as DMAP,
HOAT or
HOBT.
SCHEME 1A
Rs
O O .R'8 lHJ R8 X~ 01 O
O ~N .Ria
H 1 _4 R'° _~O
\H
1-6 1-7
~ Rs ~ Rs
R~0_1 O
R8 X~ 0 i O RB;X 1-2
~1~N/ .R'8 ~ io N
Rio ~O R ~ ~OH
R
1_8 1_9
Rs
Rs X 1 V n O Rs
~N~ Rs
R
R1o n 1 N
X R4
1-5 R2 R3
Intermediate 1-3 can also be resolved by Chiral HPLC to give 1-3a and 1-3b
(Scheme 1B). This
then would give cis/trans isomers 1-Sa and 1-Sb.
SCHEME 1B
41

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
s
O Rs O R
s Chiral Resolution
p N ~ R ~ O \ Rs
~N I ' ~ +1-3b
Y R Y~Ra
R2 R3 1-3a R2 Rs
1-3
3
R NaB(OAc)3H R X O R
~ ~R'(~ 4 R ~~
1-3a + Rs X~ ~ ~ Rs~N N ( ~ Rs ~ 1-5.1
R~o NH ~
Y- _R4
1-4 1-5a R2 R3
One of the principal routes used for preparation of Intermediate 1-1 and
Intermediate 1-6 is
outlined in Scheme 2A. According to this route, 3-oxocyclopentanecarboxylic
acid (2-1), which
can be synthesized following a known procedure (Stetter, H., Kuhlman, H.,
Liebigs Ann. Chim.,
1979, 944) is esterified under standard conditions. When Rt8 represents a tert-
Butyl group, the
respective ester 1-6 can be prepared by reacting the appropriate alcohol, in
this case tert-butanol,
with acid 2-1 in the presence of sulfuric acid. Protection of the oxo-group in
2-1 can be achieved
by a number of ways (Greene, T., Wuts, P. G. M., Protective Groups in Organic
Chemistry, John
Wiley & Sons, Inc., New York, NY 1991). The particularly suitable dimethyl
acetal protecting
group can be introduced using trimethyl orthoformate as a reagent in a
suitable solvent such as
dichloromethane and methyl alcohol in the presence of an acidic catalyst.
Alternatively, in the
case of Rts being a methyl group, the acid 2-1 can be converted to 2-3
directly by using trimethyl
orthoformate and an acidic catalyst, such as para-toluenesulfonic acid. An
alkylation of esters 2-
3 with an alkylating agent such as an alkyl chloride, bromide or iodide in the
presence of an
appropriate base such as lithium diisopropylamide, produces intermediates 2-4.
The ester
protecting group present in 2-4 can be removed in a number of ways, depending
on the nature of
the ester. Methyl esters (Rt$ = methyl) can be hydrolyzed in the presence of
an acid or base at
ambient or elevated temperatures, whereas tert-butyl esters (Rt$= tert-butyl)
can be easily
cleaved under acidic conditions. Under these conditions, the dimethyl acetal
is simultaneously
deprotected to give 1-1.
SCHEME 2A
42

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O O
O O~H R~s-OH O R's TMOF_
H H pTSA
2_1 acid 1-6
p p O.R~s R'-X, -p p O,R~s H--...
V 'H LDA ~O Ri
2-3 2-4
O
0~~~~0~ H
~\R'
1-1
Intermediate 1-1 can be prepared as a single stereoisomer (1-la) in various
ways
including those depicted in Schemes 2B and 2C. According to Scheme 2B, racemic
1-1 can be
converted to its benzyl ester. There are many ways to effect this
esterification, one of which
being by a sequence involving conversion to the corresponding acid chloride
with, for example
oxalyl chloride, followed by treatment with benzyl alcohol in the presence of
a base such as
triethylamine. Then the racemic benzyl ester 2-5 can be separated by chiral
preparative HPLC to
give 2-5a as a single stereoisomer. Removal of the benzyl group to give the
chiral ketoacid 1-la
can be accomplished in several ways. One convenient way is by hydrogenolysis
in the presence
of a catalyst such as PdIC.
SCHEME 2B
O O H 1 ) oxalyl chloride O chiral
O~ ---~ O , Bn
2) BnOH, Et3N R1 O HPLC
1-1 2-5
p H2, Pd/C p
O O, Bn ---. O O. H
:R 1 :R 1
2-5a 1-1 a
43

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
According to Scheme 2C, chiral ketoacid intermediate 1-la can be prepared
starting from
commercially available optically pure amino acid 2-6. Protection of the
carboxylic acid group
can be achieved in a variety of ways. When R'8 is methyl, esterification can
be accomplished by
treatment with methanol in the presence of an acid catalyst such as HCI.
Treatment with BoczO
results in protection of the amine group of 2-7. Stereoselective alkylation of
ester 2-8 with an
alkylating agent such as an alkyl chloride, bromide or iodide in the presence
of an appropriate
base such as lithium bis(trimethylsilyl)amide, produces intermediates 2-9.
Hydrogenation in the
presence of a catalyst such as Pd/C affords 2-10. Hydrolysis of the ester to
give 2-11 can be
achieved under standard conditions depending on the R1$ group. For example,
when R~g is
methyl (methyl ester), hydrolysis can be accomplished by treatment with a base
such as sodium
hydroxide, lithium hydroxide, or potassium hydroxide, with or without heating.
The Boc
protecting group can be removed under standard acidic conditions, such as with
HCl in a solvent
such as dioxane, or with TFA. Oxidation of 2-12 to give 1-la (as a single
stereoisomer if
constituent R' is achiral, or as a mixture of stereoisomers if constituent R1
has a chiral center)
can be achieved in several ways, including by treatment with NBS, followed by
treatment with
sodium methoxide.
SCHEME 2C
44

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
N O R~80H O Rya
HZ OH ---~ H2N O' -
H+ Boc20
2_6 O 2_7 O
Ria
BocHN O~R18-~ BocHN
LiHMDS; RX R1
2-8 O 2-9 O
H2 BocHN O~R1$ BocHN OH
~' W -~' ~ 1
R OH- R
2-10 2-11
O O
HCI
--~ H2N OH ~ O OH
R1 R'
2-12 1-1a
The enolate generated from ester 2-3 (R'8 being a benzyl or tert-Butyl group)
in the presence of a
strong base such as lithium diisopropylamide can be reacted with aldehydes
(R'aCHO) or ketones
(R~aRZaCO) to produce the appropriate hydroxyalkyl substituted intermediates 2-
4.1 as indicated
in Scheme 2D. The resulting hydroxy group can be protected in various ways,
including by
treatment with acetic anhydride in the presence of a base such as
triethylamine to give
intermediates 2-4.2. Once again the ester protecting group is removed under
conditions suitable
for the particular protecting group. In the case of the tert-butyl esters (RI8
is t-butyl), deprotection
is achieved under acidic conditions. The latter usually induces cleavage of
the acetal protecting
group as well, and the keto acids 1-1.1 can be prepared this way in an one-pot
procedure. Their
conversion to the final modulators of chemokine activity 1-9 can be achieved
as described
previously, with minor modifications to accommodate the protected hydroxy in 1-
1.1.
SCHEME 2D

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
-O O O~Ria RIaCHO, or \ O O~Ris Ac20
\O H R~aR2aC0 O U~R2a Et N
/LDA Rya/ 'OH
2-3
2-4.1
_O O O/R1$ H+ O O
,H
w
\O ' R2a R2a
Rya OAC Rya OAC
2-4.2
1-1.1
Amines 1-2 can be prepared in several ways as shown in schemes 3A-3G. The 5-
aza-
tetrahydroisoquinoline fragment can be prepared in accordance to the
literature methods of
MarCoux, J-F. et al. (J. Chem. Lett., 2000, 2 (15), 2339-2341). Alternatively,
it can be prepared
as outlined in Scheme 3A. Compound 3-1, normally obtained from commercial
sources, is
brominated (Br2, AcOH) to give 3-2. Metal halogen exchange (NaH, t-butyl
lithium) followed
by treatment with DMF provides aldehyde 3-3. Conversion of the aldehyde group
to a nitrite can
be achieved with sodium formate, hydroxylamine hydrochloride and formic acid.
The resulting
nitrite 3-4 can be treated with phosphorous oxychloride to give 2-
chloropyridine 3-5.
Displacement of the chloro group can be achieved with the sodium salt of a
dialkylmalonate.
Reduction of the nitrite group of 3-6 with hydrogen and Raney Ni catalyst is
accompanied by
cyclization to afford compound 3-7. Decarboxylation can be achieved in a
variety of ways
depending on the ester. In the case represented in Scheme 3A, the t-butyl
ester was
decarboxylated with TFA to give 3-8. Reduction (BH3), followed by protection
of the resulting
amine using Boc20, gives 3-9, which can be conveniently purified. Removal of
the Boc
protecting group to give 1-2a can be achieved in various ways, including by
treatment with
anhydrous HCl in dioxane or some other solvent.
SCHEME 3A
46

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
5 5
\ R Br2 Br \ R NaH, t-BuLi; OHC \ R
AcOH ( ~ DMF
HO N HO N HO N
3-1 3-2 3-3
5
Na02CH, HONH2 NC \ R5 POC13 NC ~ \ R
HC02H ~ N CI NJ
HO
3-4 3-5
Me02C NaH NC R5 R5
C02tBu I \ Ra~ HN
Me02C NJ O NJ
H
C02tBu 3-6 2 C02tBu
TFA R5 1 ) BH3 R5
.. HN ~ \~ BOCN \
O N 2) Boc20
N
3_8 3_9
HCI R5
H N I \~ .
N
1-2a
Compounds of the type 1-2a could also be prepared according to Scheme 3B.
Commercially available 3-10 can be methylated with methyl iodide in the
presence of a base
such as K2C03 to give 3-11. Cycloaddition with a protected piperidinone in the
presence of NH3
5 in methanol furnishes 5-azatetrahydroiso-quinoline 3-12
(R'°°can be various protecting groups
such as benzyl or benzoyl). Hydrogenation of the vitro group of compound 3-12
with hydrogen
and a catalyst such as PdIC gives 3-13. Diazonium salt formation followed by
warming with
sulfuric acid provides 5-aza-7-hydroxytetrahydroisoquinoline 3-14. Removal of
the protecting
group R'°~ is achieved in different ways depending upon the nature of
R~°'. If R'°° is benzyl,
hydrogenation in the presence of HCl and a catalyst such as Pd/C can be
applied. If R1°° is
benzoyl, hydrolysis can be achieved by heating in concentrated HCl solution.
Installation of a
Boc protecting group on to 3-15 can be easily achieved with BoczO to give 3-
16. Various Rloa
47

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
can then be incorporated generating ethers (see Scheme 3C). The Boc protecting
group on the
resulting compounds 3-17 can finally be removed with HCl or TFA to give 1-2b.
Alternatively,
Compound 3-14 itself can be converted to ethers (according to Scheme 3C). The
resulting ether
3-18 can be converted to compound 3-19 by removal of Rlo~ as described above.
SCHEME 3B
02N ~ N02 Mel 02N I ~ N02 NH~/MeOH
I, o
N OH K2C03 i O
loc~N~
3-10 3-~ ~ R
10c 10c
R ~N ~ N02 H2, Pd/C R ~N I ~ NH2 NaN02, H2S04
I ---
NJ N
3-12 3-13
R1° ~N I ~ OH - Rloc HN I ~ OH Boc20 gOCN ~ OH
N~ ~ I NJ
N
3-16
3-14 3-15
Scheme 3C Scheme 3C
RlOc\ ~, 10d
N I ~ ~ HN I ~ O~Rlod gOCN I ~ O~Rlod
10c i ~ ~
N - R NJ HCI v 'NJ
3-18 1-2b 3-17
The 5-aza-7-hydroxytetrahydroisoquinolines 3-14 and 3-16 in Scheme 3B can be
converted to various ethers (see Scheme 3C). Alkyl ethers can be generated
from an alkyl halide
and a base (such as KZC03, NaOH, or NaH) giving compounds 3-19 and 3-22. A
trifluoromethyl
ether can be prepared by initial methyl xanthate formation (NaH, CSz; MeI),
followed by
sequential treatment with 1,3-dibromo-5,5-dimethylhydantoin (or NBS) and
HF/pyridine solution
giving 3-20. Aryl ethers can be prepared by a number of methods, including
reaction of
48

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
arylboronic acids in the presence of copper (II) acetate and triethylamine, to
give compounds 3-
21.
SCHEME 3C
OH
CHCIF2, KZC03 PN~\J%~ R24_X NaOH or NaH
OCF2H ~ ' JAN ~ ~ O roe
PN I ~ 3-16: P = Boc PN~\V%~ ~R
3-14: P = R2°
3-19 1 ) NaH; CS2; Mel ~ ~ ArB(OH)2 3-22
2) NBS; HF/pyridine Cu0Ac2, Et3N
PN I ~ OCF3 PN ~ ~ O~Ar
N
N
g_2p 3-21
Compounds 1-2c where RS is a halide (IVc) can be prepared according to Scheme
3D. Compound 3-13 can be converted to the halide 3-22 according to classical
procedures via
the diazonium salt. Alternatively the known cycloaddition reaction to a
suitably protected
piperidinone can be applied. Removal of the protecting group R1°' can
be achieved as described
previously.
SCHEME 3D
49

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
Rtof~N ~ NH2 R~of~N ~ Halide
N
HBr, CuBr,
N NaN02 N R
3-13 3-22 Halide
Halide = Br or CI Me2N ~ , NMe2
-R 10f
HCI or NaOH
HN ~ Halide
iJ
N
1-2c
Halide = Br or CI
Furthermore, after incorporation into advanced intermediates, fragments 1-2c
can
be further modified so as to prepared 7-aryl-5-azotetrahydroisoquinoline
containing analogs._
This can be accomplished by coupling of the 5-aza-7-halotetrahydroisoquinoline
intermediates to
aryl boronic acids (or aryl stannanes), mediated by transition metal catalysts
such as Pd(OAc)2.
The preparation of tetrahydroisoquinoline amine components is outlined in
Schemes 3E-3G. The tetrahydroisoquinolines incorporated into the amide portion
of 1-5 often
contain one or two substituted groups on various positions. Most of these are
not available
commercially, however, can be obtained through synthesis, representative
examples of which are
shown in Schemes 3F and 3G.
An example of a synthesis of the simple tetrahydroisoquinoline (1-2d) is
depicted
in Scheme 3E. According to this, the commercially available 4-trifluoromethyl
phenylacetonitrile (3-23) is converted to the corresponding amine (3-24) using
hydrogenation in
the presence of Ra-Ni, and trifluoroacetic anhydride is then used to cap the
amine. The resultant
amide (3-25) is treated with formaldehyde in the presence of sulfuric acid to
give the cyclic
compound (3-26) which is further converted into tetrahydroisoquinoline (1-2d).
SCHEME 3E

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
CF3
NC \ I CF3 H2 NH2 / I CF3 TFAA O~NH , CF3
3-23 3-24 3-25
CF3
CHzp O~N , I CF~ HN / CF3
a . H SO l~ %~ H-
q O
2 4
3-26 1-2d
Many 5-substituted atetrahydroisoquinolines can also be prepared based on 3-26
(Scheme 3F). Iodonization on the 5-position yields intermediate 3-28. After
conversion to the
cyano compound (3-29) under palladium (0) catalyzed conditions, the amide is
cleaved to the
amine 3-30 which can be converted into amino ester 1-2ein high yield by a two
step sequence.
The iodo compound 3-28 can also be converted to other compounds as shown in
the
experimental section. Modification of these substituents can also be made
after the assembly of
the final framework (1-5) to make new chemokine modulators of the form 1-5.1
(see Scheme 1).
An example of this would be the hydrolysis of a methyl ester (from 1-2e) to
make the
corresponding carboxylic acid (see examples).
S~'.HF:MF '~F
CF3 CF3 CF3
CF3
O~N ~ CF3 NIS O~N / CFs Zn(CN)2 O~N
---.
TFA ~ I Pd(0)
3-26 3-28 I 3-29 CN
OH- HN i I CF3 ~ ) aq. H+ HN ~ I CF3
2) MeOH/AcCI
3-30 CN 1-2e COOMe
Heterocyclic 7-substituted tetrahydroisoquinolines could be obtained by
utilizing
commercially available tetrahydroisoquinoline. As described is Scheme 3G,
tetrahydroisoquinoline (3-32) is nitrated by treatment with potassium nitrate
in the presences of
concentrated sulfuric acid. The 7-nitro-tetrahydroisoquinoline 3-33 is treated
with trifluoroacetic
anhydride to protect the amine and the resulting amide then hydrogenated with
10% palladium
on carbon under hydrogen at 50 psi pressure to afford the aniline derivative 3-
34. Base hydrolysis
yields a 7-amino substituted tetrahydroisoquinoline (3-35) which could be used
in the synthesis
51

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
of further CCR2 antagonist or other tetrahydroisoquinoline derivatives.
Protection of 3-35 with
benzylchloroformate in the presence of an organic base such as triethylamine
or diisopropylethyl
amine affords the carbamate 3-37. This intermediate could be utilized to make
the tetrazole and
substituted tetrazoles such as 1-2g. Intermediate 3-37 is treated with
trifluoroacetic anhydride to
form the trifluoroacetyl protected amide which then is converted to the
trifluoromethyl
substituted tetrazole by sequential reactions with triphenylphosphine heated
to reflux for 15
hours followed by sodium azide in DMF at room temperature. Hydrogenation with
10%
palladium on carbon under hydrogen atmosphere affords the heterocyclic
substituted
tetrahydroisoquinoline 1-2g.
Alternatively 3-34 can be directly derivatized as shown to the triazole 3-36
with
N,N-dimethylforamide azine in the presences of a catalytic amount of an acid
such as toluene
sulfonic acid heated to reflux for 24 to 48 hours. Basic hydrolysis of this
intermediate gives
amine component 1-2f.
SCHEME 3G
52

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
HN / I KNOB HN / I N02 TFAA 1 Q% Pd/C
\ EtOH
H SO ~~~~ i H
2 4 5Q pS , 2
3-32 3-33
C F3
O~N / NH2 HN / NH2
\ ~ ' \ ~
OH
3-34 3-35
N-N Benzylchloro
~NJ~ I~N~ formate, base
P-TSA 1
CF3 rN I \ O~N / I NH2
O~N / NON
3-37
3-36 ~ 1. TFAA
2. PPh3
OH- 3. NaN3
O N =N
ANN \ O~N / N ,'N
HN / I I / \ I ~CF3
3-38
1-2f ~ Q% Pd/C
H2
N =N
HN / N~N
\ ~ CF3
1-2g
Additional examples of tetrhydroisoquinolines incorporated into the amide
portion of compounds within the scope of the instant invention, as well as
their syntheses are
further described in the Experimental section.
Amines 1-4 were obtained from various sources. Most were commercially
available, some were known from the literature and could be prepared according
to published
procedures, and some were prepared as described herein. Since their structures
and the methods
for their preparation are diverse, only two schemes will be outlined in this
section; individual
syntheses of amines 1-4 can be found in the Experimental Section. Scheme 4A
shows one
53

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
method for the synthesis of 4-aryl substituted piperidines. Enol triflate 4-1
(prepared according
to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995.) could be coupled
to boronic acids 4-
2 as described by Wustrow and Wise. Hydrogenation of the olefin in 4-3 could
be achieved
using hydrogen in the presence of a catalyst such as Pd(OH)2/C. Removal of the
Boc protecting
group could be achieved using standard acidic conditions, such as HCl in
dioxane or TFA/DCM
to afford piperidine 1-4.1.
SCHEME 4A
Rig
OTf ~s
Pd(PPh3)4 ~ H2, Pd/C
N LiCI, Na2C03
Boc B(OH)2 NJ
Boc
4 1 4-2 4-3
Rig R~s R1~
NJ N J HCI
Boc H
4-4 1-4.1
Another example of the synthesis of amine 1-4 is shown in Scheme 4B.
Commercially available alcohol (4-5) is first sulfonylated with
methanesulfonyl chloride to give
intermediate 4-6 which can be directly substituted with tetrazole to give
heteroaryl piperidine 4-
7. Removal of the Boc protecting group under the standard conditions gives the
amine
hydrochloride 4-8.
SCHEME 4B
54

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
_ N-N /N-N
OH ~ N ~N.N 'N.N
OMs
MsCI N
H HCI
N N N N
Boc Boc H
Boc
4_5 4_6 4_7 4_8
Another principal route for the synthesis of chemokine receptor modulators is
depicted in Scheme 5. According to this route, intermediate 2-11 (described in
Scheme 2C) is
condensed with amine 1-2 (described in Scheme 1) using a peptide coupling
reagent such as
EDC to give 5-1. The Boc protecting group is removed under standard conditions
such as with
HCl in a solvent such as dioxane followed by treatment of the resulting amine
5-2 with a
dialdehyde 5-3 in the presence of a reducing agent such as sodium
triacetoxyborohydride leads to
a double reductive alkylation sequence with concomitant cyclization to give 1-
5.2. In accord
with Scheme 1, further modifications, such as hydrolysis of an ester group
present within 1-5.2
can be effected to give new chemokine receptor modulators 1-5.3.
SCHEME 5

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Rs
O s
BocHN ,H HN I ~ R5 E~ BocHN O N \ R5
~O ~ ~/
Y R4 ~R~
R2 R3 ~Y R4
2-11 R2 Rs
1-2 5_1
O Rs
HCI H N R5 NaB(OAc)3H
N
~R~ I ~ a R9
_Y R R~
R2 R3 R8 X CHO
5-2
R~s~CHO
5-3
R9
R~
Rs~X~ O Rs
R~o~N N ~ R5 Further modifications
1-5.3
R~ I Y~R4 such as ester hydrolysis,
R2 R3 etc.
1-5.2
One way of preparing dialdehydes 5-3 is outlined in Scheme 6. According to
this route, a
cycloalkene 6-1 is oxidatively cleaved with, for example, ozone followed by
dimethylsulfide, to
give the dialdehyde. Alternatively, in place of the dialdehydes 5-3 the
intermediate ozonides 6-2
can themselves be used directly in the double reductive amination reaction
leading to 1-5.2.
SCHEME 6
R5 Rs
R3 03; DMS R4RX~CHO
Ra.X
Rs 03 Rs CHO
R3 R5 5-6
Ra~X
Rs _O
6-2
In some cases the order of carrying out the foregoing reaction schemes may be
varied to facilitate the reaction or to avoid unwanted reaction products. The
following examples
56

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
are provided for the purpose of further illustration only and are not intended
to be limitations on
the disclosed invention.
Concentration of solutions was generally carned out on a rotary evaporator
under
reduced pressure. Flash chromatography was carried out on silica gel (230-400
mesh). MPLC
refers to medium pressure liquid chromatography and was carried out on a
silica gel stationary
phase unless otherwise noted. NMR spectra were obtained in CDC13 solution
unless otherwise
noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether
(ether),
triethylamine (TEA), N,N-diisopropylethylamine (DIEA) saturated aqueous
(sat'd), room
temperature (rt), hour(s) (h), minutes) (min).
The following are representative procedures for the preparation of the
compounds
used in the following Examples or which can be substituted for the compounds
used in the
following Examples which may not be commercially available.
In some cases the order of carrying out the foregoing reaction schemes may be
varied to facilitate the reaction or to avoid unwanted reaction products. The
following examples
are provided for the purpose of further illustration only and are not intended
to be limitations on
the disclosed invention.
Concentration of solutions was generally carried out on a rotary evaporator
under
reduced pressure. Flash chromatography was carried out on silica gel (230-400
mesh). NMR
spectra were obtained in CDCl3 solution unless otherwise noted. Coupling
constants (J) are in
hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N,N-
diisopropylethylamine (DIEA) saturated aqueous (sat'd), room temperature (rt),
hour(s) (h),
minutes) (min).
The following are representative Procedures for the preparation of the
compounds
used in the following Examples or which can be substituted for the compounds
used in the
following Examples which may not be commercially available.
INTERMEDIATE 1
HN ~ ~ CF3
57

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step A:
CF3
p ~ \
F3C" N /
H
A solution of 4-trifluoromethylphenylacetonitrile (10 g , 49 mmol) in a
mixture of
ethanol (100 mL) and ammonium hydroxide (20 mL of a 29.3% aqueous solution)
was
hydrogenated over Raney nickel (1 g) for 16 h. The catalyst was removed by
filtration through
celite and the filtrate evaporated to dryness. The neat residue was added in a
dropwise manner to
trifluoroacetic anhydride (25 mL , 180 mmol) cooled at 0 °C and the
resulting mixture stirred at 0
°C for 30 minutes. The reaction mixture was poured onto ice (250 mL)
and the resulting mixture
stirred for 30 minutes after which the precipitate was removed by filtration
and air dried to give
the product as a white solid (13.4 g , 90%).
Step B:
O
F3C~N ~ CF3
To a mixture of the product from step A (13.4 g, 44.0 mmol) and
paraformaldehyde (2 g ,
50 mmol) was added in one portion a mixture of concentrated sulfuric acid (90
mL) and glacial
acetic acid (60 mL) and the resulting mixture stirred at room temperature for
16 hours. The
reaction mixture was poured onto a mixture of ice and water (1 L) and
extracted with ethyl
acetate (3 x 150 mL); the combined ethyl acetate layers were washed with water
(3 x 500 mL),
saturated NaHC03 (200 mL), and sat NaCI (100 mL), dried over MgS04 , filtered
and
evaporated in vacuo. The residue was purified by column chromatography on
silica elution with
10 % Et20 in hexanes to give the product (8.29 g , 60 %).
Step C:
HN ~ ~ CF3
To a solution of the trifluoroacetamide formed in Step B (8.29 g , 26.0 mmol)
in ethanol
(200 mL) was added a solution of potassium carbonate (20 g , 150 mmol) in
water (50 mL), and
the resulting mixture stirred at reflux for 1 hour. The ethanol was removed by
rotary evaporation
58

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
and water (150 mL) was added to the residue. Extracted with CHZC12 (3 x 100
mL), the
combined CHZCI2 layers were washed with sat NaCI (100 mL), dried over NaZS04,
filtered and
evaporated in vacuo to give the product (5.2 g , 91%); 'H NMR SOOMHz (CDCl3) 8
= 1.81 (1H ,
br s), 2.84 (2H , d , J = 6.0 Hz), 3.15 (2H , t , J = 6.0 Hz), 4.05 (2H , s),
7.19 (1H , d , J = 8.0
Hz), 7.27 (1H , s), 7.37 (1H , d , J = 8.0 Hz).
INTERMEDIATE 2
HN I ~ CF3
N
Step A:
Br /' ~ /CF3
HO N
To a solution of 5-trifluoromethyl-2-pyridinol (51.0 g, 307 mmol) and sodium
acetate
(26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL,
325 mmol) and
the resulting mixture was heated at 80 °C for 2.5 hours. The reaction
was allow to cool to room
temperature and then was evaporated under reduced pressure. The residue was
neutralized with
saturated NaHC03 solution and extracted with ethyl acetate (3 x 200 mL). The
organic layers
were combined, dried over MgS04, filtered, and evaporated in vacuo to yield
74.45 g (98.7%) of
the crude product. ~H NMR (400 MHz, CDCl3) 8 8.04 (d, J=2.6 Hz, 1H), 7.89 (m,
1H).
Step B:
O
H ~ CF3
HO NJ
Under nitrogen, the substituted pyridine, described in Step A (48.8g, 202
mmol) was
added by small portions to a suspension of NaH (8.9 g, 220 mmol) in anhydrous
THF (500 mL).
After complete addition of the intermediate, the reaction mixture was cooled
to -78 °C and
treated with tert-butyllithium (260 mL, 444 mmol) added dropwise via syringe.
After stirnng
for 5 minutes, DMF (50 mL, 707 mmol) was added slowly to maintain the
temperature below -
50 °C. The resulting mixture was then stirred for 10 hours allowing to
warm to room
temperature. The mixture was quenched with 2N HCl and then diluted with ethyl
acetate (1000
59

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
mL). The organic layer was separated, washed with brine, dried over MgS04, and
evaporated in
vacuo. The desired product was precipitated out of ethyl acetate and hexane
and filtered to yield
a light brown solid (28.55 g, 73.8%). 'H NMR (500 MHz, CD30D) 8 10.13 (s, 1H),
8.21 (s,
2H).
Step C:
NC ~ CF3
HO N
A mixture of the intermediate from Step B (18 g, 95 mmol), sodium formate (7.1
g, 105
rrimol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and formic acid (150
mL) was stirred at
room temperature for 2 hours and then refluxed overnight. The reaction mixture
was cooled and
let stand at room temperature for 7 days. The reaction was poured into water
and extracted with
ethyl acetate (3x). Combined organic layers were washed with water (2x),
saturated NaHC03
and brine, dried over Na2S04, filtered, and concentrated in vacuo to yield the
desired product as a
brown powder (17.84 g, 89.8%). 'H NMR (400 MHz, CD30D) 8 8.37 (d, J = 2.7 Hz,
1H), 8.19
(q, J = 0.7 Hz, 0.3??/Hz, 1H).
Step D:
NC ~ CF3
CI N
To a mixture of phosphorous oxychloride (13.4 mL, 144 mmol) and quinoline (8.7
mL,
73.4 mmol) was added the product from Step C (24.6 g, 131 mmol) and the
resulting mixture
was refluxed for 3 hours. The reaction was cooled to 100 °C before
water (70 mL) was slowly
added. The mixture was further cooled to room temperature and neutralized
carefully with
saturated NaHC03 solution. The aqueous layer was extracted with ethyl acetate
(3x) and the
organic layers were combined, dried over MgS04, filtered, and evaporated in
vacuo. The crude
product was purified by flash chromatography to afford (23.5 g, 87.0%) of the
desired
compound. ~H NMR (500 MHz, CDCl3) 8 8.88 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.5 Hz,
1H).
Step E:
NC ~ CF3
Me02C I NJ
C02tBu

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
To a suspension of NaH (7.8 g, 200 mmol) in THF (100 mL) under nitrogen was
added
dropwise a solution of tert-butyl methyl malonate (20 mL, 120 mmol) in
anhydrous THF (100
mL) via syringe. The reaction mixture was stirred for 0.5 h before a solution
of the intermediate
prepared in Step D (20.1 g, 97.6 mmol) in THF (200 mL) was added slowly via
syringe. The
reaction was stirred at room temperature overnight, then quenched with a
saturated solution of
NH4C1. The organic layer was separated and the aqueous layer extracted with
ethyl acetate (3x).
The combined organic layers were washed with water (3 x), dried over Na2S04,
filtered, and
evaporated in vacuo. Flash chromatography afforded 31.76 g (94.6%) of the pure
desired
product. 1H NMR (500 MHz, CDC13) 8 9.03 (d, J=1.5 Hz, 1H), 8.25 (d, J=2.0 Hz,
1H), 5.25 (s,
1H), 3.86 (s, 3H), 1.52 (s, 9H).
Step F:
HN ~ CF3
O NJ
co2tBu
A suspension of Raney Ni (1g) and the product from Step E (18.2 g, 52.9 mmol)
in
ethanol (130 mL) was placed on a Parr Apparatus and hydrogenated at 40 psi
overnight. The
suspension was filtered through celite and the filtrate evaporated in vacuo to
afford 16.35 g
(97.8%) of crude product. 'H NMR (500 MHz, CDC13) 8 8.83 (s, 1H), 7.89 (s,
1H), 7.82 (s,
1H), 4.83 (d, J=16 Hz, 1H), 4.72 (s, 1H), 4.49 (d, J=16 Hz, 1H), 1.45 (s, 9H).
Step G:
HN ~ CF3
O N
To the mixture of the product from Step F (16 g, 51 mmol) in DCM (60 mL) was
added
TFA (30 mL) and the resulting mixture stirred at room temperature for 0.5 h.
The solution was
evaporated under reduced pressure and the residue was dissolved in DCM. The
mixture was
neutralized by slow addition of a solution of saturated sodium bicarbonate and
the organic layer
removed. The aqueous was extracted with DCM (4 x) and then all organic layers
were combined,
dried over Na2S04, filtered, and evaporated in vacuo to afford 10.42 g (95.2%)
of the desired
product. 1H NMR (400 MHz, CDC13) 8 8.81 (s, 1H), 7.78 (s, 1H), 7.30 (s, 1H),
4.63 (s, 2H),
3.90 (s, 2H).
61

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step H:
BocN I ~ CF3
N
To a solution of the product from Step G (18.0 g, 83.3 mmol) in THF (50 mL)
was added
1.0 M Borane in THF (417 mL, 420 mmol) and the resulting solution stirred at
room temperature
overnight. The solution was evaporated under reduced pressure and then the
residue was treated
with 1% HCl/ MeOH solution in which the resulting mixture was heated at 50
°C overnight to
breakdown the borane complex. Treatment with acidic methanol was repeated
twice to insure
that the borane complex was eliminated. The crude product from this reaction
was then
immediately used for the next reaction.
A solution of crude product described immediately above (83.3 mmol, assuming
100%
conversion) and DIEA (43 mL, 250 mmol) in DCM was treated with di-tert-butyl
dicarbonate
(36.4 g, 167 mmol) and the resulting mixture stirred at room temperature
overnight. The
solution was washed with saturated sodium bicarbonate solution, water, and
brine. The aqueous
layers were combined and back-washed with DCM (2 x). The combined organic
layers were
then dried over NaZS04, filtered, and evaporated to dryness. The crude product
was purified by
flash chromatography and MPLC to afford (11.89 g, 47.2% for last two steps) as
a yellow solid.
~H NMR (500 MHz, CDCl3) 8 8.69 (s, 1H), 7.66 (s, 1H), 4.67 (s, 2H), 3.79 (t,
J=6.0 Hz, 2H),
3.08 (t, J=5.5 Hz, 2H), 1.51 (s, 9H).
Step I:
HN ~ CF3
N
The product described in Step H (11.89 g) was treated with a solution of 4 M
HCl in
dioxane. The solution was stirred at room temperature for 2 hours and then
evaporated in vacuo
to afford Intermediate 2 (10.85 g, 99%) as a yellow powder. LC-MS for
C9H~oF3Nz[M+H+~
calculated 202.07, found 203Ø
INTERMEDIATE 3
62

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
O C F3
vN ( W
Step A:
O
Me0 ~~
Me0 OMe
A solution of methyl-3-oxocyclopentane-carboxylate (20 g, 160 mmol) and
trimethyl
orthoformate (85 mL, 780 mmol) in methanol was treated with a catalytic amount
of p-
toluenesulfonic acid (3.00 g, 15.6 mmol) and the resulting solution was
stirred for 4 h at room
temperature. The solvent was evaporated under reduced pressure and the residue
was then
dissolved in ether (600 mL). The solution was washed with saturated sodium
bicarbonate (2 x
200 mL), water (150 mL), brine (200 mL), dried over anhydrous sodium sulfate,
filtered, and the
solvent evaporated as before. Purification by flash column chromatography
(eluant: 25%
ether/pentane) afforded 21.52 g (73%) of the desired product as a clear oil.
'H NMR (500 MHz,
CDCl3) b 3.68 (s, 3H), 3.21 (d, J = 9.9 Hz, 6H), 2.89 (p, J = 8.5 Hz, 1H),
2.14-2.05 (m, 2H),
2.02-1.80 (m, 4H).
Step B:
O
Me0
Me0 ~/~OMe
A flame dried 500 mL round bottom flask was charged with 150 mL of dry THF,
and
then, set under nitrogen and cooled to -78 °C using an acetone/dry ice
bath. Diisopropylamine
(19.2 mL, 137 mmol) was added to the cooled solvent via syringe followed by
the slow addition
of 2.5M n-butyllithium in hexane (55 mL, 140 mmol). After 5 minutes stirnng,
the methyl ketal
described in Step A, Intermediate 3 (21.52 g, 114.4 mmol) in 50 mL of THF was
added
dropwise via syringe and the resulting mixture stirred at -78 °C for 2
hours. 2-Iodopropane
(34.3 mL, 343 mmol) was then added dropwise via syringe and the resulting
mixture was stirred
overnight allowing to warm slowly to room temperature. The reaction was
quenched with a
solution of 10% citric acid and the organics separated. The aqueous layer was
extracted with
ether (3 x 150 mL) and all the organics combined, dried over anhydrous sodium
sulfate, filtered,
63

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
and evaporated under reduced pressure. The crude product was purified by flask
column using an
eluant of 20% ether/pentane to afford 16.74 g (64%) of the desired product. .
'H NMR (400
MHz, CDC13) S 3.69 (s, 3H), 3.18 (d, J = 20.5 Hz, 6H), 2.57 (d, J = 13.9 Hz,
1H), 2.29-2.20 (m,
1H), 1.90 (p, J = 6.8 Hz, 1H), 1.88-1.80 (m, 2H), 1.69-1.61 (m, 2H), 0.89 (dd,
J = 11.9 Hz, 6.8
Hz, 6H).
Step C:
O
O
~~OH
A solution of the ester (described in Step B, Intermediate 3, 16.7 g, 72.7
mmol) in
ethanol (30 mL) was treated with 5 M NaOH ( 55 mL) and the resulting mixture
heated to reflux
for three days. The mixture was then cooled to room temperature and acidified
with concentrated
hydrochloric acid. The organic solvent was evaporated under reduced pressure
and the aqueous
layer was then extracted with DCM (5 x 100 mL). The organic extracts were
combined, dried
over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield
the crude 3-
oxocyclopentane carboxylic acid (11.07 g, 90%) as a yellow oil. 1H NMR (500
MHz, CDC13) 8
2.70 (d, J = 18.1 Hz, 1H), 2.44-2.39 (m, 1H), 2.30-2.15 (m, 2H), 2.14 (dd, J =
18.1, 1.0 Hz, 1H),
2.06 (p, J = 6.9 Hz, 1H), 1.98 (m, 1H), 0.98 (dd, J = 11.4, 6.9 Hz, 6H).
Step D:
O
O CFs
\ N
Procedure A:
To a solution of acid (described in Step C, Intermediate 3, 2.00 g, 11.8 mmol)
in DCM
(50 mL) was added oxalyl chloride (1.54 mL, 17.6 mmol) followed by 2 drops of
DMF. The
solution was stirred at room temperature for 80 minutes and then evaporated
under reduced
pressure. The residue was dissolved in DCM (2 mL) and added via syringe to a
prepared solution
of Intermediate 1. (2.36 g, 11.8 mmol) and triethylamine (2.13 mL, 15.3 mmol)
in DCM (40 mL).
The resulting mixture was stirred at room temperature for 18 hours and then
quenched with
water (25 mL). The organics were separated, washed with 1 N HCI, saturated
sodium
64

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
bicarbonate, and brine, dried over anhydrous magnesium sulfate, filtered, and
evaporated. The
crude product was purified by MPLC using an eluant of 60% ethyl acetate/hexane
to afford
Intermediate 3 (3.18 g, 77%).'H NMR (500 MHz, CDCl3) S 7.46 (d, J=7.3 Hz, 1H),
7.39 (s,
1H), 7.29 (d, J=7.7 Hz, 1H), 4.81 (m, 2H), 3.93 (m, 1H), 3.82 (m, 1H), 2.94
(m, 3H), 2.54 (m,
1H), 2.43 (d, J=8.5 Hz, 1H), 2.32 (m, 2 H), 2.26 (p, J=6.6 Hz, 1H), 2.16 (m,
1H), 0.93 (dd,
J=19.7 Hz, 6.8 Hz, 6H). LC-MS for C,~H23F3N02 calculated 353.16, found [M+H+]
354.25.
Procedure B:
A mixture of the acid prepared in Step C, Intermediate 3 (1.0 g, 5.9 mmol),
Intermediate
1 (1.18g, 5.88 mmol), DMAP (71 mg, 0.59 mmol), and N,N-diisopropyl ethylamine
(1.02 mL,
5.88 mmol) in dichloromethane (20 mL) was treated with 1-[3-
(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (EDC, 2.25 g, 11.7 mmol) and stirred at room
temperature
overnight. The reaction mixture was diluted with dichloromethane (30 mL),
washed with water
(2 x 20 mL), brine (1 x 30 mL), dried over anhydrous sodium sulfate and the
solvent was
evaporated.. The pure compound was obtained by MPLC purification (eluant 60%
ethyl
acetate/hexane), 1.08 g (52%). LC-MS for C»H23F3N02 calculated 353.16, found
[M+H+]
354.25.
INTERMEDIATE 4
O
O CFs
\N~~J~~
N
To a solution of acid (described in Step C, Intermediate 3, 540 mg, 3.20 mmol)
in DCM
(50 mL) was added oxalyl chloride (0.834 mL, 9.60 mmol) followed by 2 drops of
DMF. The
solution was stirred at room temperature for 80 minutes and then evaporated
under reduced
pressure. The residue was dissolved in DCM (2 mL) and added via syringe to a
prepared solution
of Intermediate 2 (880 mg, 3.20 mmol) and triethylamine (0.820 mL, 6.50 mmol)
in DCM (20
mL). The resulting mixture was stirred at room temperature for 18 hours and
then quenched with
water (25 mL). The organics were separated, washed with saturated sodium
bicarbonate and

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The
crude product was
purified by MPLC using a step-wise gradient eluant of 0-70% ethyl
acetate/hexane to afford
Intermediate 2 (720 mg, 64%). ESI-MS calculated for C18H21F3N2O2: 354.16;
found 355
(M+H)
INTERMEDIATE 5
O
O N ~ CFs
N
Resolution of Intermediate 4 to its individual enantiomers was accomplished by
chiral
separation using HPLC equipped with a Preparative ChiralPak AD column. The
separation was
completed by injecting 100 mg/run and using an eluant of 25% isopropanol and
75% heptane
with a flow rate of 9 mL/min.
INTERMEDIATE 6
Step A:
O
O CFa
N
HO
O
O
Procedure A:
A solution of 3-oxo-cyclopentane carboxylic acid (Stetter, H., Kuhlmann, H.
Liebigs
Ann. Chem., 1979, 7, 944-9) (5.72 g, 44.6 mmol) in dichloromethane (30 mL) was
treated with
N,N'-diisopropyl-O-tert-butyl-iso-urea (21.2 mL, 89.3 mmol) and the reaction
mixture was
stirred at ambient temperature overnight. The precipitated N,N'-diisopropyl
urea was filtered
off, the filtrate concentrated in vacuo and the residue was purified by
distillation (bp: 125-129 °C
@ 18 mmHg) to yield 4.74 g (58 %) of the pure product. 'H NMR (500 MHz,
CDCl3): 8 3.02
66

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
(p, J = 7.8 Hz, 1H), 2.05 - 2.50 (m, 6H), 1.45 (s, 9H). '3C NMR (125 MHz,
CDCl3): 8 217.00,
173.47, 80.99, 41.88, 41.14, 27.94, 26.57.
Procedure B:
A 2 L round RBF was charged with anhydrous magnesium sulfate (113 g, 940 mmol)
and
dichloromethane (940 mL) was added. While stirring, the suspension was treated
with
concentrated sulfuric acid (12.5 mL, 235 mmol) followed in 15 minutes by 3-oxo-
cyclopentane
carboxylic acid (30.1 g, 235 mmol). After stirring for 15 minutes, tert-
butanol (87 g, 1.2 mol)
was added. The reaction vessel was closed with a stopper to aid retention of
isobutylene, and
stirred at ambient temperature for 72 hours. The solid was filtered off
through a plug of celite,
volume of the filtrate was reduced to approximately 500 mL, and washed with
saturated solution
of sodium bicarbonate (2 x 150 mL). The organic phase was dried with anhydrous
magnesium
sulfate, filtered, and the solvent was removed by distillation at reduced
pressure (180 mmHg).
The crude product was purified by distillation to yield 39.12 g (90 %) of pure
product.
Step B:
O
Me0 ~~
Me0 O
A solution of ten-Butyl 3-oxocyclopentane carboxylate (11.54 g, 62.64 mmol) in
dichloromethane (200 mL) was treated with trimethyl orthoformate (41.4 mL, 251
mmol) in the
presence of p-toluenesulfonic acid (400 mg) and stirred at room temperature
for 48 hours. The
dark reaction mixture was poured onto saturated solution of sodium
bicarbonate, and the crude
product was extracted with dichloromethane. The combined organic extracts were
dried with
anhydrous magnesium sulfate, the solvent was removed in vacuo, and the crude
product was
purified by distillation (bp.: 104 °C C~ 4 mmHg) to yield 12.32 g (85
%) of the desired product.
'H NMR (500 MHz, CDC13): S 3.21 (s, 3H), 3.20 (s, 3H), 2.80 (m, 1H), 2.10 to
1.80 (bm, 6H),
1.46 (s, 9H). ~3C NMR (125 MHz, CDCl3): 8 174.9, 111.2, 80.3, 67.8, 49.2,
42.5, 37.4, 33.8,
28.3, 22Ø
Step C:
67

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
Me0
Me0
HO
A flame dried 500 mL round bottom flask was charged with 100 mL of dry THF,
and then, set
under nitrogen and cooled to -78°C using an acetone/dry ice bath.
Diisopropylamine (7.9 mL,
56 mmol) was added to the cooled solvent via syringe followed by the slow
addition of 2.5 M n-
butyllithium in hexane (22.6 mL, 56.45 mmol). After 5 minutes stirring, the
acetal (described in
Step B, Intermediate 6 ,10.0 g, 43.4 mmol) in 50 mL of THF was added dropwise
via syringe
and the resulting mixture stirred at -78°C for 2 hours. Acetylaldehyde
(7.3 mL, 130 mmol) was
then added dropwise via syringe and the resulting mixture was stirred for 2 h
at -78 °C. The
reaction was quenched by pouring the mixture into a solution of 10°Io
citric acid (300 mL) and
then extracting with dichloromethane (2 x 150 mL). The organics were combined,
dried over
anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure.
During the
reaction or work-up some of the acetal was hydrolyzed to the ketone,
therefore, the crude
mixture was taken onto the next step without purification.
Step D:
O
O
~~OH
HO
The crude intermediate (described in Step C, Intermediate 6, 56.45 mmol
assumed 100°l0
conversion for Step C) was treated with a solution of 10°lo
trifluoroacetic acid in
dichloromethane and the resulting mixture stirred overnight at room
temperature. The reaction
was concentrated in vacuo, then diluted with water, and extracted with
dichloromethane. The
organics were combined, dried over anhydrous magnesium sulfate, filtered, and
evaporated under
reduced pressure to afforded 8.04 g (83°l0) of the crude product that
was used without further
purification.
Step E:
O
O CFs
~N I w
HO
68

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
A mixture of the acid (described in Step D, Intermediate 6, 300 mg, 1.74
mmol),
Intermediate 2 (486, 1.74 mmol), HOAt (237 mg, 1.74 mmol), and N,N-diisopropyl
ethylamine
(0.606 mL, 3.48 mmol) in dichloromethane (15 mL) was treated with 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 667 mg, 3.48
mmol) and
stirred at room temperature for five days. The reaction mixture was diluted
with
dichloromethane (30 mL), washed with water (20 mL), brine (20 mL), dried over
anhydrous
sodium sulfate, filtered, and the solvent was evaporated in vacuo. The
product, Intermediate 6,
was obtained by preparative plate purification (eluant 100% ethyl acetate),
260 mg (42%).
INTERMEDIATE 7
HN ~ CF3
F
Step A
~ CF3
F3C~ N
H F
A solution of 2-fluoro-4-trifluoromethylphenylacetonitrile (10 g , 49 mmol) in
a mixture of
ethanol (100 mL) and ammonium hydroxide (20 mL of a 29.3% aqueous solution)
was
hydrogenated over Raney nickel (1 g) for 16 h. The catalyst was removed by
filtration through
celite and the filtrate evaporated to dryness. The neat residue was added in a
dropwise manner to
trifluoroacetic anhydride (25 mL , 180 mmol) cooled at 0°C and the
resulting mixture was stirred
at 0°C for 30 minutes. The reaction mixture was poured onto ice (250 g)
and the resulting
mixture was stirred for 30 minutes after which time the precipitate was
removed by filtration and
air dried to give the product as a white solid (13.4 g , 90%); IH NMR 500MHz
(CDC13) S = 3.02
(2H,t,J=7.OHz),3.66(2H,q,J=6.6Hz),6.44(lH,brs),7.34(2H,m),7.41 (lH,d,J=
7.8 Hz).
Step B
69

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
F C~N ~ CF3
3
F
To a mixture of the product from Step A (13 g , 44 mmol) and paraformaldehyde
(2.0 g , 48
mmol) was added in one portion a mixture of concentrated sulfuric acid (90 mL)
and glacial
acetic acid (60 mL) and the resulting mixture was stirred at room temperature
for 16 h. The
reaction mixture was poured onto a mixture of ice and water (1 L) and
extracted with' ethyl
acetate (3 x 150 mL); the combined ethyl acetate layers were washed with water
(3 x 500 mL),
saturated NaHC03 (200 mL), and saturated NaCI (100 mL), dried over MgS04 ,
filtered and
evaporated in vacuo. The residue was purified by column chromatography on
silica elution with
10 % Et20 in hexanes to give the product (8.29 g , 60 %); 'H NMR 500MHz
(CDC13) S = 3.01
(2H , m), 3.91 and 3.97 (2H , t , J = 6.2 Hz), 4.83 and 4.88 (2H , s), 7.21-
7.28 (3H , m).
Step C
HN ~ CF3
F
To a solution of the trifluoroacetamide formed in Step B (8.3 g , 26 mmol) in
ethanol (200 mL)
was added a solution of potassium carbonate (20 g , 150 mmol) in water (50
mL), and the
resulting mixture was stirred at reflux for 1 h. The ethanol was removed under
reduced pressure
and water (150 mL) was added to the residue and extracted with CHZC12 (3 x 100
mL). The
combined CHZCIz layers were washed with saturated NaCI (100 mL), dried over
Na2S04, filtered
and evaporated in vacuo to give the product (5.2 g , 91%); 'H NMR 500MHz
(CDC13) 8 = 1.74
(1H , br s), 2.78 (2H , d , J = 6.0 Hz), 3.17 (2H , t , J = 6.0 Hz), 4.05 (2H
, s), 7.04-7.14 (3H ,
m).
INTERMEDIATE 8

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
n
N iN
N
HCI
Step A
n
N iN
N
A 3-neck round bottomed flask equipped with an addition funnel and condenser
and containing
zinc dust (2.45 g, 37.4 mmol) was flame dried. After cooling, and purging the
system with
nitrogen gas, 6 mL of THF was added, followed by 1,2-dibromoethane (0.298 mL,
3.46 mmol).
The mixture was warmed to a vigorous reflux using a heat gun and stirred at
reflux for ~30
seconds (gas evolution was observed), then cooled to room temperature. The
warming and
cooling was repeated two more times. Then chlorotrimethylsilane (0.402 mL,
3.17 mmol) was
added and the mixture was stirred at room temperature for 20 minutes. N-t-
butoxycarbonyl-4-
iodo-piperidine (known: Billotte, S. Synlett (1998), 379., 8.97 g, 28.8 mmol)
in 15 mL of THF
was added over a period of about 1 minutes. The reaction mixture was stirred
at 50 °C for 1.5 h,
then was cooled to room temperature. Meanwhile, a mixture of tri-2-
furylphosphine (267 mg,
1.15 mmol) and Tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct
(298 mg, 0.288
mmol) was dissolved in 6 mL of THF under a nitrogen atmosphere, stirred for 15
minutes at
room temperature, and added to the organozinc solution. Then a solution of 2-
bromopyrimidine
(5.50 g, 34.6 mmol) in a mixture of 58 mL of THF and 20 mL of N,N-
dimethylacetamide was
added. The reaction mixture was warmed to 80 °C and stirred for 3.5 h,
then was cooled to room
temperature and stirred for 36 h. The reaction mixture was filtered through
celite and the filter
cake was washed with ethyl acetate. The filtrate was diluted further with
ethyl acetate, and
washed with saturated NaHC03 solution. The aqueous layer was back extracted
with ethyl
acetate, the organic layers were combined and washed twice with water and once
with brine.
71

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The organic phase was dried over anhydrous MgS04, filtered, and concentrated.
Purification by
flash chromatography (silica, stepwise gradient: 25 % ethyl acetate/hexane, 40
% ethyl
acetate/hexane, 60 % ethyl acetate/hexane, 80 % ethyl acetate/hexane, 100 %
ethyl acetate) to
afford 4.92 g of pure 4-(2-pyrimidyl)-piperidine product (65 %). 1H NMR (500
MHz, CDC13): S
8.70 (d, J = 5.0 Hz, 2H), 7.16 ( app t, J = 4.5 Hz, 1H), 4.24 (br s, 2H), 3.05
(m, 1H), 2.89 (br m,
2 H), 2.01 (br d, J = 13 Hz, 2H), 1.84 (dq, J = 4.5, 12.5 Hz, 2H), 1.49 (s,
9H).
Step B
n
N iN
N-
H HCI
The N-t-butoxycarbonylpiperidine prepared in Step A (4.64 g, 17.6 mmol) was
dissolved in 4 N
HC1 in dioxane (50 mL) and stirred at room temperature for 2.25 h. The
reaction mixture was
concentrated to afford 4.16 g of piperidine hydrochloride (100%) which
required no further
purification. 'H NMR (500 MHz, CD30D): S 8.95 (d, J = 5.5 Hz, 2H), 7.60 (t, J
= 5.0 Hz, 1H),
3.53 (dt, J = 13, 3.5 Hz, 2H), 3.35 (tt, J = 4.0, 11.0 Hz, 1H), 3.20 (br t, J
= 13.8 Hz, 2H), 2.30 (br
d, J = 14.0 Hz, 2H), 2.11-2.20 (m, 2H); ESI-MS calc. for C9H13N3: 163; Found:
164 (M+H).
INTERMEDIATE 9
NON
I ,
HCI
This intermediate was prepared using the procedure described for Intermediate
8 except that 4-
bromo pyrimidine was used in place of 2-bromo pyrimidine. LC-MS for C9H,3N3
calculated
163.28, found [M + H]+ 164.
72

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
INTERMEDIATE 10
4-(1H-1,2,4-triazol-1-yl)piperidine hydrochloride
H
N
N
N
Step A
tert-butyl 4-hydroxypiperidine-1-carboxylate
Boc
N
OH
To a stirred solution of 4-hydroxypiperidine (60.8 g) in dichloromethane (500
mL) was added a
solution of di-ter-butyl dicarbonate (19 g, 0.55 mol) in dichloromethane (500
mL) very slowly.
After the addition, which took 1 h, the resulted mixture was stirred at
ambient temperature for 5
h. The mixture was then washed with saturated NaHC03, 3 N HCI, brine, dried
and evaporated
to give tert-butyl 4-hydroxypiperidine-1-carboxylate as a thick oil (90 g).
Step B: tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate
Boc
N
OMs
To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (21.1 g,
100 mmol) and
triethyl amine (22 mL) in dichloromethane (250 mL) at 0 °C was slowly
added methanesulfonyl
chloride (9.0 mL, 1.1 equiv.). The resulting mixture was stirred for an
additional 1 h and during
this time white solid was formed. The mixture was then washed with 3 N HCI,
dried over
73

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Na2S04 and evaporated to give: tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-
carboxylate as a
white solid (29.2 g). ~H NMR (400 MHz, CDC13): 8 4.92-4.87 (m, 1H), 3.75-3.69
(m, 2H), 3.34-
3.28 (m, 2H), 3.05 (s, 3H), 2.01-1.94 (m, 2H), 1.87-1.78 (m, 2H).
Step C: 4-(1H-1,2,4-triazol-1-yl)piperidine hydrochloride
To a stirred solution of : tent-butyl 4-[(methylsulfonyl)oxy]piperidine-1-
carboxylate (5.9 g, 21
mmol) and 1,2,4-triazole (1.8 g, 25 mmol eGuiv.) in DMF at ambient temperature
was added
sodium hydride (60 % in mineral oil, 1.0 g, 25 mmol). The mixture was stirred
at 60 °C for 5
days, and the TLC showed no starting mesylate left. The mixture was poured
into ice water and
extracted with ethyl acetate (3 x). The organic layer was dried, evaporated
and purified by silica
flash column eluting with 0-10 % methanol in ethyl acetate to give tert-butyl
4-(1H-1,2,4-triazol-
1-yl)piperidine-1-carboxylate as a white solid. The solid was then treated
with hydrogen
chloride in dioxane (4 N, 10 mL) for 2 h. The mixture was then evaporated to
remove most of
the dioxane to give a white solid, which was washed with ethyl acetate to give
the desired 4-(1H-
1,2,4-triazol-1-yl)piperidine hydrochloride salt (5.55 g). 'H NMR (300 MHz,
CD30D): 8 10.00
(s, 1H), 8.97 (s, 1H), 5.10-5.00 (m, 1H), 3.63-3.58 (br. d, 2H), 3.33-3.26
(br. d, 2H), 2.50-2.30
(m, 4H).
The following intermediates 10-16 were prepared in a similar fashion to
Intermediate 10 using
tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate and the appropriate
heterocycles
INTERMEDIATE 11
4-(1H-pyrazol-1-yl)piperidine hydrochloride
H
N
N
~ /N
Prepared using pyrazole according to the procedure for Intermediate 10.
74

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
INTERMEDIATE 12
4-(1H-imidazol-1-yl)piperidine hydrochloride
H
N
N
N
Prepared from imidazole according to the procedure for Intermediate 10: 'H NMR
(400 MHz,
CD30D): 8 9.18 (s, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 4.9-4.8 (hidden under
CD30D peak, 1H),
3.61-3.61 (br. d., 2H), 3.33-3.26 (m, 2H), 2.49-2.45 (br. d, 2H), 2.39-2.28
(m, 2H).
INTERMEDIATE 13
4-(1H-1,2,3-triazol-1-yl)piperidine hydrochloride
H
N
N
~~N
N
Prepared from 1,2,3-triazole according to the procedure for Intermediate 10.
4-(1H-1,2,3-triazol-1-yl)piperidine hydrochloride: 'H NMR (400 MHz, CD30D): 8
8.77 (s, 1H),
8.54 (s, 1H), 5.26-5.19 (m, 1H), 3.65-3.59 (m, 2H), 3.37-3.29 (m, 2H), 2.60-
2.54 (m, 2H), 2.50-
2.39 (m, 2H).
INTERMEDIATE 14
4-(2H-1,2,3-triazol-2-yl)piperidine hydrochloride:

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
H
N
N~N~N
' V
Prepared from 1,2,3-triazole according to the procedure for Intermediate 10.
4-(2H-1,2,3-triazol-2-yl)piperidine hydrochloride: 'H NMR (400 MHz, CD30D): 8
7.72 (s, 2H),
4.94-4.87 (m, 1H), 3.54-3.48 (m, 2H), 3.28-3.22 (m, 2H), 2.46-2.32 (m, 4H).
INTERMEDIATE 15
4-(1H-tetraazol-1-yl)piperidine hydrochloride
H
N
N
~N
N-N
Prepared from tetrazole according to the procedure for Intermediate 10.
4-(1H-tetraazol-1-yl)piperidine hydrochloride: 1H NMR (400 MHz, CD30D): S 8.77
(s, 1H),
5.30-5.23 (m, 1H), 3.58-3.53 (m, 2H), 3.35-3.29 (m, 2H), 2.58-2.2.52 (m, 2H),
2.48-2.38 (m,
2H).
INTERMEDIATE 16
4-(2H-tetraazol-2-yl)piperidine hydrochloride
H
N
N~N~N
~N
76

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Prepared from tetrazole according to the procedure for Intermediate 10.
4-(2H-tetraazol-2-yl)piperidine hydrochloride: IH NMR (400 MHz, CD30D): 8 9.32
(s, 1H),
5.08-5.00 (m, 1H), 3.61-3.57 (m, 2H), 3.33-3.28 (m, 2H), 2.52-2.47 (m, 2H),
2.42-2.32 (m, 2H).
INTERMEDIATE 17
~N
N//~N~N
NJ
H HCI
Prepared from 5-methyltetrazole according to the procedure for Intermediate
10.
1H NMR (400 MHz, CD30D): 8 5.08-5.00 (m, 1H), 3.61-3.57 (m, 2H), 3.33-3.28 (m,
2H), 2.52-
2.47 (m, 2H), 2.42-2.32 (m, 2H), 1.68 (s, 3H).
INTERMEDIATE 18
O
~S
HN / N
NJ
H HCI
Step A
HO
H2N i\N
N
Boc
77

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Hydroxylamine hydrochloride (8.26 g, 119 mmol) and triethylamine (16.6 mL, 119
mmol) were
combined in 50 mL of DMSO. The suspension was filtered to remove triethylamine
hydrochloride and the filter cake was washed with THF. The filtrate was
partially concentrated
to remove the THF. Then commercially available 1-tert-butoxycarbonyl-4-
cyanopiperidine (5.0
g, 24 mmol) was added to the DMSO solution and the resulting reaction mixture
was stirred at
75 °C for 3 h, and then at room temperature overnight. The reaction
mixture was diluted with
ethyl acetate and washed with water. The aqueous layer was back-extracted with
more ethyl
acetate and the combined organic layers were washed four times with water and
once with brine.
The organic layer was dried over anhydrous MgS04, filtered, and concentrated
to give 3.51 g of
product.
Step B
O
-S
HN i N
N
H HCI
A solution of the intermediate from Step A (1.02 g, 4.19 mmol) in 20 mL THF
was treated with
thiocarbonyldiimidazole (897 mg, 5.03 mmol), whereupon gas evolution and an
exotherm were
noted. The reaction mixture was stirred at room temperature for 1 h, then was
transferred to a
suspension of silica gel #60 (20 g) in 180 mL of 5:1 CHCl3/methanol. The
reaction mixture was
stirred at room temperature for 5 days, then filtered and concentrated.
Purification by MPLC
(silica, 50 % ethyl acetate/hexane) afforded 143 mg of thiodiazolone.
Boc intermediate 'H NMR (500 MHz, CD30D): 8 4.16 (m, 2H), 2.86 (t, J = 11.5
Hz, 2H), 2.77
(tt, J = 4.0, 11.0 Hz, 1H), 1.98 (dd, J = 2.0, 13.0 Hz, 2H), 1.73 (dq, J =
4.5, 12.0 Hz, 2H), 1.47
(s, 9H).
78

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The Boc intermediate (139 mg, 0.487 mmol) was dissolved in 4 N HCl in dioxane
(5 mL) and
stirred at room temperature for 1.5 h. The reaction mixture was concentrated
to give 94.3 mg of
piperidine hydrochloride product.
INTERMEDIATE 19
4-(1H-pyrazol-3-yl)piperidine
H
N
~ ~NH
-N
Step A: 4-(1H-pyrazol-3-yl)pyridine
To a mixture of 4-acetylpyridine (75 mL, 0.68 mol) and ethyl formate (109 mL)
in anhydrous
benzene (1 L) was added sodium methoxide (73 g) and the resulting mixture was
refluxed for 18
h. The mixture was cooled and benzene decanted from a sticky solid, which had
formed during
the reaction. The crude product was dissolved in water (700 mL) and hydrazine
dihydrochloride
was added and the resulting mixture was stirred at room temperature for 2 h.
The mixture ws
redissolved by addition of 5 N NaOH. Precipitate formed which was removed by
filtration and
dried to give 4-(1H-pyrazol-3-yl)pyridine (35 g).
StepB:l-benzyl-4-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine
To a hot (80 °C) solution of 4-(1H-pyrazol-3-yl)pyridine (9.6 g) in 2-
propanol (60 mL) was
added benzyl bromide (20 ml,, 2.5 equiv.) and the resulting mixture was heated
at reflux for 10
minutes. After cooling in an ice bath, the precipitate was filtered and washed
with more 2-
propanol and air dried. The solid was suspended in ethanol at 0 °C and
sodium borohydride (13
g) was added in several portions over 30 minutes, and the mixture was stirred
for an additional
minutes. The reaction was quenched by the careful addition of water, the
ethanol was
79

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
removed by evaporation, and the residue was partitioned between
dichloromethane and water.
The organic layer was dried over MgS04, filtrated and evaporated to give 1-
benzyl-4-(1H-
pyrazol-3-yl)-1,2,3,6-tetrahydropyridine (16 g)
Step C: 4-(1H-pyrazol-3-yl)piperidine
A solution of 1-benzyl-4-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine (16 g)
was hydrogenated
over palladium on carbon (10 °Io, 1 g) at 40 psi overnight. The
catalyst was removed by filtration
through celite and the filtrate was evaporated. NMR shows the product is 1-
benzyl-4-(1H-
pyrazol-3-yl)-piperidine (16 g).
To a solution of 1-benzyl-4-(1H-pyrazol-3-yl)-piperidine (16 g) and formic
acid (30 mL) in
ethanol (400 mL) was added palladium on carbon (10 °lo, 2 g) and the
resulting mixture was
stirred at room temperature overnight. The catalyst was removed by filtration
and the filtrate
evaporated. The product was purified by adding di-tert-butyl dicarbonate (2
equiv.) and triethyl
amine (1.5 equiv.) in dichloromethane to give a Boc protected intermediate.
Evaporated and
purification by column chromatography on silica eluting with 20-40 % ethyl
acetate in hexane
give pure tert-butyl 4-(1H-pyrazol-3-yl)piperidine-1-carboxylate. The Boc
intermediate was then
treated with methanolic HC1 to give 4-(1H-pyrazol-3-yl)piperidine
hydrochloride salt (3.5 g).
Loss of material was due to the formation of the di-Boc product, which was not
collected. 'H
NMR (400 MHz, CDCl3): 8 8.00 (s, 2 H), 3.48 (br. d, J = 13 Hz, 2H), 3.28-3.20
(m, 1 H), 3.13
(br. t, J =13 Hz, 2H), 2.23 (br. d, J= 14 Hz, 2H), 1.97-1.85 (m, 2H).
INTERMEDIATE 20
HN I ~ Br
Step A:
C I ~ Br
F3C~N
H

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
To a mixture of 4-bromophenethylamine hydrobromide (25 g , 89 mmol) and
pyridine (36 mL ,
445 mmol) in CHZC12 (100 mL) cooled at 0°C was added dropwise
trifluoroacetic anhydride
(18.8 mL , 133 mmol). After complete addition the mixture was stirred at room
temperature for
48 hours then poured onto ice (500 g). The mixture was extracted with CHzCl2
(4 x 100 mL), the
combined CHZCIZ layers were washed with 1N HCl (4 x 100 mL), sat NaCI (100
mL), dried over
MgS04, filtered and evaporated in vacuo to give the product (26.13 g , 100 %);
'H NMR
500MHz (CDCI3) ~ = 2.86 (2H , t , J = 7.1 Hz), 3.59 (2H , q , J = 6.6 Hz),
6.57 (1H , br s ), 7.09
(2H , d , J = 8.5 Hz), 7.43 (2H , d , J = 8.5 Hz).
Step B:
HN ~ Br
To a mixture of the product from Step A (26 g , 88 mmol) and paraformaldehyde
(5.6 g , 130
mmol), was added in one portion a mixture of concentrated sulfuric acid (130
mL) and glacial
acetic acid (195 mL), and the resulting mixture stirred at room temperature
for 17 hours. The
reaction mixture was poured onto ice / water (1.5 L) and extracted with ethyl
acetate (3 x 300
mL), the combined ethyl acetate layers were washed with water (2 x 600 mL),
sat NaHC03 (300
mL), and saturated NaCI (150 mL), dried over MgS04, filtered and evaporated in
vacuo. The
residue was dissolved in ethanol (450 mL), and a solution of potassium
carbonate (60 g , 434
mmol) in water (150m1) was added. The mixture was heated to reflux for 1 hour
then cooled and
evaporated in vacuo. Water (500 mL) was added to the residue and extracted
with CHZCIz (3 x
300 mL); the combined CHZCIZ layers were washed with water (500 mL), sat NaCI
(150 mL),
dried over Na2S04, filtered and concentrated in vacuo. The residue was
purified by column
chromatography on silica elution with 5% CH30H in CH2CIz containing 0.5% NHQOH
to give
the product (10 g , 54%); ~H NMR 500MHz (CDCl3) 8 = 1.77 (1H , br s), 2.77 (2H
, d , J= 6.0
Hz), 3.11 (2H , t , J = 6.0 Hz), 3.97 (2H , s), 6.95 (1H , d , J = 8.0 Hz),
7.15 (1H , s) 7.23 (1H ,
dd , J = 1.2 and 8.2 Hz).
INTERMEDIATE 21
81

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
F / 1 F
O ~ ~ O
N N~,,
~OH + OH
Cis racemate
Step A
O
~O~
To a solution of 3-cyclopentene-1-carboxylic acid (Org. Synth. 75, p195-200,
1998) (31.5 g, 281
mmol) in anhydrous N,N-dimethylformamide (300 mL), under an atmosphere of
nitrogen, was
added potassium carbonate (97 g, 710 mmol), and iodomethane (35 mL, 560 mmol).
The
resulting mixture was stirred at room temperature for 16 h, then poured into
water (1 L), and
extracted with diethyl ether (3 x 400 mL). The combined diethyl ether layers
were washed with
water (3 x 500 mL), saturated NaCI (200 mL), dried over MgS04, filtered and
concentrated in
vacuo, to give 34 g (96 %).
'H NMR (CDC13, 500 MHz): 8 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J = 8.5
Hz, 1H), 2.63 (d,
J = 8.3 Hz, 4 H).
Step B
O
~O~
To a cooled (-78 °C) solution of diisopropylamine (34.4 mL, 250 mmol)
in anhydrous
tetrahydrofuran (250 mL) under an atmosphere of nitrogen was added slowly n-
butyllithium (100
mL of a 2.5M solution in hexanes, 250 mmol), and the resulting mixture was
stirred at -78 °C for
82

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
minutes. To this mixture was added methyl-3-cyclopentenecarboxylate (25.8 g,
200 mmol),
after stirring for a further 15 minutes 2-iodopropane (41 mL, 410 mmol) was
added, and the
mixture stirred at -78 °C for 30 minutes then allowed to rise to + 4
°C and was left standing at
this temperature for 72 h. The reaction mixture was poured in 5 % citric acid
(700 mL) and
5 extracted with diethyl ether (3 x 300 mL). The combined diethyl ether layers
were washed with
water (2 x 500 mL), saturated NaCI (1 x 100mL), dried over MgS04 , filtered
and concentrated
in vacuo. The residue was purified by vacuum distillation 50 °C @ 5
mmHg to provide 28.9 g
(86 %) of product.
'H NMR (CDC13, 500 MHz): 8 5.54 (s, 2H), 3.67 (s, 3H), 2.85 (d, J = 15.1 Hz,
2H), 2.30 (dd, J =
10 14.9 Hz, 2H), 2.07 (t, J = 6.6 Hz, 1H), 0.82 (d, J = 6.6 Hz, 6H).
Step C
O
HO
O'
To a cooled (0 °C) solution of borane-methyl sulfide (20 mL, 200 mmol)
in anhydrous
tetrahydrofuran (100 mL), under an atmosphere of nitrogen, was added, using a
double ended
needle, a solution of the cyclopentene ester prepared in Step B (28.9 g, 172
mmol). After
complete addition the reaction mixture was stirred at room temperature for 20
h. The mixture
was cooled in an ice bath and sodium hydroxide (60 mL of a 3 N solution, 181
mmol) was added
dropwise, followed by 30 % hydrogen peroxide (65 mL) and the resulting mixture
was stirred at
40 °C for 1 h. The mixture was poured into water (600mL) and extracted
with diethyl ether (3 x
200 mL), the combined diethyl ether layers were washed with water (3 x 500
mL), saturated
NaCI (100 mL), dried over MgS04, filtered and concentrated in vacuo. The
residue was purified
by column chromatography on silica elution with 20 % EtOAc/hexanes to give
18.5 g (58%) of
product.
Step D
83

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
O _
To a (-78 °C) solution of oxalyl chloride (55 mL, 110 mmol) in
anhydrous dichloromethane (300
mL) under an atmosphere of nitrogen was added in a dropwise manner dimethyl
sulfoxide (15.5
mL, 219 mmol), and the resulting mixture stirred at -78 °C for 10
minutes. To this mixture was
added, using a double ended needle, a solution of the product from Step C
(18.5 g, 100 mmol) in
anhydrous dichloromethane (100 mL). The reaction mixture was stirred at -78
°C for a further 15
minutes, then triethylamine (69 mL, 500 mmol) was added and the resulting
mixture was
allowed to rise to room temperature over 2 h. The reaction mixture was washed
with water (500
mL), saturated NaCI (150 mL), dried over MgS04, filtered and concentrated in
vacuo, to give 18
g of product which was used in the next step without further purification.
Step E
F
O
N
O'
To a solution of the cyclopentanone prepared in Step D (18 g, 98 mmol) in
anhydrous 1,2-
dichloroethane (500 mL), under an atmosphere of nitrogen, was added 4-(4-
fluorophenyl)piperidine hydrochloride (25 g, 120 mmol), diisopropylethylamine
(20.4 mL, 116
mmol), sodium triacetoxyborohydride (112 g, 531 mmol), and 4 ~1 molecular
sieves (powder 10
g). The mixture was stirred at room temperature for 48 h, and then diluted
with dichloromethane
(500 mL), and filtered through celite. The filtrate was washed with saturated
NaHC03 solution
(500 mL), water (500 mL), saturated NaCI (200 mL), dried over Na2S04, filtered
and
concentrated in vacuo to give 28 g (82 %) of product. This material was used
in the next step
without further purification.
Step F
84

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
1-isopropyl-3-(4-(4-fluorophenyl)piperidin-1-yl)cyclopentanecarboxylic acid
F
O
N
OH
To a solution of the cyclopentane methyl ester prepared in Step E (28 g, 81
mmol) in ethanol
(500 mL), was added a solution of potassium hydroxide (30 g, 540 mmol) in
water (100 mL),
and the resulting mixture was heated at reflux for 18 h. The cooled mixture
was concentrated in
vacuo to remove the ethanol, and water (200 mL) was added to the residue. The
mixture was
extracted with diethyl ether (3 x 200 mL), and the aqueous layer was
neutralized by the addition
of concentrated hydrochloric acid. The mixture was extracted with a mixture of
9/1
chloroform/2-propanol (3 x 150 mL), and the combined organic extracts were
dried over
Na2S04, filtered and concentrated in vacuo. To the residue was added acetone
(70 mL) and the
mixture was heated to reflux briefly and then was left standing at +5
°C for 16 h. The acetone
was decanted way from the white solid, and the remaining solid was dried to
give 11.5 g (43 %)
of product which was a 10:1 mixture of cis and trans isomers.
ESI-MS calc. for C20H28FN02: 333; Found: 334 (M+H).
INTERMEDIATE 22
CBZ
2,5-Dimethyl-3-pyrroline (3.128 g, 32.19 mmol) was dissolved in triethylamine
(8.97 mL, 64.4
mmol) and cooled to 0 °C. Carbobenzyloxychloride (10.11 mL, 70.83 mmol)
in a minimal
amount of dichloromethane was added dropwise. The reaction mixture was slowly
warmed to
room temperature and stirred for 48 h. The reaction was quenched with
saturated sodium
bicarbonate solution (150 mL), and the organic layer was then washed with
saturated sodium
bicarbonate solution (2 x 100 mL) and brine (1 x 100 mL), dried over MgS04,
filtered, and

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
concentrated. Intermediate 1 (3.844 g) was obtained in a 52% yield through
purification by silica
gel flash column chromatography using a gradient solvent system of 5% EtOAc in
hexanes to
10% EtOAc in hexanes. ESI-MS calculated for C~4H1~N02: 231.29, found 232
(M+H).
INTERMEDIATE 23
H O
~O~N~
OH
O
Procedure A:
Step A
O
H2N
home
A mixture of (1S)-(+)-2-azabicyclo[2.2.1]kept-5-en-3-one (10.3 g, 94.4 mmol)
in
ethyl acetate (200 mL) and 10% Pd/C (0.5 g), was hydrogenated at room
temperature. After 24
h the reaction mixture was filtered and evaporated leaving behind 10.4 g
(100%) of the product
that was taken in 250 mL methanol and HCl (12 M, 6 mL). The resultant mixture
was stirred at
room temperature, until the reaction was complete (72 h). Evaporation of
methanol followed by
drying under high vacuum, yielded title compound as an off white solid (16.0
g, 96%). 'H NMR
(500 MHz, DZO): b 3.70 (s, 3H), 3.01 (m, 1H), 2.38 (m, 1H), 2.16-1.73 (m, 6H).
Step B
O
Ph~N
home
Ph
86

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
To a suspension of the intermediate from Step A (10.2 g, 56.8 mmol) in dry
dichloromethane (200 mL) was added benzophenone imine (10.2 g, 56.8 mmol) at
room
temperature and the resultant mixture was stirred for 24 h. The reaction
mixture was filtered and
the filtrate was evaporated, to leave behind a yellow oil that was triturated
with ether (100 mL),
filtered and evaporated. This operation was repeated twice to ensure that the
product was free of
ammonium chloride impurities. The resultant oil was thoroughly dried under
vacuum to yield
the title compound (18.03 g, >100%) and required no further purification. 1H
NMR (500 MHz,
CDC13): S 7.5-7.18 (m, 10H), 3.75 (m, 1H), 3.7 (s, 3H), 2.78 (m, 1H), 2.26-
1.71 (m, 6H).
Step C
H O
~O~N~
OMe
O
To a solution of lithium diisopropylamide (prepared from diisopropylamine (7.7
g, 76 mmol) and n-butyllithium (30.4 mL, 2.5 M in hexanes, 76 mmol) in
tetrahydrofuran (120
mL) at -78 °C was added the ester from Step B (18.0 g, 58.6 mmol). The
resultant burgundy
colored solution was stirred for 20 min after which it was quenched with 2-
iodopropane (14.9 g,
88.0 mmol). The reaction mixture was gradually warmed over 3 h to 0 °C
and this temperature
was maintained for an additional 3 h. Reaction was quenched with water and
extracted with
ethyl acetate. The organic layer was washed with water, brine, dried
(anhydrous magnesium
sulfate) and concentrated to yield an oil. To the solution of the crude Schiff
base (20.0 g) in
tetrahydrofuran (100 mL) was added HCl (5.0 mL, 12 M). The resulting reaction
mixture was
allowed to stir at room temperature for 3 h. After the removal of all
volatiles, the hydrochloride
salt was taken up into dichloromethane (250 mL), saturated solution of sodium
bicarbonate (250
mL) and di-tert-butyl dicarbonate (26.0 g, 1.4 Eq.) were added. The resultant
mixture was
vigorously stirred overnight at room temperature. The organic layer was
separated and washed
with water, brine, dried (anhydrous magnesium sulfate) and concentrated to
yield an oil.
Purification by flash column chromatography (eluent: hexanes/ethyl acetate 19
: 1) gave the
87

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
desired product (4.91 g, 30%). 1H NMR (500 MHz, CDC13): 4.79 (br, 1H), 4.01
(m, 1H), 3.71
(s, 3H), 2.18-1.60 (m, 6H), 1.44 (s, 9H), 0.87 (d, J = 6.9 Hz, 3H), 0.86 (d, J
= 6.9 Hz, 3H).
Step D
H O
~O~N~
-OH
O
To a solution of the ester from Step C (4.91 g, 17.2 mmol) in methanol (100
mL)
was added a solution of LiOH (3.6 g, 85 mmol) in water (20 mL) and
tetrahydrofuran (10 mL).
The resultant mixture was heated at 80 °C until the reaction was
complete (18 h). The methanol
was removed in vacuo and the crude product was taken up with water/ethyl
acetate (200 mL, 1:4)
and cooled to 0 °C. The acidity of the mixture was adjusted to pH 6.
The ethyl acetate layer was
separated, washed with water, brine, dried (anhydrous magnesium sulfate) and
concentrated to
yield an oil. Purification by flash column chromatography (eluent:
hexanes/ethyl acetate 1:1 +
2% AcOH) gave Intermediate 11 (3.9 g, 84%). 1H NMR (500 MHz, CDC13): 11.36
(br, 1H),
6.49 (br, 1H), 4.83 (m, 1H), 3.71 (s, 3H), 2.30-1.55 (m, 6H), 1.46 (s, 9H),
0.94 (d, J = 6.9 Hz,
3H), 0.933 (d, J = 6.9 Hz, 3H).
Procedure B:
Step A:
HCI O
H2N ~Oi
Commercially available (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid was
converted to its methyl ester hydrochloride salt via classical procedures.
Step B:
88

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
H O
~O~ N
IOI V -O
To a suspension of amine from Step A (6.31 g, 35.5 mmol) in acetone (40 mL)
and water
(20 mL) was added solid NaHC03 (6.6 g, 78 mmol) in portions. After 5 min, a
solution of di-
tert-butyl dicarbonate (8.5 g, 39 mmol) in acetone (60 mL) was added and the
reaction mixture
was stirred at room temperature. After 3 h, acetone was removed in vacuo and
the residue was
partitioned between ether (500 mL) and saturated aqueous NaHC03 solution (120
mL). The
ether layer was further washed with aqueous NaHC03 solution (1 x 100 mL),
brine (1x100 mL),
dried over anhydrous Na2S04, concentrated and purified by flash chromatography
(15% ethyl
acetate/hexanes) to afford the product (7.25 g, 85%).
Step C:
H O
\ /OUN
~O
O
To a solution of lithium bis(trimethylsilyl)amide (10.4 g, 62.1 mmol) in
tetrahydrofuran
(100 mL) was added a solution of the intermediate from Step B (6.71 g, 27.8
mmol) in
tetrahydrofuran (10 mL) over 10 min at -78 °C. The resulting solution
was stirred at -78 °C for
30 min before isopropyl iodide (3.3 mL, 33 mmol) was added in one portion. The
reaction was
allowed to warm up to -25 °C and this temperature was maintained
overnight. The reaction was
then quenched with an aqueous saturated NHQCI solution (250 mL). The organic
layer was
separated and the aqueous layer was further extracted with diethyl ether (3 x
100 mL). The
combined organic layers were then washed with brine (1 x 100 mL), dried over
anhydrous
NaZS04, filtered, concentrated and purified by flash chromatography (5-10%
ethyl
acetate/hexanes) to give the product (5.66 g, 72%) as a clear oil (cis/trans =
4.3/1). 'H NMR
(500 MHz, CDCl3) cis-isomer: 8 5.79 (s, 2H), 4.75 (m, 1H), 3.72 (s, 3H), 2.28-
2.20 (m, 2H), 2.0
(dd, J = 15, 4 Hz, 1H), 1.45 (s, 9H), 0.85 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 7
Hz, 3H).
89

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step D:
H O
~O~N~
OH
O
To a solution of the product from Step C (1.6 g, 5.7 mmol) in tetrahydrofuran
(50
mL), methanol (50 mL) and water (10 mL) was added LiOH monohydrate (400 mg)
and the
reaction was heated to reflux overnight until the TLC indicated that the
reaction was complete.
The organic solvents were removed in vacuo and the aqueous layer was.washed
with ether (1 x)
and then acidified slowly with concentrated HCl until the pH reached 4. The
resulting
suspension was extracted with CH2Cl2 (3 x). The combined organic layers were
dried over
anhydrous MgS04, filtered and concentrated to give the product as a mixture of
two cis/trans
isomers (1.5 g) as a foaming yellow solid. This solid was dissolved in ethyl
acetate (2 mL) with
heating and diluted with hexanes (50 mL) to give a clear solution. This
solution was allowed to
cool to room temperate slowly over 1 h and then maintained at -25 °C in
a freezer overnight.
The trans-isomer was crystalized out along with some of the desired cis-isomer
(500 mg total).
The mother solution was collected and concentrated to give the title compound
(1 g, 66%, cis-
isomer only).'H NMR (500 MHz, CDC13) cis-isomer: 8 5.80 (m, 2H), 4.80 (m, 1H),
2.40-2.20
(m, 2H), 2.15-2.0 (m, 1H), 1.5 (m, 9H), 1.0-0.8 (m, 3H).
Step E:
H O
\ /OUN~OH
IOI
To a solution of the product from Step D (1 g) in ethanol (30 mL) was added
10%
Pd/C (100 mg) and the resulting mixture was agitated on a Parr apparatus at 50
1b pressure of H2
overnight. The mixture was filtered through celite and concentrated in vacuo
to afford the title
compound (1 g, 99%). 1H NMR (500 MHz, CDC13): 11.36 (br, 1H), 6.49 (br, 1H),
4.83 (m,
1H), 3.71 (s, 3H), 2.30-1.55 (m, 6H), 1.46 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H),
0.933 (d, J = 6.9 Hz,
3H).

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
INTERMEDIATE 24
O
H2N~N ~ CF3
N
Step A
H O
~O~N~N I ~ CF3
II ~(~jO
N
Intermediate 2 (4.6 g, 16 mmol) and Intermediate 23 (4.0 g, 14 mmol) were
first
dried by azeotropic distillation with toluene (3x 50 mL) and placed under high
vacuum for 30
min. Under nitrogen, 4-dimethylaminopyridine (1.08 g, 8.60 mmol), anhydrous
dichloromethane
(40 mL), and diisopropylethylamine (7.0 mL, 40 mmol) were added sequentially.
After the
intermediates were in solution, bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate (6.80
g, 14.3 mmol) was added, immediately followed by additional
diisopropylethylamine (7.0 mL,
40 mmol). The reaction mixture was stirred at room temperature overnight and
then quenched
with saturated NaHC03. The aqueous layer was back washed with dichloromethane
(3 x 50
mL) and the organic layers were combined, dried over NaZS04, filtered, and
evaporated in vacuo.
The crude product was purified by flash chromatography (stepwise gradient 0-
60%, ethyl
acetate/hexanes) to afford the product (4.80 g, 74%) as a yellow foam. 1H NMR
(500 MHz,
CDCL3) 8 8.72 (s, 1H), 7.70 (s, 1H), 4.88 (br d, J = 17.0 Hz, 1H), 4.78 (d, J
= 17.6 Hz, 1H),
4.04-3.84 (m, 2 H), 3.52 (br s, 1H), 3.12 (br t, J = 5.6 Hz, 1H), 2.32-2.06
(m, 3H), 1.98-1.70 (m,
4H), 1.64-1.54 (m, 1H), 1.44 (s, 9H), 0.92-0.82 (m, 6H). LC-MS for
CZ3H32FsN303 calculated
455.24, found [M+H]+ 456.2.
Step B
O
H2N~N ~ CF3
~ N
91

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The product from Step A (1.2 g, 2.6 mmol) was dissolved in 4 M HCl in dioxane
(50 mL) and the resulting solution was stirred at room temperature for 1 h.
The reaction mixture
was evaporated under vacuum to afford the product (904 mg, 97%) as a white
powder. LC-MS
calculated for CI8H24F3N3O is 355.20, found [M+H]+ 356.2.
INTERMEDIATE 25
0
H2N
CF3
N~~~~
Step A
H O
N
Boc~ CF3
~N
To a flask was added Intermediate 23 (1.l g, 4.0 mmol), Intermediate 1 (0.944
g, 4.00 mmol),
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.85 g, 4.00 mmol),
DMAP (0.29 g,
2.4 mmol), DIEA (2.77 mL, 16 mmol) and DCM (20 mL). The resulting mixture was
stirred for
36 h under nitrogen. The entire mixture was applied onto a silica gel column
and eluted with
20% EtOAc/Hexane. The desired Boc-amide was obtained as a gummy solid (1.5 g,
82%). ESI-
MS calc. for C24H33F3N2O3: 454; Found: 455 (M+H).
Step B
0
HpN
~ ~ CF3
y _N
The Boc amino amide from Step A was treated with 10 mL of 4 N HC1/Dioxane for
1 h. the
reaction mixture was evaporated and the product was dried under vacuum.
Intermediate 25 was
obtained as a yellow solid (1.2 g). ESI-MS calc. for C19H25F3N20: 354; Found:
355 (M+H).
INTERMEDIATE 26
HN ~ CF3
N02
92

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step A
O
~O~N ~ CFs
/
N02
To a flask containing Intermediate 1 (10 g, 50 mmol) was added 30 mL of
70°lo nitric acid. The mixture was cooled at 0 °C, 30 mL of
concentrated sulfuric acid was added
over 30 min. The resulting solution was stirred at RT overnight, poured into
an ice-water
mixture, adjusted to pH > 10 with solid LiOH-H20 at 0 °C. Under
vigorous stirring, a solution
of di-tert-butyl carbonate (21.8 g, 100 mmol) in 500 mL of DCM was added. The
mixture was
stirred for 30 min, the organic layer was separated, the aqueous layer was
extracted with DCM (2
X 200 mL). The combined extracts were washed with water (500 mL), dried over
NaZS04, and
evaporated. The crude product was purified by flash chromatography (silica
gel, 20%
EtOAc/Hexane) to afford the title compound as a white solid (17.0 g, 98%). 1H
NMR (400
MHz, CDC13) S 8.05 (s, 1H), 7.62 (s, 1H), 4.72 (s, 2H), 3.67 (t, J=6.0 Hz,
2H), 3.13 (t, J=6.0 Hz,
2H), 1.49 (s, 9H).
Step B
HN ~ CF3
/
N02
The above intermediate from Step A (17.0 g) was dissolved in 100 mL of 4 M
HCl/dioxane,
stirred for one hour, evaporated and dried under vacuum. Intermediate 26 was
obtained as white
solid. 1H NMR (400 MHz, CD30D) 8 8.75 (s, 1H), 8.00(s, 1H), 2.58 (s, 2H), 3.57
(t, J=6.0 Hz,
2H), 3.42 (t, J=6.0 Hz, 2H).
INTERMEDIATE 27
H2N O
N ~ CF3
N02
93

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step A
BocHN O
~N ~ CFs
N02
To a flask was added Intermediate 27 (1.10 g, 4.00 mmol), Intermediate 23
(1.15 g, 4.00 mmol),
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.85 g, 4.00 mmol),
DMAP (0.29 g,
2.4 mmol), DIEA (2.7 mL, 16 mmol) and DCM (20 mL). The resulting mixture was
stirred for
36 h under nitrogen. The entire mixture was applied onto a silica gel column
and eluted with
20% EtOAc/Hexane to yield the title compound as a gummy solid (1.5 g, 75%).
ESI-MS calc. for
C24H32F3N3O5: 499; Found: 500 (M+H).
Step B
H2N O
N ~ CF3
N02
The coupling product from the previous step (1.5 g) was treated with 10 mL of
4N HCl/Dioxane
for 1 h, evaporated and dried under high vacuum to yield the title compound as
a yellow solid
(1.2 g). 1H NMR (400 MHz, CD30D) 8 8.20 (s, 1H), 7.95(wide, 1H), 4.98 (s, 2H),
4.00 (dd,
2H), 3.90 (t, 2H), 3.68 (m, 1H), 3.45 (m, 3H), 3.20 (s, 2H), 2.15-2.50 (m,
3H), 1.80-2.10 (m,
2H), 1.80 (m, 2H), 0.90 (m, 6H). ESI-MS calc. for C 19H24F3N3O3: 399; Found:
400 (M+H).
INTERMEDIATE 2
HN ~ CF3
COOMe
Step A
94

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
F C~N ~ CF3
3
To a stirring mixture of N-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-
tetrahydroisoquinoline, from
Intermediate 1, Step B (6.0 g, 20 mmol), NIS (6.9 g, 30 mmol) and TFA (15 mL)
vvas added
dropwise concentrated sulfuric acid (1.5 mL). A large amount of solid was
formed. The mixture
was stirred overnight at RT, poured into an ice-water mixture, extracted with
ethyl acetate (3 X).
The combined organic phases were washed with water and brine, dried over
Na2S04, evaporated.
The residue was purified on silica gel (eluted with 10% EtOAc/Hexane). The
combined
fractions were washed with sat. NaHS03, dried over NazS04, evaporated and
dried under
vacuum to afford the title compound as a white solid (5.0 g). 1H NMR (400 MHz,
CDC13) 8
8.02 (d, J=2.5 Hz, 1H), 7.42 (d, j=3.OHz, 1H), 4.85, 4.79 (ss, 2H), 3.95, 3.90
(tt, J=1.5, 1.5 Hz,
2H), 2.97 (m, 2H). ESI-MS calc. For C12H8F6IN0: 423; Found: 424 (M+H).
Step B
O
F C~N ~ CF3
3
CN
A mixture of the iodo compound (Step A, 4.2 g, 10 mmol), zinc cyanide (2.3 g,
20 mmol) and
tetrakis-triphenyl phosphene palladium (0) complex (0.4 g) in 50 mL of DMF was
purged with
nitrogen several times, then heated at 85 °C overnight under nitrogen.
LC-MS showed a
complete conversion. The insoluble material was removed by filtration. The
filtrate was diluted
with water and extracted with ethyl acetate (3 x). The ethyl acetate layers
were combined,
filtered through celite, then washed with water, dried over Na2S04, and
evaporated. The residue
was purified on silica gel (eluted with 10% EtOAc/Hex) to yield the title
compound as a white
solid (2.5 g). 1H NMR (400 MHz, CDC13) S 7.85 (d, J=2.1 Hz, 1H), 7.65 (d,
J=2.6 Hz, 1H),
4.91, 4.86 (ss, 2H), 4.00 (m, 2H), 3.25 (m, 2H). ESI-MS calc. For C13H8F6N20:
323; Found:
323 (M+H).
95

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step C
HN ~ CF3
/
CN
A mixture of the amide Intermediate from Step B (500 mg, 1.55 mmol), potassium
carbonate
(1.5 g), ethanol (20 mL) and water (0.5 mL) was heated at 80 °C until
TLC showed complete
cleavage. The solvent was evaporated, diluted with water, extracted with DCM
(3 x), dried over
Na2S04, evaporated, and dried under vacuum. The title product was obtained as
a white solid
(0.41 g). ESI-MS calc. For C11H9F3N2: 226; Found: 227 (M+H).
Step D
HN I ~ CF3
O OH
The above cyano intermediate from Step C (1.9 g, 8.5 mmol) was refluxed with
50 mL of
concentrated aq. HCl for 48 h. LC-MS showed a complete hydrolysis. The mixture
was cooled
to RT and the resultant precipitate was collected by filtration and washing
with concentrated aq.
HCI. The desired product as its HCl salt (1.75 g, 73%) was obtained after
drying under high
vacuum. 'H NMR (CD30D, 400 MHz): 8 8.20 (s, 1H), 7.80 (s, 1H), 4.51 (s, 2H),
3.55 (m, 4H).
LC-MS for C11H10F3N02 calculated 245, found [M+H]+ 246.
Step E
HN ~ CF3
/
O O~
To a suspension of the above amino acid HC1 salt from Step D (1.75 g, 6.25
mmol) in 50 mL of
methanol was added slowly a neat solution of acetyl chloride (5 mL). The
resultant mixture was
refluxed until LC-MS showed a complete esterification (~3 h), then the solvent
was evaporated
and dried under high vacuum to yield the title compound as a white solid (1.85
g, 100%). 'H
NMR (CD30D, 400 MHz): 8.19 (s, 1H), 7.82 (s, 1H), 4.50 (s, 2H), 3.94 (s, 3H),
3.53 (s, 4H).
LC-MS for C12H12F3N02 calculated 259, found [M+H]+ 260.
96

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
INTERMEDIATE 29
O~C02H
Procedure A:
Step A:
O C02H H2S~4~ M9S04 C02-t-Bu
t-BuOH, DCM
HZS04 (cone, 15.3 g, 8.30 mL, 156 mmol) was added dropwise to a vigorously
stirred
suspension of MgS04 (75 g, 620 mmol) in DCM (650 mL). The mixture was stirred
for 0.5 h,
then known cyclopentanone-3-carboxylate (20.0 g, 156 mmol) was added, followed
by t-butanol
(58 g, 780 mmol). The reaction vessel was tightly sealed and the mixture was
stirred overnight
at room temperature. The next morning another 30 mL of t-butanol was added.
Again the
reaction vessel was tightly sealed, and the reaction mixture was stirred over
the weekend. The
reaction mixture was then filtered through celite. The filtrate was washed
with 2 N NaOH. The
aqueous layer was back-washed with DCM. The organic layers were combined,
washed with
water, then brine, dried over anhydrous MgS04, filtered, and concentrated to
afford 19.9 g (69%)
of ten-butyl 3-oxocyclopentanecarboxylate. The reaction progress was monitored
by TLC using
50% ethyl acetate/hexane and staining with anisaldehyde stain (SM and product
stain purple).
~H NMR (500 MHz, CDCI3): 3.02 (p, J = 7.8 Hz, 1H), 2.05 - 2.50 (m, 6H), 1.45
(s, 9H). '3C
NMR (125 MHz, CDC13): 217.00, 173.47, 80.99, 41.88, 41.14, 27.94, 26.57.
Step B:
trimethylorthoformate nneo CO -t-Bu
O~C02-t-Bu
TsOH, MeOH, DCM Me0
To a solution of tert-butyl 3-oxocyclopentanecarboxylate (19.8 g, 107 mmol) in
1:1
DCM/methanol (150 mL) was added trimethylorthoformate (46.8 mL, 428 mmol),
followed by
TsOH~H20 (~0.5 g). The reaction mixture was stirred at room temperature for 2
h. Then more
TsOH~HZO 00.25 g) was added and the reaction mixture was stirred overnight.
The reaction
mixture was concentrated at room temperature and the resulting residue was
dissolved in ether
and washed with saturated NaHC03 solution, then with brine. The ethereal layer
was dried over
97

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
anhydrous MgS04, filtered, and concentrated. Purification by flash
chromatography (silica, 15%
ethyl acetate/hexane) gave 22.2 g (90%) of tert-butyl 3,3-
dimethoxycyclopentanecarboxylate.
~H NMR (500 MHz, CDC13): 3.21 (s, 3H), 3.20 (s, 3H), 2.80 (m, 1H), 2.10 to
1.80 (bm, 6H),
1.46 (s, 9H). ~3C NMR (125 MHz, CDC13): 174.9, 111.2, 80.3, 67.8, 49.2, 42.5,
37.4, 33.8,
28.3, 22Ø
Step C:
Me0 Co2-t-Bu FDA; 2-iodopropane Me0 CO -t-Bu
z
MeO~ Me0
To a cooled (-78 °C) solution of LDA (1.5 M in cyclohexane, 41 mL, 61
mmol) in THF (150
mL) was added dropwise over 10 min tent-butyl 3,3-
dimethoxycyclopentanecarboxylate (9.37 g,
40.7 mmol) in 25 mL of THF. The resulting mixture was stirred at -78 °C
for 30 min, then was
treated dropwise with 2-iodopropane (16.3 mL, 163 mmol). After stirring for an
additional 10
min, the reaction mixture was permitted to warm to room temperature. After
stirring overnight,
the reaction mixture was diluted with ether and washed with brine. The
ethereal layer was dried
over anhydrous MgS04, filtered, and concentrated. After storing the crude
product under
vacuum overnight, it was purified by MPLC (silica, 20% ethyl acetate/hexane)
to give 8.32 g of
tert-butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (75%).
'H NMR (500 MHz, CDCl3) ~ 3.21 (s, 3H), 3.18 (s, 3H), 2.56 (app d, J = 14 Hz,
1H), 2.26 (m,
1H), 1.78-1.89 (m, 3
Step D:
Meo 4N HCI in dioxane O Co2H
C02-t-Bu
Me0
tert-Butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (8.32 g, 30.5
mmol) was dissolved
in 4 N anhydrous HCl in dioxane (50 mL) and water (10 mL) was added. The
reaction mixture
was stirred at room temperature overnight, then was concentrated. The residue
was dissolved in
DCM, dried over anhydrous MgS04, filtered, and concentrated to give 5.44 g of
1-isopropyl-3-
oxocyclopentanecarboxylic acid (used without purification).
98

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
'H NMR (500 MHz, CDC13) 8 2.70 (d, J = 18.1 Hz, 1H), 2.44-2.39 (m, 1H), 2.30-
2.15 (m, 2H),
2.14 (dd, J = 18.1, 1.0 Hz, 1H), 2.06 (p, J = 6.9 Hz, 1H), 1.98 (m, 1H), 0.98
(dd, J = 11.4, 6.9
Hz, 6H).
Step E:
p~o2H oxalyl chloride; o Cp2Bn Chiral HPLC p~CO2Bn
BnOH ~ OD column
15% i-ProH/hexane Faster eluting peak
A cooled (0 °C) solution of 1-isopropyl-3-oxocyclopentanecarboxylic
acid (5.44 g, 32.0 mmol)
in DCM (75 mL) was treated with oxalyl chloride (8.36 mL, 95.9 mmol), followed
by 3 drops of
DMF. The reaction mixture was permitted to warm to room temperature and stir
for 1.75 h. The
reaction mixture was then concentrated and stored under vacuum for 30 min. The
resulting acid
chloride was dissolved in DCM (75 mL), cooled to 0 °C, and treated with
benzyl alcohol (8.28
mL, 80.0 mmol), followed by triethyl amine (8.92 mL, 64.0 mmol, dropwise).
Then
approximately 100 mg of DMAP was added and the reaction mixture was warmed to
room
temperature and stirred for 2 h. The reaction mixture was diluted with DCM and
washed with 1
N HCl solution, saturated NaHC03 solution, and brine. The organic layer was
dried over
anhydrous MgS04, filtered, and concentrated. Purification by MPLC (silica, 50%
ethyl
acetate/hexane) gave 6.11 g (73%) of benzyl 1-isopropyl-3-
oxocyclopentanecarboxylate.
1HNMR (CDC13, 500 MHz): S 7.36 (m, 5 H), 5.17 (d, J = 2.5 Hz, 2H), 2.85 (d, J
= 18.5 Hz, 1H),
2.48 (m, 1H), 2.29 (dd, J = 10.0, 3.0 Hz, 1H), 1.98-2.23 (m, 3H), 1.93 (m,
1H), 0.95 (m, 6H).
Resolution of the racemic product was accomplished by chiral HPLC using a
chiralcel OD
column, and eluting with 15% 2-propanol/hexane (100 mg/injection; was
accomplished using a
programmed Gilson HPLC system). 2.11 g Of the desired faster eluting isomer,
benzyl (1S)-1-
isopropyl-3-oxocyclopentanecarboxylate, were obtained.
Step F:
O~C02Bn H2, Pd/C O~C02H
MeOH
Benzyl (1S)-1-isopropyl-3-oxocyclopentanecarboxylate (1.27 g, 4.88 mmol) was
combined with
Pd/C (10% Degussa, 500 mg) in 20 mL of methanol and stirred under a hydrogen
atmosphere
(balloon) for 2 h. The reaction had only proceeded part way (~30% conversion)
so the reaction
99

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
mixture was filtered, another portion of Pd/C (500 mg) was added, and the
mixture was stirred
under a hydrogen atmosphere for 5 h. Since the reaction had now gone to
completion, the
reaction mixture was filtered through celite and concentrated to afford 704 mg
of (1S)-1-
isopropyl-3-oxocyclopentanecarboxylic acid that did not require further
purification. Note that
the large quantities of catalyst were used because the ester obtained after
chiral separation must
have been poisoned by an impurity. This was unique to this particular sample.
Normally much
smaller quantities of catalyst are used. 1H NMR was identical to that of the
racemic acid above
(Step D).
Procedure B:
O O O
BocHN~OH ~'CI+H3N OH ~ O'~OH
HCI/dioxane ~ NBS ~'~~
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-
isopropylcyclopentanecarboxylic acid
(7.46 g, 27.5 mmol) in dioxane (10 mL) was added 4 N HCl in dioxane (30 mL).
The reaction
mixture was stirred at room temperature for 2 hours, then concentrated in
vacuo to give the
corresponding aminoacid salt as a white solid. This solid was then dissolved
in CHZC12 (100
mL) and solid NaHC03 (7.0 g, 82.5 mmol) was added. After cooled to 0
°C, a solution of NBS
(20.0 g, 110 mmol) in CHZCIZ (200 mL) was slowly added to the reaction over 4
hours. After the
addition, the reaction was concentrated to dryness in vacuo and then dissolved
in ethanol (100
mL). To this ethanol solution was added NaOMe (4.45 g, 82.5 mmol) and the
reaction was
heated to reflex. After 1 hour at reflex, the reaction was cooled to 0
°C and 2N aqueous H2S04
(50 mL) was added. The mixture was stirred at room temperature for 1 hour
before
concentrating in vacuo to about 60 mL in volume. The remaining mixture was
partitioned
between water (150 mL) and ethyl acetate (100 mL). The aqueous layer was
further extracted
with ethyl acetate twice. The organic layers were combined and dried over
anhydrous MgS04,
concentrated and purified by flash chromatography (silca, ethyl
acetate/hexanes) to give (1S)-1-
isopropyl-3-oxocyclopentanecarboxylic acid (3.00 g, 64%).
INTERMEDIATE 30
100

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
C02Et
HN ""' ~ ~ trans racemate
Step A:
C02Et
BocN
O
To a stirred solution of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]piperidine-1-
carboxylate (48 g,
220 mmol) in chloroform (900 mL) was added ruthenium (IV) oxide hydrate (6.0
g, 45 mmol)
followed by a solution of sodium periodate (150 g, 700 mmol) in water (900 m
L). The resulting
heterogenous reaction mixture was stirred at room temperature for 11 days
before being filtered
through a short column of celite. The organic layer was removed and the
aqueous layer was
extracted twice with DCM. The combined organic layers were washed with a 10%
solution of
sodium thiosulfate in water twice, and once with brine. This solution was
dried over MgS04,
filtered, and concetrated udner reduced pressure. The product was purified by
flash
chromatography (silica gel, 20% EA/hexanes) to give 22.5 g (64.8 mmol) of tert-
butyl 4-[3-
(ethoxycarbonyl)phenyl]-2-oxopiperidine-1-carboxylate (29%).
ESI-MS calculated for C19H25N05: 347.17; found 370.1 (M+Na)
Step B:
C02Et
BocN
O
Potassium bis(trimethylsilyl)amide (14 g, 71 mmol) was mixed with 300 mL of
THF in a 1000
mL flame-dried round bottomed flask and the resulting mixture was cooled to -
78 °C. tert-butyl
4-[3-(ethoxycarbonyl)phenyl]-2-oxopiperidine-1-carboxylate (22.5 g, 64.8 mmol)
dissolved in
150 mL of THF was added slowly to the mixture, via an addition funnel, and the
resulting
reaction mixture was stirred at -78 °C for 30 min. Methyl iodide (12.1
mL, 195 mmol) was then
added dropwise and the reaction mixture was allowed to stir at -78 °C
for 4 h before being
allowed to warm to room temperature overnight. The reaction was quenched with
saturated
ammonium chloride and extracted 3 times with ether. The combined ethereal
layers were
washed with brine and dried over MgS04, filtered, and concentrated under
reduced pressure.
The product was purified by flash chromatography (10-20% EA/hexanes) to give
6.1 g of the
101

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
trans racemate of tent-butyl 4-[3-(ethoxycarbonyl)phenyl]-3-methyl-2-
oxopiperidine-1-
carboxylate (26%).
ESI-MS calculated for C20H27N05: 361.19; found 384.25 (M+Na).
Step C:
C02Et
HN
O
The product from Step B (6.1 g, 17 mmol) was dissolved in 4.0 M HCl in dioxane
and stirred at
room temperature for 2 h before being concentrated under reduced pressure to
give the desired
product as an orange solid which was sued directly in the next step without
further purification.
ESI-MS calculated for C15H19N03: 261.14; found 262.1 (M+H).
Step D:
C02Et
HN ~~~~~ ~ ~ trans racemate
The product from the previous step (entire amount ~17 mmol) was dissolved in
THF (100 mL)
and treated dropwise with 2.0 M borane-methyl sulfide solution in THF (31 mL,
62 mmol). The
resulting solution was stirred at room temperature for 4 h before being stored
at 4 °C for 72 h.
The solvent was removed under reduced pressure and the resulting residue was
dissolved in 0.5
M HCl (aqueous ~38%) in ethanol. This solutionw as heated to 50 °C and
stirred for 4 h. The
solvent was removed and the procedure was repeated again to ensure the break
up of the borane
complex. The solvent was removed and the product was purified by MPLC (0-15%
(10%
NH40H/MeOH)/DCM) to give the desired product which was 80% pure. This crude
material
was dissolved in DCM (100 mL) and treated with di-tert-butyl dicarbonate (2.95
g, 13.5 mmol),
diisopropylethylamine (2.30 mL, 13.5 mmol) and DMAP (10 mg). The resulting
reaction
mixture was stirred overnight at room temperature before being diluted with
DCM and washed
with 1 N aqueous, aqueous saturated sodium bicarbonate, and brine. The organic
layer was dried
over MgS04, filtered and concentrated under reduced pressure. The intermediate
was purified by
MPLC (0-40% EA/hexanes). The resulting colorless oil was dissolved in 4.0 M
HCl in dioxane
and the resulting reaction mixture was stirred at room temperature for 1.5 h.
The reaction
mixture was concentrated to dryness to give 2.13 g (7.52 mmol) of the desired
HCl salt.
ESI-MS calculated for C15H21N02: 247.16; found 248.15 (M+H)
102

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 1
Et02C 0
~N C F3
N ~
\
To a solution of Intermediate 3 (150 mg, 0.425 mmol), 4-carbethoxypiperidine
(125 mg,
0.425 mmol), and DCM (25 mL) was added molecular sieves (4 t~) and NaBH(OAc)3
(450 mg,
2.12 mmol). The reaction mixture was stirred at room temperature for 18 h
before being filtered
through celite, diluted with saturated NaHC03, and extracted with DCM (3 x).
The combined
organic layers were dried over NazS04 and purified by preparative TLC
(3/96.7/0.3,
MeOH/DCM/NH40H) to yield Example 1 (220 mg, 97.8°!0). LC-MS for
Cz7H3gF3N2O3 [M+H+]
calculated 495.28, found 495.25.
A number of compounds were prepared as detailed in Example 1 using various
amines. These
compounds are summarized in the table below.
Table 1 (EXAMPLES 2 to 6)
O
N \ CFs
I/
ExampleR Molecular Calculated Found
Formula [M+H+] [M+H+]
2 \v~N Cz~H3gF3Nz03 495.28 495.15
Me02 ~/C
3 Et02C N Cz~H38F3N203 485.28 495.15
4 Et02C N CzsHaoFsNz03 509.29 509.35
5 Me02C~ CzsH3aF3Nz03 467.24 467.1
.N
103

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
6 Me02C'~ C26H36F3N2~3 481.26 481.2
I~'N
EXAMPLE 7
H02C O
~N CF3
N
A mixture of the product from Example 1 (185 mg, 0.349 mmol), 5 N NaOH (200
~L,
1.04 mmol), and MeOH (5 mL) was heated at 60 °C for 3 hours before
adding a solution of 4N
HCl in dioxane to neutralize the base. The reaction solution was concentrated
and purified by
reverse phase HPLC to yield Example 7 (115 mg, 65.7%). LC-MS for CZSH34F3NZO3
[M+I-~]
calculated 467.24, found 467.35.
Examples 8-12 were prepared as detailed in Example 7 using Examples 2-6 as
starting materials.
These compounds are summarized in the table below.
Table 2 (EXAMPLES 8 to 12)
O
R N \ CFs
ExampleR Molecular Calculated Found
Formula [M+H+] [M+H+]
N C26H36F3N2~3 481.26 481.3
\v/~
H02C
9 H02C N Cz5H34F3N203 467.24 467.3
10 H02C'~~~N C26H36F3N2~3 481.26 481.3
104

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
11 H02C~ CzaH3zF3Nz~3 453.23 453.25
.N
12 H02C'~ C25H33F3N2~3 467.24 467.25
N
EXAMPLE 13
0
~N \ CFs
'N~
~O~N J
IIIf N
O
To a solution of Intermediate 4 (50 mg, 0.14 mmol) in methylene chloride (20
mL) was added 1-
ethoxycarbonylpiperazine (23 mg, 0.14 mmol). After adding powdered 4 A
molecular sieves (25
mg), sodium triacetoxyborohydride (180 mg, 0.84 mmol) was added and the
reaction mixture
was stirred overnight. The mixture was diluted with methylene chloride, washed
with aqueous
saturated sodium bicarbonate, dried under sodium sulfate and concentrated in
vacuo. The crude
product was purified by preparative TLC (7/92.3/.7, methanol/methylene
chloride/ammonium
hydroxide) to yield Example 13 as a mixture of 4 diastereomers (55 mg, 79%).
LC-MS: MW
calculated 496.27, found 497.3.
A number of compounds were prepared as detailed in Example 13 using various
piperazines
instead of 1-ethoxycarbonylpiperazine. These compounds, prepared as mixtures
of 4
diastereomers each, are summarized in the table below.
Table 3 (EXAMPLES 14 to 16)
O
R N \ CFs
' N
Example R Molecular Calculated Found
Formula [M+H+] [M+H+]
105

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
14 ~N C28H36F3N40 501.28 501.25
NJ
I~
15 ~ N CZ~H3~F3N40 515.29 515.3
NJ
I,
16 ~ Cz9I335F3N40 528.27 529.25
N
~N
EXAMPLE 17
0
/ ~N ~ CF3
O
To a solution of Intermediate 4 (50 mg, 0.14 mmol) in methylene chloride (20
mL) was
added 4-benzoylpiperidine hydrochloride (32 mg, 0.14 mmol) and N,N-
diisopropylethylamine
(73 ~L, 0.42 mmol). After adding 4 A powdered molecular sieves (25 mg), sodium
triacetoxyborohydride (180 mg, 0.84 mmol) was added and the reaction mixture
was stirred
overnight. The mixture was extracted with methylene chloride, washed with
sodium
bicarbonate, dried under sodium sulfate and concentrated in vacuo. The crude
product was
purified by preparative TLC (7/92.3/.7, methanol/methylene chloride/ammonium
hydroxide) to
yield Example 17 (30 mg, 43%) as a mixture of 4 diastereomers.
ESI-MS: calculated MW: 527.28, found 528.25.
EXAMPLE 18
O
HN
0
N CFs
N ~I
~ \N
106

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
A mixture of the Intermediate 4 (176 mg, 0.5 mmol), the spiropiperidine (as
HCl salt, 115 mg,
0.6 mmol), DIEA (100 mg, 0.8 mmol), molecular sieves (4 A, 200 mg) and sodium
triacetoxyborohydride (212 mg, 1.0 mmol) in dichloromethane (10 mL) was
stirred overnight.
The reaction was quenched with sat. aq. sodium carbonate. The solid was
removed by filtration
through celite. The crude product was extracted into dichloromethane and
purified on
preparative TLC (1000 micron, 10%[aq. NH40H/MeOH 1/9]/DCM). The title compound
was
obtained as a mixture of cis and trans racemic isomers (155 mg, 63%). LC-MS
calc. for
C26H35F3N4O2: 492; Found: 493 (M+H).
C. ZHOU
EXAMPLE 19
O
~N CF3
~N
N
To a stirred solution of Intermediate 5 (50 mg, 0.14 mmol) and piperidine (28
~L,
0.28 mmol), in DCM (10 mL), was added 4 A powdered molecular sieves (50 mg)
and sodium
triacetoxyborohydride (150 mg, 0.71 mmol). The resulting solution was allowed
to stir at room
temperature for 3 days before being filtered through celite and washed with
saturated aqueous
sodium bicarbonate and brine. The organic layer was dried over NaZS04,
filtered, and
concentrated under reduced pressure to give a crude oil that was purified by
preparative TLC (0.5
% NH40H/4.5 % MeOH/95 % DCM) to give 16 mg of a colorless solid as a mixture
of 2
diastereomers. A small portion of this free base was converted to its
hydrochloride salt by the
addition of 2 N HCl in ethyl ether.
ESI-MS calc. for C23H32F3N30: 423.25; found 424 (M+H).
Several other examples were made according to the procedure described in
Example 19 except that various substituted piperidines where used as the amine
component in
place of piperidine. The examples are compiled in Table 4.
Table 4 (EXAMPLES 20 to 28)
107

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
R N / CFa
N
Example Structure Molecular Calculated Found MW
Formula MW [M+H]
20 HN~ C25H35F3N402 480.27 481
O, ~N
21 ~ C26H36F3N303 495.27 496
~O
N
22 C26H36F3N303 495.27 496
~O N
O
23 ~~ C24H34F3N30 437.27 438
N
24 C24H34F3N30 437.27 438
IV
25 C25H36F3N30 451.28 452
IV
26 ~H C23H32F3N302 439.24 440
N
27 H~ C23H32F3N302 439.24 440
~N
28 ~ C24H32F3N30 435.25 436
N
108

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 29 and EXAMPLE 30
Et02C O Et02C O
\~N,,, CF3 ~N CF3
~N / I ~N
N ~ N
The free base of the product prepared in Example 22 (55 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
25 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. 27 mg of the faster eluting diastereomer (Example
29) and 20 mg of
the slower eluting diastereomer (Example 30) were recovered.
Example 29: ESI-MS talc. for C26H36F3N3O3: 495.27; found 496 (M+H).
Example 30: ESI-MS talc. for C26H36F3N3O3: 495.27; found 496 (M+H).
EXAMPLE 31
H02C O
~N,,, / CF3
~N
N
Example 29 (10 mg, 0.018 mmol), was dissolved in a mixture of methanol (1 mL)
and THF (1 mL), and treated with a solution of lithium hydroxide monohydrate
(5 mg, 0.12
mmol) in water (1 mL). The resulting solution was stirred for 18 h at room
temperature before
being concentrated under reduced pressure. The product was purified by reverse
phase HPLC
(C18, 20-100 % MeCN/HZO) and converted to its hydrochloride salt by addition
of 2 N HCl in
ethyl ether to give 6.8 mg of product (70 %).
ESI-MS talc. for C24H32F3N3O3: 467.24; found 468 (M+H).
EXAMPLE 32
H02C O
~N C F3
~N /
N
Example 30 (10 mg, 0.018 mmol), was dissolved in a mixture of methanol (1 mL)
and THF (1 mL), and treated with a solution of lithium hydroxide monohydrate
(5 mg, 0.12
109

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
mmol) in water (1 mL). The resulting solution was stirred for 18 h at room
temperature before
being concentrated under reduced pressure. The product was purified by reverse
phase HPLC
(C18, 20-100 % MeCN/H20) and converted to its hydrochloride salt by addition
of 2 N HCl in
ethyl ether to give 3.8 mg of product (39 %).
ESI-MS calc. for C24H32F3N3O3: 467.24; found 468 (M+H).
EXAMPLE 33
HO~~~~ O
N N / CFs
N
To a solution of Example 30 (15 mg, 0.026 mmol), in THF (2 mL) was added
lithium triethylborohydride (1.0 M solution in THF, 150 p,L, 0.15 mmol). After
18 h at room
temperature an additional portion of lithium triethylborohydride (100 pL) was
added and the
resulting mixture was stirred for 24 h before being concentrated under reduced
pressure. The
resulting residue was dissolved in DCM and washed with aqueous saturated
sodium bicarbonate,
1 N aqueous HCI, and then brine. The organic layer was dried over Na2S04,
filtered, treated
with 2 N HCl in ether followed by hexanes and concentrated under reduced
pressure to give 1.5
mg of the desired product as a hydrochloride salt (11 %).
ESI-MS calc. for C24H34F3N3O2: 453.26; found 454 (M+H).
EXAMPLE 34 and EXAMPLE 35
O O
~N O ~N O
N,,,~N / CF3 H N~N / CF3
~ N ~ N
The free base of the product prepared in Example 20 (60 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
% ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. 26 mg of the faster eluting diastereomer (Example
34) and 17 mg of
25 the slower eluting diastereomer (Example 35) were recovered.
110

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example 34: ESI-MS talc. for C25H35F3N4O2: 480.27; found 481 (M+H).
Example 35: ESI-MS talc. for C25H35F3N4O2: 480.27; found 481 (M+H).
EXAMPLE 36 and EXAMPLE 37
O O
%~N~,. CF3 N CF
Et0 C N / 3
2 ~ I Et02C N
I
N
~ N
The free base of the product prepared in Example 22 (54 mg) was resolved into
2
mixtures of 2 diastereomers using an HPLC equipped with a ChiralCel OD column,
eluting with
13 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. 33 mg of the faster eluting diastereomers (Example
36) and 10 mg of
the slower eluting diastereomers (Example 37) were recovered.
Example 36: ESI-MS talc. for C26H36F3N3O3: 495.27; found 496 (M+H).
Example 37: ESI-MS talc. for C26H36F3N3O3: 495.27; found 496 (M+H).
EXAMPLES 38-41
O
~~N~ C F3
V= N
~ N
The free base of the product prepared in Example 24 (40 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
% ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. 15 mg of the fastest eluting diastereomer (Example
38), 1.5 mg of
20 diastereomer 2 (Example 39), 7 mg of diastereomer 3 (Example 40), and 6 mg
of the slowest
eluting diastereomer (Example 41) were recovered.
Example 38: ESI-MS talc. for C24H34F3N30:found 438
437.27; (M+H).
Example 39: ESI-MS talc. for C24H34F3N30:found 438
437.27; (M+H).
Example 40: ESI-MS talc. for C24H34F3N30:found 438
437.27; (M+H).
Example ESI-MS talc. for C24H34F3N30:found 438
41: 437.27; (M+H).
111

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLES 42-46
1 0
N N / CFs
I
N
The free base of the product prepared in Example 25 (40 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
20 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. All 6 diastereomers were resolved, but peaks 2 and
6 were combined
in overlapping runs to give 4 pure diatereomers and one mixture of 2.
Example 42: Peak 1: ESI-MS calc. for C25H36F3N30:found 452 (M+H).
451.28;
Example 43: Peak 2/6: ESI-MS calc. for C25H36F3N30:; found 452
451.28 (M+H).
Example Peak 3: ESI-MS calc. for C25H36F3N30:found 452 (M+H).
44: 451.28;
Example 45: Peak 4: ESI-MS calc. for C25H36F3N30:found 452 (M+H).
451.28;
Example 46: Peak 5: ESI-MS calc. for C25H36F3N30:found 452 (M+H).
451.28;
EXAMPLE 47 and EXAMPLE 48
HO O HO
O
~N~~. C Fa N C F
~ / 3
~N I _ N
I
~ N ~ N
The free base of the product prepared in Example 27 (20 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
% ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. 7 mg of the faster eluting diastereomer (Example
47) and 6 mg of the
20 slower eluting diastereomer (Example 48) were recovered.
Example 47: ESI-MS calc. for C23H32F3N302: 439.24; found 440 (M+H).
Example 48: ESI-MS calc. for C23H32F3N302: 439.24; found 440 (M+H).
EXAMPLE 49
112

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O~ O
~N N / CF3
N
To a stirred solution of Intermediate 5 (50 mg, 0.14 mmol) and morpholine (25
pL, 0.28 mmol), in DCM (10 mL), was added 4 ~ powdered molecular sieves (50
mg) and
sodium triacetoxyborohydride (150 mg, 0.71 mmol). The resulting solution was
stirred at room
temperature for 3 days before being filtered through celite and washed with
saturated aqueous
sodium bicarbonate and brine. The organic layer was dried over NaZS04,
filtered, and
concentrated under reduced pressure to give a crude oil that was purified by
preparative TLC (0.5
% NH40H/4.5 % MeOH/95 % DCM) to give 57 mg of a colorless solid as a mixture
of 2
diastereomers. A small portion of this free base was converted to its
hydrochloride salt by the
addition of 2 N HCl in ethyl ether.
ESI-MS calc. for C22H30F3N302: 425.23; found 426 (M+H).
Several other examples were made according to the procedure described in
Example 49 except
that various substituted morpholines where used as the amine component in
place of morpholine.
The examples are compiled in Table 5.
Table 5 (EXAMPLES 50 to 53)
O
R~N , CF3
N
Example Structure Molecular Calculated Found MW
Formula MW [M+H]
50 C24H34F3N302 453.26 454
O
~N
113

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
51 I ~ C29H36F3N3O3 531.27 532
/
O
O N
52 O~ C23H30F3N3O2 437.23 438
N
EXAMPLE 53 and EXAMPLE 54
0 1 0 0 1 0
~N,,,~N / CF3 ~N~N / CF3
I '(~~ ~ I
N ~ N
The free base of the product prepared in Example 50 (60 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
20 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
of 2 N HCl in ethyl ether. 26 mg of the faster eluting diastereomer (Example
53) and 27 mg of
the slower eluting diastereomer (Example 54) were recovered.
Example 53: ESI-MS calc. for C24H34F3N3O2: 453.26; found 454 (M+H).
Example 54: ESI-MS calc. for C24H34F3N3O2: 453.26; found 454 (M+H).
EXAMPLE 55 and EXAMPLE 56
O O~ O
~N~,, CF3 ~N' CF3
~N / I ~N /
N ~ N
The free base of the product prepared in Example 52 (48 mg) was resolved into
its individual diastereomers using an HPLC equipped with a ChiralCel OD
column, eluting with
% ethanol/hexanes. Each compound was converted to its hydrochloride salt by
the addition
114

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
of 2 N HCl in ethyl ether. 18 mg of the faster eluting diastereomer (Example
53) and 23 mg of
the slower eluting diastereomer (Example 54) were recovered.
Example 55: ESI-MS calc. for C23H30F3N302: 437.23; found 438 (M+H).
Example 56: ESI-MS calc. for C23H30F3N302: 437.23; found 438 (M+H).
EXAMPLE 57
O
CN CF3
~N
N
To a stirred solution of Intermediate 5 (50 mg, 0.14 mmol) and pyrrolidine (23
pL, 0.28 mmol), in DCM (10 mL), was added 4 A powdered molecular sieves (50
mg) and
sodium triacetoxyborohydride (150 mg, 0.71 mmol). The resulting solution was
stirred at room
temperature for 3 days before being filtered through celite and washed with
saturated aqueous
sodium bicarbonate and brine. The organic layer was dried over Na2S04,
filtered, and
concentrated under reduced pressure to give a crude oil that was purified by
preparative TLC (0.5
% NH40H/4.5 % MeOH/95 % DCM) to give 15 mg of a higher running diastereomer
and 35.5
mg of a lower running isomer both of which where recoved as colorless solid. A
small portion
of the free base was converted to its hydrochloride salt by the addition of 2
N HCl in ethyl ether.
Top: ESI-MS calc. for C22H30F3N30: 409.23; found 410 (M+H).
Bottom: ESI-MS calc. for C22H30F3N30: 409.23; found 410 (M+H).
Several other examples were made according to the procedure described in
Example 57 except
that various substituted pyrollidines where used as the amine component in
place of pyrrolidine.
The examples are compiled in Table 6.
Table 6 (EXAMPLES 58 to 62)
O
R~N / I CFa
~ N
115

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example Structure Molecular Calculated Found MW
Formula MW [M+H]
58 C27H36F3N3O2 491.28 492
CC~~N
59 C27H33F3N40 486.26 487
N/\~ N
''
60 C27H33F3N40 486.26 487
N ~ N
61 N C27H33F3N40 486.26 487
N
62 ~ p C28H40F3N3O3 523.30 524
0.~~~N
EXAMPLE 63
F
O
N CFs
N ~I
A mixture of the Intermediate 3 (55 mg, 0.15 mmol), (1S,4S)-(-)2-(4-
fluorophenyl)-2,5-
diazabicyclo[2.2.1]heptane (as HBr salt, 85 mg, 0.3 mmol), DIEA (65 mg, 0.5
mmol), molecular
sieves (4 ~, 250 mg) and sodium triacetoxyborohydride (212 mg, 1.0 mmol) in
dichloromethane
(5 mL) was stirred overnight. The reaction was quenched with sat. aq. sodium
carbonate. The
solid was removed by filtration through celite. The crude product was
extracted into
dichloromethane and purified on preparative TLC (1000 micron, 5%[aq.
NH40H/MeOH
116

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
1/9]/DCM). The title compound was obtained as a mixture of cis and traps
racemic isomers (75
mg, 95%). LC-MS calc. for C30H35F4N30: 529; Found: 530 (M+H).
EXAMPLE 64
O
N CFs
N ~I
A mixture of the Intermediate 3 (55 mg, 0.15 mmol), (1S,4S)-(-)2-(2-methyl)-
2,5-
diazabicyclo[2.2.1]heptane (as malefic acid salt, 100 mg, 0.3 mmol), DIEA (65
mg, 0.5 mmol),
molecular sieves (4 A, 250 mg) and sodium triacetoxyborohydride (212 mg, 1.0
mmol) in
dichloromethane (5 mL) was stirred overnight. The reaction was quenched with
sat. aq. sodium
carbonate. The solid was removed by filtration through celite. The crude
product was extracted
into dichloromethane and purified on preparative TLC (1000 micron, 5%[aq.
NH40H/MeOH
1/9]/DCM). The title compound was obtained as a mixture of cis and traps
racemic isomers (52
mg, 66%). LC-MS calc. for C31H38F3N30: 525; Found: 526 (M+H).
EXAMPLE 65
O~ O
~N CF3
N ~I
~NH
2
Step A:
O
/ ~N
I
S
~N=CPh
2
117

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
A neat mixture of 54 g (0.29 mole) ethyl (2-aminothiazol-4-yl)acetate and 50 g
(0.276 mole)
benzophenone imine was stirred at 190 °C for 5 h and then cooled at RT
and diluted with 100
mL of CH2C12. The entire mixture was transferred onto a silica gel column and
eluted with 20%
EtOAc/Hexane. The title compound was obtained as light-yellow solid (70 g, 69%
yield). 1H
NMR (300 MHz, CDC13): S 1.26 (t, 3H), 3.74 (s, 2H), 4.15 (q, 2H), 6.87 (s,
1H), 77.25-7.86 (m,
H); Mass Spectrum (NH3-CI): m/z 351 (M+1).
Step B:
O
O~
/ ~N
I
S
~N=CPh
2
To a mixture of 35 g (0.10 Mole) of the Schiff base ester form Step A, cis-1,3-
dichloro-2-butene
10 (13 mL, 0.11 Mole) in 500 mL of DME at RT was added in multiple portions
solid NaH (60%
oil, 10.0 g, 0.25 Mole). The resulting mixture was stirred for 2 days, poured
into 2000 mL of
ice-water, extracted with 1500 mL of ether. The ether layer was washed with
water (3 x 500
mL), dried over Na2S04 and evaporated. FC (Silica Gel, 5% EtOAc/Hexane)
afforded the title
compound as an oil (24 g, 59%). 1H NMR (300 MHz, CDCl3): S 1.20 (t, 3H), 2.87
(d, 2H), 3.19
(d, 2H), 4.14 (q, 2H), 5.29 (s, 2H), 6.71 (s, 1H), 7.26-7.81 (m, 10H). Mass
Spectrum (NH3-CI):
m/z 403 (M+1).
Step C:
O
/ ~N
S
NH2
24.0 g (0.059 mol) of the cyclopentene Schiff base from Step B was dissolved
in 100 mL of 4 N
HCl/dioxane. After 1 h, 1.8 mL of water was added. The mixture was stirred for
3 h, evaporated
to dryness. The residue was dissolved in 100 mL of CH2Cl2 and added 15 mL of
DIEA. The
entire mixture was dumped onto a silica gel column, eluted with 20%
EtOAc/Hexane to remove
118

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
benzophenone, then eluted with 40% EtOAc/Hexane to give the title compound as
a light yellow
solid (12.0 g, 85%). 1H NMR (300 MHz, CDC13): S 1.19 (t, 3H), 2.79 (d, 12H),
3.15 (d, 2H),
4.13 (q, 2H), 5.66 (s, 2H), 5.82 (wide, 2H), 6.19 (s, 1H).
Step D:
O
/ ~N
S
N(Boc)2
A mixture of 12 g (50 mmol) of the aminothiazole from Step C, 28 g (130 mmol)
of di-tert-butyl
dicarbonate and 0.6 g of DMAP in 250 mL of DCM was stirred overnight, and
evaporated. The
title compound (21.0 g, 96%) was obtained as a yellow oil after flash
chromatography
purification on silica gel (10% EtOAc/Hexane). 1H NMR (300 MHz, CDC13): S 1.18
(t, 3H),
1.49 (d, 18H), 2.88 (d, 2H), 3.18 (d, 2H), 4.13 (q, 2H), 5.65 (s, 2H), 6.83
(s, 1H). Mass Spectrum
(NH3-CI): m/z 439 (M+1).
Step E_
O
O
N(Boc)2
To a solution of 13.1 g (30.0 mmol) of the ester from Step D in 50 mL of
anhydrous ether at -78
°C was added dropwise a solution of BH3.DMS in THF (14 mL, 24 mmol).
The cooling bath
was removed and the mixture was stirred at room temperature for 3 h, diluted
with 250 mL of
DCM, added 25 g of sodium acetate and 55 g of PCC. The mixture was stirred
overnight. The
entire mixture was applied to a silica gel column and eluted with in 10 %
EtOAc/Hexane and
then 30% EtOAc/Hexane. Two components were obtained. The fast-eluted isomer
(yellow oil,
119

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
6.0 g) was identified as the title compound. 1H NMR (300 MHz, CDCl3): ~ 1.21
(t, 3H), 1.50 (s,
18H), 2.33 (t,2H), 2.42-2.70 (m, 2H), 2.78-3.10 (dd, 2H), 4.18 (q, 3H), 6.88
(s, 1H). Mass
Spectrum (NH3-CI): m/z 455 (M+1).
Step F:
O
O
NHBoc
The slow-eluted component from above was proved to be the title compound
(gummy material,
1.80 g). 1H NMR (300 MHz, CDC13): S (t, 3H), 1.46 (s, 9H), 2.27 (3, 2H), 2.38-
2.62 (m,2H),
2.64-3.00 (dd, 2H), 4.11 (q, 2H), 6.66 (s, 1H). Mass Spectrum (NH3-CI): m/z
355 (M+1).
Step G:
O
O OH
/'N
S
NHBoc
A mixture of 1.40 g (4.00 mmol) of the keto ester from Step F and 0.82 g (13
mmol) of lithium
hydroxide monohydrate in a solution of 20 mL of MeOH and 2 mL of water was
stirred at room
temperature overnight. The entire mixture was applied to a silica gel column
and eluted with
10%MeOH/CH2C12. Evaporation in vacuo afforded a light yellow solid. 1.30 g of
the title
product was obtained as a fluffy solid. 1H NMR (300 MHz, CDCl3): b (t, 9H),
2.10-3.20 (m,
8H), 6.60 (s, 1H).
Step H:
O
O CFs
N ~I
~NHBoc
120

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
A mixture of the keto acid prepared in Step G (1.0 g, 3.0 mmol), Intermediate
1 (as HCl
salt, 0.66 g, 3.0 mmol) and EDC (0.95 g, 5.0 mmol) in dichloromethane (10 mL)
was stirred for
2 days. The mixture was diluted with dichloromethane and washed with 1 N aq.
HCI, dried over
sodium sulfate and evaporated. The residue was purified on preparative TLC
(1500 micron,
10%[aq. NH40H/MeOH 1/9]/DCM) to yield the title product as a yellow solid
(0.52 g, 34%).
LC-MS talc. for C25H27F3N2O4S: 508; Found: 509 (M+H).
Step I:
O
O CFa
N ~I
~NH
2
The product from step H (510 mg, 1.0 mmol) was mixed with TFA (10 mL) for 30
min. TFA
was removed and the residue was purified on preparative TLC (10%[aq.
NH40H/MeOH
1/9]/DCM) to yield the desired product as a white solid (223 mg, 55%).. LC-MS
talc. for
C20H19F3N2O2S: 408; Found: 409 (M+H).
Step J:
O~ O
~N CF3
N ~I
~NH
2
A mixture of the product from Step I (210 mg, 0.50 mmol), morpholine (440 mg,
S.0
mmol), molecular sieves (4 A, 500 mg) and sodium triacetoxyborohydride (420
mg, 2.0 mmol)
in dichloromethane (lS.mL) was stirred overnight. The reaction was quenched
with sat. aq.
sodium carbonate. The solid was removed by filtration through celite. The
crude product was
extracted into dichloromethane and purified on preparative TLC (1000 micron,
10%[aq.
NH40H/MeOH 1/9]/DCM). The title compound was obtained as a mixture of cis and
traps
racemic isomers (200 mg, 84%). LC-MS talc. for C24H28F3N3O2S: 479; Found: 480
(M+H).
EXAMPLE 66
121

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O ~ O
~N N ~ CF3
A mixture of the Intermediate 3 (70 mg, 0.20 mmol), cis-2,6-dimethylmorpholine
(23 p,L,,
0.20 mmol), molecular sieve ( 4 ~L, 200 mg), and sodium triacetoxyborohydride
( 210 mg, 0.99
mmol) in DCM was stirred for 5 days. The reaction mixture was diluted by DCM,
filtered, and
washed with sat. aq. NaHC03, water and brine. DCM layers were dried over
Na2S04, filtered
and concentrated. The residue was purified on preparative TLC (1000 micron)
(developed by
3% [aq. NH40H/MeOH 1/9]/DCM) to yield the final title compound as a free base.
Its HCl salt
(62.2 mg) was formed by treatment with 4 N HCl/dioxane. ESI-MS calc. for
C25H35F3N2O2:
452.27; Found: 453 (M+H).
The diastereoisomers were separated into one mixture of 2 cis diastereoisomers
and two single
diastereomers using HPLC (AD column, 5% EtOH/hexane).
EXAMPLE 67
H
O O
~N ~ CFs
N
H
Example 68 was prepared starting from Intermediate 3 and (1S,4S)-(+)-2-aza-5-
oxabiclclo[2.2.1]heptane hydrochloride as detailed in Example 66. The cis and
traps isomers
were resolved on preparative TLC (4/95.6/0.4, MeOH/DCM/NH40H). Top spot: ESI-
MS calc.
for C24H31F3N2O2: 436.23; Found: 437 (M+H). Bottom spot: ESI-MS calc. for
C24H31F3N2O2: 436.23; Found: 437 (M+H).
EXAMPLE 68
O
~N w CFs
Nl~..
122

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example 68 was prepared starting from piperidine and Intermediate 3 as
detailed in
Example 49. ESI-MS calc. for C24H33F3N20: 422.25; Found: 423 (M+H).
EXAMPLE 69
0 J~
~~N1 1 O
I / /vN V= N FF
F
N
Intermediate 22 (563 mg, 2.43 mmol) was dissolved in dichloromethane and
cooled to -78 °C.
Ozone was bubbled into the solution until a blue color persisted. Nitrogen gas
was then bubbled
through the solution until disappearance of the blue color. NaZS04 was added
into the stirring
solution. The reaction mixture was filtered into a flask containing
Intermediate 23.
Dichloromethane (20 mL), triethylamine (136 pL, 0.974 mmol), and NaB(OAc)3H
(929 mg, 4.38
mmol) were added to the reaction flask. The reaction mixture was stirred at
room temperature
under N2 gas for two hours and then diluted with dichloromethane and washed
with saturated
sodium bicarbonate solution (2 x 100 mL) and brine (1 x 100 mL). The organic
layers were
dried over MgS04, filtered, and concentrated. The crude products were divided
into three
batches and loaded onto three ion exchange column. Impurities were flushed
away with using
40% MeOH/hexanes (100 mL). The desired product was then eluted from the
columns with a
30% solution 2N NH3 in MeOH further diluted in dichloromethane. Example 69
(131 mg, 0.223
mmol, 46% yield) was purified by preparatory TLC using 32% EtOAc/hex. The
diastereomers
were then isolated through preparatory TLC using 45% EtOAc/hex (top isomer: 20
mg, 0.034
mmol, 7% yield; middle isomer: 45 mg, 0.076 mmol, 16% yield; bottom isomer: 54
mg, 0.092
mmol, 19% yield). ESI-MS calculated for C32H4,F3N4O3: 586.69, found 587 (M+H).
Several other piperazines and homo-piperazines where made according to the
same
procedure described in Example 69. Table 7 summarizes these compounds.
Table 7 (EXAMPLES 70 to72)
123

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
R~N / CF3
I
N
Example Structure Molecular Calculated Found MW
Formula MW [M+H]
70 C26H37F3N40 478.29 479
~
N
71 ~ C25H35F3N40 464.28 465
N
72 C27H35F3N60 516.28 517
\ ~
N N
~N
EXAMPLE 73
H
N O
N~ I N~ CF3
~N /
N
The above compound was prepared from Intermediate 5 and 4,5,6,7-tetrahydro-
1H-pyrazolo[4,3-]pyridine according to the procedure described in Example 49.
ESI-MS calc.
for C24H30F3N50: 461.24; found 462 (M+H).
EXAMPLE 74
HN~ O
O~N N / CFs
I
N
The above compound was prepared from Intermediate 5 and 1,4-diazepan-5-one
according to procedure described in Example 49. ESI-MS calc. for C23H31F3N402:
452.24;
found 453 (M+H).
124

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 75
O~ O
N N / CF3
N
The above compound was prepared from Intermediate 5 and 2,3,4,5-tetrahydro-
1,4-benzoxazepine according to the procedure described in Example 57. Top
spot: ESI-MS
calc. for C27H32F3N3O2: 487.24; found 488 (M+H). Bottom spot: ESI-MS calc. for
C27H32F3N3O2: 487.24; found 488 (M+H).
EXAMPLE 76
HN 1 O
~N
V 'N F
F
F
NJ
Palladium catalyst on carbon (top: 6 mg, middle: 18 mg, bottom: 20 mg) was
added to three
flasks each containing one of the three diastereomers of Example 70 (top: 29.6
mg, middle: 89.9
mg, bottom: 102.3 mg). The mixtures were dissolved in MeOH (3-6 mL), and the
reaction
vessels were flushed repeatedly with hydrogen gas. The reaction was stirred at
room temperature
under a hydrogen atmosphere for 4.5 hours and then passed through an Acrodisc~
syringe filter
with a 0.45 ~m PTFE membrane. Compound 76 (top isomer: 16.0 mg, 0.0354 mmol,
71% yield;
middle isomer: 42.7 mg, 0.0943 mmol, 62% yield; bottom isomer: 34.5 mg, 0.0762
mmol, 44%
yield) was isolated through preparatory TLC using a 10% NH40H/MeOH (1:9) in
dichloromethane solvent system. ESI-MS calculated for C24H35F3N4O: 452.56,
found 453
(M+H).
EXAMPLE 77
125

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
~O~ N O
N ~~~~~ F
N F
~F
N
Example 76 (middle stereoisomer on TLC, 11 mg, 0.024 mmol) was dissolved in
dichloromethane (3 mL) and cooled to 0°C. Ethylchloroformate (5 p.L,
0.05 mmol),
triethylamine (10 pL, 0.07 mmol), and a catalytic amount of DMAP (1-2 mg) was
added to the
reaction flask. The reaction was warmed to room temperature and stirred for
two hours under a
nitrogen atmosphere. Thereafter, the reaction was diluted with DCM and washed
with saturated
sodium bicarbonate solution (1 x 25 mL) and brine (1 x 25 mL). The organic
layer was dried
over MgS04, filtered, and concentrated. Example 77 (4.2 mg, 0.0080 mmol, 33%
yield) was
purified through preparatory TLC using a 2% NHaOH/MeOH (1:9) in
dichloromethane solvent
system. ESI-MS calculated for Cz7H39F3N4O3: 524.62, found: 525 (M+H).
EXAMPLE 78
O
/ 'N O
~N
N F
F
NJ
Example 76 (middle stereoisomer on TLC, 11 mg, 0.024 mmol) was dissolved in
dichloromethane (3 mL) and cooled to 0 °C. Acetic anhydride (11 p,L,
0.12 mmol),
triethylamine (23 p,L, 0.17 mmol), and a catalytic amount of DMAP (1-2 mg) was
added to the
reaction flask. The reaction was warmed to room temperature and stirred for
2.5 hrs. under a
nitrogen atmosphere. The reaction was then diluted with DCM and washed with
saturated
sodium bicarbonate solution (1 x 25 mL) and brine (1 x 25 mL). The organic
layer was dried
over MgS04, filtered, and concentrated. Example 78 (5.3 mg, 0.011 mmol, 45%
yield) was
126

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
purified through preparatory TLC using a 2% NH40H/MeOH (1:9) in
dichloromethane solvent
system. ESI-MS calculated for CZ~H3~F3N402: 494.59, found: 495 (M+H).
EXAMPLE 79
HN~
N~ O
O N_~ ~/
~N F
F
F
N
Dichloromethane (2-3 mL per flask) was added to three separate flasks
containing the three
,diastereomers of Example 77 (top: 16 mg, 0.035 mmol, middle: 11 mg, 0.023
mmol, bottom: 14
mg, 0.031 mmol). Methylisocyanate (top: 21 pL, 0.35 mmol, middle: 14 pL, 0.23
mmol,
bottom: 19 p,L, 0.31 mmol) was added to each reaction vessel. The reactions
were stirred for
three hours and then concentrated before isolating Example 79 (top isomer:
12.8 mg, 0.0251
mmol, 72% yield; middle isomer: 10.4 mg, 0.0204 mmol, 89% yield; bottom
isomer: 11.1 mg,
0.0218 mmol, 70% yield) by preparatory TLC using a 2% NH40H/MeOH (1:9) in
dichloromethane solvent system. ESI-MS calculated for CZ~H3gF3N5O2: 509.61,
found: 510
(M+H).
EXAMPLE 80
' O
~N N ~ C F3
Step A
127

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
HO/~ O
N OMe
~O
O
A solution of cis-hydroxy-D-proline (2.98 g, 22.7 mmol) in methanol (20 mL)
was treated with
thionyl chloride (1.78 mL, 24.4 mmol) and stirred at room temperature for 1 h.
The reaction
mixture was then heated to 65 °C overnight. Evaporation of the
volatiles gave the crude methyl
ester (4.0816 g), which was dissolved in dichloromethane (50 mL) and
diisopropyl ethyl amine
(9.59 mL, 55.1 mmol) was added. The reaction mixture was cooled to 0 °C
and neat benzyl
chloroformate (3.71 mL, 26.0 mmol) was added via syringe. After stirnng at 0
°C for 30 minutes
the cooling bath was removed. The reaction was quenched by pouring into an
aqueous solution
of citric acid (10 %, 50 mL) and the product was extracted into
dichloromethane. The combined
organic phases were back-washed with brine, dried with anhydrous sodium
sulfate, and the
solvent was removed in vacuo. The crude product was purified by flash
chromatography (silica
gel, ethyl acetate : hexanes/4 : 6) to yield 4.0717 g (69 °Io) of the
pure product. 1H NMR (500
MHz, CDC13): 8 7.35 m (5H), 5.21 (d, J = 12.6 Hz, 2H), 5.10 (d, J = 13 Hz,
1H), 5.06 (d, J =
12.35 Hz, 1H), 4.45 (m, 2H), 3.80 (s, 3H), 2.35 (m, 1H), 2.15 (m, 1H).
Step B
~s~,oi.~ \o
OMe
O
O
A solution of the alcohol from the previous step (2.63 g, 9.42 mmol) and
diisopropylethylamine
(3.28 mL, 18.8 mmol) in dichloromethane 40 mL was cooled to -78 °C and
tert-
butyldimethylsilyl trifluoromethane sulfonate (2.596 mL, 11.30 mmol) was added
via syringe.
128

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The reaction mixture was stirred at -78 °C for 2 h, and quenched by
pouring onto 50 mL of
saturated solution of sodium bicarbonate. The organic phase was separated,
dried with
magnesium sulfate and the volatiles were removed in vacuo. The residue (6.0 g)
was further
purified by column chromatography (silica gel, ethyl acetate : hexanes/1 : 4)
to afford 2.8355 g
(76 %) of the pure product. 'H NMR (500 MHz, CDC13): 7.35 m (5H), 5.20 (m=
2H), 4.45 (m,
2H), 3.70 (m, 4H), 3.45 (m, 1H), 2.23 (m, 2H)0.87 (bs, 9H), 0.05 (m, 6H).
Step C
~s~'°~,
OH
O
O
A solution of the ester from previous step (2.83 g, 7.19 mmol) in THF (10 mL)
was treated with
lithium borohydride (250 mg, 11.5 mmol) at 0 °C and the reaction
mixture was stirred at room
temperature for 72 h. It was then diluted with diethyl ether, washed with
water and a 1 M
solution of phosphoric acid. The combined organic extracts were dried (sodium
sulfate) and the
solvent was removed in vacuo. The crude product was further purified by column
chromatography (silica gel, ethyl acetate : hexanes/ 3 : 7) to yield 1.5636 g
(60 %) of the pure
product. LC MS: for C,9H3,N04Si calculated 365.20, found 366.25 [M + H ]+.
Step D
~s~'°~.
o_ o
0
0
A solution of the alcohol from the previous step (1.56 g, 4.27 mmol) and
diisopropylethylamine
(1.49 mL, 8.53 mmol) in dichloromethane (20 mL) was treated with
methanesulfonyl chloride
(496 ~,L, 6.41 mmol) at 0 °C. The reaction mixture was stirred at cold
for 15 minutes, then at
129

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
room temperature for another 30 minutes. It was diluted with dichloromethane,
washed with
water and dried with magnesium sulfate. The solvent was removed in vacuo and
the crude
product was used without any delay in the next step as obtained. LC MS: for
CZOH33NS06Si
calculated 443.18, found 444.25 [M + H ]+.
Step E
O-
N
O
A solution of the TBS-ether from the previous step (1.82 g, 4.10 mmol) in THF
(50 mL) was
treated with tetrabutylammonium fluoride (4.51 mL, 1 M solution in THF). And
the reaction
mixture was stirred at room temperature until LC MS analysis indicated
complete removal of the
TBS group, about 15 minutes. The reaction mixture was then cooled to 0
°C and sodium hydride
(180 mg, 60 % suspension, 45.1 mmol) was added. Stirring at room temperature
was continued
for 24 h. The reaction was quenched by pouring onto water, and the crude
product was extracted
into ethyl acetate. The solvent was removed in vacuo, and the crude product
was purified by
flash chromatography (dichloromethane : ether/? : 3) to afford 595 mg (59 %)
of the desired
product. 'H NMR (500 MHz, CDC13): 7.38 (m, SH), 5.30 (m, 2H), 4.52 (m, 2H),
3.80 (m, 2H),
3.40 (m, 2H), 1.70 (m, 2H).
Step F
O
N H
A solution of the CBZ-amine from the previous step (590 mg, 2.53 mmol) in
ethyl alcohol (30
mL) was hydrogenated in the presence of Pd/C (142 mg, 10 %) under balloon
pressure. The
130

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
reaction was monitored by LC by the disappearance of the starting material and
appearance of
toluene. The catalyst was filtered off and the filtrate was evaporated to
dryness to leave 321 mg
(94 %) of the desired product.
Step G
_o~~' o
~N N ~ C F3
A solution of Intermediate 3 (120 mg, 0.340 mmol), amine hydrochloride from
previous step (46
mg, 0.34 mmol), diisopropyl ethylamine (60 ~,L, 0.34 mmol) and 4 ~ molecular
sieves (crushed,
360 mg) in dichloroethane (10 mL) was treated with sodium
triacetoxyborohydride, and stirred at
room temperature for 24 h. The reaction was quenched by pouring onto saturated
solution of
sodium bicarbonate and the crude product was extracted with dichloromethane.
The volatiles
were removed in vacuo, and preparative TLC (ethyl acetate : ethyl alcohol :
ammonium
hydroxide/90 : 8 : 2 gave the pure product (118 mg, 80 %). LC MS: for
Cz4H3iN2F3O2
calculated 436.23, found 437.20 [M + H ]+.
EXAMPLE 81
F
O
CF3
To a solution of Intermediate 21 (150 mg, 0.43 mmol) in dichloromethane (10
mL) was added
EDC (414 mg, 2.16 mmol), HOAt (59 mg, 0.43 mmol) and Intermediate 1 (87 mg,
0.43 mmol)
and the resulting mixture was stirred at room temperature for 4 days. The
reaction was quenched
with water and diluted with 20 mL of dichloromethane. The organic layer was
separated and the
aqueous layer was extracted with DCM (2 x 20 mL). The organics were combined,
dried over
sodium sulfate, filtered and evaporated under reduced pressure. The residue
was purified by
preparative TLC (eluant: 10 % methanol: 89.5 % dichloromethane : 0.5 % NHaOH)
to yield 40
131

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
mg (17 %) of the final pure desired product as a mixture of two cis isomers.
LC-MS for
C3oH36N20F4 calculated 516.28, found [M + H]+ 517.
EXAMPLE 82
CN
O
\N ~N N ~ CF3
The hydrochloride salt of the pyrimidyl piperidine (Intermediate 8) (67 mg,
0.34 mmol) was
combined with Intermediate 4 (100 mg, 0.28 mmol), triethylamine (46 pL, 0.35
mmol), and 4 A
powdered molecular sieves (100 mg) in DCM. After 15 minutes at room
temperature, sodium
triacetoxyborohydride (240 mg, 1.13 mmol) was added and the resulting mixture
was stirred for
3 days before being filtered through celite, diluted with DCM and washed with
saturated sodium
bicarbonate and brine. The organic layer was dried over MgS04, filtered and
concentrated under
reduced pressure to give a crude oil that was purified by preparative TLC
(silica gel, 0.3 %
NH40H/ 2.7 % MeOH/ 97 % DCM) to give 110 mg of a colorless oil. Resolution of
the
individual diastereomers was accomplished by HPLC using a ChiralPak AD column
eluting with
30 % isopropanol/ hexanes to give 2 single diastereomers and a single mixture
of the 2 other
di astereomers.
First peak 10 mg: ESI-MS calc. for C28H35F3N40: 500.28; found 504 (M+H).
Second peak 11 mg: ESI-MS calc. for C28H35F3N40: 500.28; found 504 (M+H).
Third peak 7.0 mg ESI-MS calc. for C28H35F3N40: 500.28; found 504 (M+H).
EXAMPLES 83-91
R~ O
'\~N N ~ CF3
Several other examples where prepared in a similar fashion to Example 82,
utilizing different
piperidine intermediates. These Examples (83-91) are shown below.
132

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example R' Molecular Calculated Found
Formula [M] [M+H]
83 -N C27H36F3N40 488.27 489
CN
84 C27H36F3N40 488.27 489
~
NO
N !'S
85 ~ C27H36F3N40 488.27 489
NON
a
86 N-N C26H35F3N50 489.27 490
~N
~
87 N C26H35F3N50 489.27 490
~ .
\
N ~
~
N ~S
88 N~ C26H35F3N50 489.27 490
ON~N~S'
89 N--N C25H34F3N60 490.26 491
N~/N~S'
90 N---N C25H34F3N60 490.26 491
~
N
N~
~
91 N_~ C26H36F3N60 504.26 505
~
NON ~S~
133

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 92
CN
O
N CFs
N I W
This product was prepared in an analogous fashion to that of Example 81,
except Intermediate 21
was replaced with commercially available 4-cyano-4-phenylpiperidine. The crude
product was
purified by preparative TLC (eluant: 5 % methanol: 94.5 % DCM: 0.5 % NH40H) to
yield
Example 92 as a mixture of four isomers. LC-MS for C3,H36F3N3O calculated
523.28, found
[M+H]+ 524.
EXAMPLE 93
O
N CFs
N
This product was prepared in an analogous fashion to that of Example 81,
except Intermediate 21
was replaced with commercially available 4-phenylpiperidine. The crude product
was purified
by preparative TLC (eluant: 10 % methanol: 89.5 % DCM: 0.5 % NH40H) to yield
Example 93
as a mixture of four isomers. LC-MS for C3pH37F3N2O calculated 498.29, found
[M+H]+ 499.
EXAMPLE 94
134

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Step A
F
O
N CFs
.N ( W
F
O
O CFs
.N I W
F
To a solution of the cyclopentanone carboxylic acid (from Step C, Intermediate
3) (2.3 g, 14
mmol) in dichloromethane (70 mL) was added oxalyl chloride (1.8 mL, 21 mmol)
followed by 2
drops of DMF. The solution was stirred at room temperature for 80 minutes and
then evaporated
under reduced pressure. The residue was dissolved in DCM (20 mL) and added via
syringe to a
prepared solution of Intermediate 3 (3.0 g, 14 mmol) and triethylamine (2.1
mL, 15 mmol) in
DCM (50 mL). The resulting mixture was stirred at room temperature for 18 h
and then
quenched with water (25 mL). The organics were separated, washed with 1 N HCI,
saturated
sodium bicarbonate solution, and brine, dried over anhydrous magnesium
sulfate, filtered, and
evaporated. The residue was purified on a Biotage Flash 40 (eluant: 40 % ethyl
acetate/ 60 %
hexane) to afford 2.2g (43 %) of the title compound.
Step B
F
O
N CFa
.N
F
A solution of the product described in Step A (200 mg, 0.54 mmol) commercially
available 4-
fluorophenylpiperidine hydrochloride (120 mg, 0.54 mmol),
diisopropylethylamine (94 p,L, 0.54
mmol) and crushed molecular sieves (4 A, 100 mg) in dichloromethane (10 mL)
was treated with
135

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
sodium triacetoxyborohydride (343 mg, 1.60 mmol) and stirred at room
temperature overnight.
The reaction was quenched with saturated sodium bicarbonate (10 mL) and
diluted with an
additional 10 mL of DCM. The organic layer was separated and the aqueous
washed with
dichloromethane (2 x 5 mL). The organics were combined, dried over anhydrous
sodium sulfate,
filtered and evaporated. The residue was purified by preparative TLC (eluant:
8 % ethanol: 90 %
ethyl acetate: 2 % NH40H) to yield two isomers, higher eluting (25 mg, 5 %)
and lower eluting
(37.2 mg, 7.6 %) of unknown absolute stereochemistry. LC-MS for C3oH35NZOF5
calculated
534.28, found [M+H]+ 535.
EXAMPLE 95
N
O
N~
N N \ CF3
I/
F
This product was prepared in an analogous fashion to that of Example 94,
except 4-
fluorophenylpiperidine hydrochloride was replaced with Intermediate 9. The
crude product was
purified by preparative TLC (eluent: 90 % ethyl acetate: 8 % ethanol: 2 %
NH40H) to yield 450
mg (66 %) of the title product as a mixture of four isomers. LC-MS for
CZ8H34N40F4 calculated
518.27, found [M+H]+ 519.
O
~~~N \ CFs
1~/ 'N
F
Several other examples where prepared in a similar fashion to Example 94,
utilizing different
piperidine intermediates. These Examples (96-104) are shown below.
136

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example R' Molecular Calculated Found
Formula [M] [M+H]
96 N--N C25H33F4N60 508.26 509
I
N~/ N
~S
97 N--N C25H33F4N60 508.26 509
N
C
,
N ~S
98 -N C27H35F4N40 506.27 507
CN
99 N-N C26H34F4N50 507.27 508
I
~N
~p
100 N C26H34F4N50 507.27 508
~
'
N
~
N~
~S
101 N~ C26H34F4N50 507.27 508
N ~ N~S~
102 C27H35F4N40 506.27 507
~
NO
N ' 5'
103 ~ C27H35F4N40 506.27 507
N~/N~5'
104 N~N~ C26H35F4N60 522.28 523
~
Nv
N
137

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 105
F
O
~N~ Br
N I \
To a solution of Intermediate 21 (150 mg, 0.43 mmol) in dichloromethane (10
mL) was added
EDC (170 mg, 0.86 mmol), HOAt (59 mg, 0.43 mmol) and Intermediate 21 (91 mg,
0.43 mmol)
and the resulting mixture was stirred at room temperature for 3 days. The
reaction was quenched
with water and diluted with 20 mL of dichloromethane. The organic layer was
separated and the
aqueous layer was extracted with DCM (2 x 20 mL). The organics were combined,
dried over
sodium sulfate, filtered and evaporated under reduced pressure. The residue
was purified by
preparative TLC (eluant: 7 % ethanol: 92 % dichloromethane : 1.0 % NH40H) to
yield 121 mg
(50 %) of the final desired product as a mixture of two cis isomers. LC-MS for
CZ~H36BrFN20
calculated 526.28, found [M+H]+ 527 and [(M+2)+H]+ 529.
EXAMPLE 106
F
O
N
~N \
I
To a solution of Example 105 (100 mg, 0.210 mmol), phenylboronic acid (30 mg,
0.23 mmol),
toluene (1.4 mL), and MeOH (0.6 mL) was added a solution of Na2C03 (80 mg,
0.74 mmol) and
Pd(PPh3)zClz (8 mg, 0.01 mmol) in HZO (0.4 mL). The reaction mixture was
heated at 80 °C in
a high pressure tube for 12 h before filtered through celite and concentrated
to dryness. The
concentrate was diluted with DCM, washed with 1 N NaOH solution (3 x), dried
over Na2S04,
138

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
and concentrated in vacuo. The crude product was purified by preparative TLC
(eluent:
5/94.5/0.5, MeOH/DCM/NH40H) to yield Example 106 (63.3 mg, 63.3 %) a mixture
of 2 cis
isomers. LC-MS for C35H4,FNZO calculated 524.29, found [M+H]+ 525.4.
EXAMPLE 107
F /
O ~ N
N
N~\~%
This product was prepared in an analogous fashion to that of Example 106,
except phenylboronic
acid was replaced with 4-pyridylboronic acid. The crude product was purified
by preparative
TLC (eluent: 10/89/1.0, MeOH/DCOH) to yield Example 107 as a mixture of two
cis
isomers. LC-MS for C34H40~3O calculated 525.26, found [M+H]+ 526.3.
EXAMPLE 108
F
O /
~ ~ 1~ I I
~N ~ W N
This product was prepared in an analogous fashion to that of Example 106,
except phenylboronic
acid was replaced with 3-pyridylboronic acid. The crude product was purified
by preparative
TLC (eluent: 10/89/1.0, MeOH/DCM/NHQOH) to yield Example 108 as a mixture of
two cis
isomers. LC-MS for C34H4oFN3O calculated 525.26, found [M+H]+ 526.3.
EXAMPLE 109
139

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
F
O /
,J
N~\J%~ ~ N
This product was prepared in an analogous fashion to that of Example 106,
except phenylboronic
acid was replaced with 2-pyridylboronic acid. The crude product was purified
by preparative
TLC (eluent: 10/89/1.0, MeOH/DCM/NH40H) to yield Example 109 as a mixture of
two cis
isomers.. LC-MS for C34H4of'NsO calculated 525.26, found [M+H]+ 526.3.
EXAMPLE 110
F
O ~N
N \ NON
~N
Step A
HN ~ NQ2
To ice cold concentrated sulfuric acid was added in a dropwise manner 1,2,3,4-
tetrahydroisoquinoline (23 mL , 170 mmol), followed by potassium nitrate (18.8
g , 186 mmol)
at such a rate that the temperature did not rise above 5 °C. After
complete addition the mixture
was stirred at room temperature for 18 h then poured onto a stirred mixture of
ice (700 g) and
NH40H (150 mL). The mixture was extracted with CHC13 ( 3 x 300 mL). The
combined CHCl3
layers were washed with saturated NaCI (200 mL), dried over Na2S04, filtered
and concentrated
in vacuo. The residue was dissolved in ethanol (130 mL) and cooled in an ice
bath as
concentrated hydrochloric acid (22 mL ) was added. The formed precipitate was
removed by
filtration and recrystallized from methanol to give the product (12.45 g , 34
%); 'H NMR
SOOMHz (DMSO-d6) 8 = 3.13 (2H , t , J = 6.2 Hz), 3.35 (2H , t , J = 6.2 Hz),
4.35 (2H , s), 7.50
(lH,d,J=8.SHz),8.07(lH,dd,J=2.3and8.5Hz),8.19(lH,d,J=2.3 Hz) 10.02(2H,br
s).
Step B
140

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
F C~N ~ N02
3
To a suspension of the product from Step A (12 g , 58 mmol), and pyridine
(23.7 mL , 293
mmol) in anhydrous CHZCIz (50 mL) cooled at 0 °C was added in a
dropwise manner
trifluoroacetic anhydride (12 mL , 87 mmol), and the resulting mixture was
stirred at room
temperature for 18 h. The reaction mixture was poured onto ice (500 g) and
extracted with
CHZC12 (4 x 150 mL). The combined CHZCIZ layers were washed with 1 N HCl (4 x
100 mL),
saturated NaCI (100 mL), dried over NazS04, filtered and evaporated in vacuo
to give the
product (15.92 g , 89 %); 'H NMR 500MHz (CDC13) 8 = 3.07 (2H , m), 3.91 and
3.94 (2H , t , J
= 6.2 Hz), 4.85 and 4.88 (2H , s), 7.36 (1H , dd , J= 8.7 and 11.9 Hz), 8.07
(1H , dd , J= 2.3 and
8.5 Hz), 8.01-8.08 (2H m).
Step C
O
F C~N ~ NH2
3
/
A solution of the product from Step B (16 g , 58 mmol) in ethanol (200 mL) was
hydrogenated in
a Parr Apparatus at 50 psi over Pt02 until hydrogen uptake ceased. The
catalyst was removed by
filtration through celite and the filtrate was concentrated in vacuo to give
to the product (14.2 g ,
100 %); 'H NMR 500MHz (CDC13) 8 = 2.84 (2H , t , J = 5.7 Hz), 3.35 (2H , br
s), 3.80 and 3.84
(2H,t,J=6.OHz),4.64and4.69(2H,s),6.45(lH,d,J=lO.OHz),6.57(lH,td,J=2.4
and 8.5 Hz), 6.95 (1H , d , J= 8.5 Hz).
Step D
O N,
II ~~N
F3C~N I ~ N~/
141

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
To a solution of the product from Step C (2.0 g , 8.7 mmol) in toluene (50 mL)
was added N,N-
dimethylformamide azine (2.3 g, 16 mmol) and a spatula end of toluene sulfonic
acid, and the
resulting mixture was heated at reflux for 24 h. The mixture was concentrated
in vacuo and the
residue was partitioned between CHzCIZ (50 mL) and water (50 mL). The organic
layer was
separated and washed with saturated NaHC03 (25 mL) and saturated NaCI (25 mL),
dried over
MgS04, filtered and concentrated in vacuo. The residue was triturated with
CHZCl2 (4 mL),
filtered and dried to give the product (1.0 g , 39 %); 'H NMR 500MHz (CDCl3) 8
= 3.05 (2H , t ,
J = 5.7 Hz), 3.90 and 3.95 (2H , t , J = 6.0 Hz), 4.83 and 4.89 (2H , s), 7.20
(1H , d ), 7.26 (1H , t
), 7.38 (1H , t ) 8.45 (2H , s).
Step E
N
N i,N
HN
To a solution of the product from Step D (1.0 g, 3.4 mmol) in ethanol (50 mL)
was added a
solution of potassium carbonate (2.3 g , 17 mmol) in water (10 mL) and the
resulting mixture
was heated at reflux for 90 minutes. The cooled reaction mixture was
concentrated in vacuo and
the solid residue was extracted with CHZCIz (3 x 10 mL). The combined CHZCIz
layers were
evaporated in vacuo and the residue was purified by column chromatography on
silica eluting
with 10 % CH30H in CHZCIz containing 0.5 % NH40H to give the product (550 mg ,
82 %); 'H
NMR 500MHz (CDCl3) 8 = 2.69 (1H , br s), 2.85 (2H , t , J = 5.9 Hz), 3.17 (2H
, t , J = 6.0 Hz),
4.07(2H,s),7.20(lH,d,J=1.8Hz),7.14(lH,dd,J=l.8and8.OHz),7.23(lH,d,J=8.0
Hz), 8.43 (2H , s).
Step F
F
O ~N,
~N~N ~ N~%N
/
142

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
This product was prepared in an analogous fashion to that of Example 81,
except Intermediate 1
was replaced with the product described in Step E. The crude product was
purified by
preparative TLC (eluant: 10 % methanol: 89.5 % DCM: 0.5 % NH40H) to yield
Example 30 as a
mixture of two cis isomers. LC-MS for C3,H3gFN5O calculated 515.31, found
[M+H]+ 516.
EXAMPLE 111
F /
O N ~N
~N~N \ N~N
I / CF3
Step A
HN \ NH2
I
To a solution of the trifluoroacetamide produced in Step C of Example 110 (7.5
g , 31 mmol) in
ethanol (200 mL) was added a solution of potassium carbonate (17 g , 120 mmol)
in water (50
mL), and the resulting mixture was heated at reflux for 90 minutes. The cooled
reaction mixture
was concentrated in vacuo, and the residue was diluted with water (200 mL).
The mixture was
extracted with CHZCIZ (3 x 100 mL). The combined CHZC12 layers were dried over
NaZS04,
filtered and concentrated to give the product (3.76 g , 83 %); 1H NMR SOOMHz
(CDCl3) b =
2.69 (2H , t , J = 6.0 Hz), 3.11 (2H , t , J = 6.0 Hz), 3.45 (2H , br s), 3.92
(2H , s), 6.36 (1H , d , J
=2.3Hz),6.52(lH,dd,J=2.3and8.OHz),6.89(lH,d,J=8.OHz).
Step B
O
\ O~N I \ NH2
143

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
To a solution of the product from Step A (3.76 g, 25.4 mmol) in
tetrahydrofuran (100 mL) was
added triethylamine (4.24 mL , 30.5 mmol), and benzyl chloroformate (4.0 mL ,
28 mmol), and
the resulting mixture was stirred at room temperature for 4 h. Ethyl acetate
(100 mL) was added
to the reaction mixture and the whole was washed with water (250 mL), 5 %
citric acid solution
(150 mL), saturated NaHC03 (150 mL), and saturated NaCI (100 mL), dried over
MgS04,
filtered and concentrated in vacuo to give the product (7.2 g , 100%).
Step C:
O N =N
\ O~N I \ N IN
CFs
To a solution of the product from Step B (7.2 g , 25 mmol) and pyridine (5.1
mL , 64 mmol) in
CHZCIz (150 mL) cooled in an ice bath was added trifluoroacetic anhydride
(5.38 mL , 38.1
mmol), and the resulting mixture was stirred at room temperature for 5 h. The
mixture was
poured onto ice (150 g) and extracted with CHZCIZ (4 x 100 mL). The combined
CHZC12 layers
were washed with 1 N HCl (4 x 75 mL), saturated NaCI (100 mL), dried over
MgS04, filtered
and evaporated. The residue was dissolved in CCI4 (200 mL) and
triphenylphosphine (10 g , 38
mmol) was added and the resulting mixture was heated at reflux for 15 h,
cooled and
concentrated in vacuo. The residue was dissolved in anhydrous N,N-dimethyl
formamide (150
mL) and this solution was added to a solution of sodium azide (1.65 g , 25.4
mmol) in anhydrous
N,N-dimethyl formamide (75 mL), and the resulting mixture was stirred at room
temperature for
3 h. The reaction mixture was poured into water (500 mL) and extracted with
Et20 (3 x 100
mL). The combined Et20 layers were washed with water (2 x 250 mL), saturated
NaCI (100mL),
dried over MgS04, filtered and concentrated in vacuo. The residue was purified
by column
chromatography on silica eluting with a gradient ranging from 10 % EtOAc in
hexanes to 20 %
EtOAc in hexanes to give the product (3.4 g , 33%); 1H NMR 500MHz (CDC13) 8 =
2.99 (2H ,
br m), 3.80 (2H , t , J = 6.0 Hz), 4.75 (2H , s), 5.21 (2H , s), 7.20-7.45 (8H
, m).
Step D:
144

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
N _N
HN ~ N~N
1CF3
To a nitrogen flushed solution of the product from step C (3.4 g , 8.4 mmol)
in methanol (100
mL) was added 10 % palladium on carbon (500 mg) and the resulting mixture was
stirred under a
balloon of hydrogen for 5 h. The catalyst was removed by filtration through
celite and the filtrate
was evaporated in vacuo to give the product (2.2 g , 97 %); ~H NMR SOOMHz
(CDCl3) 8 = 2.33
(lH,brs),2.91 (2H,t,J=6.OHz),3.19(2H,t,J=6.OHz),4.08(2H,s),7.14(lH,d, 1.8
Hz),7.22(lH,dd,J=l.8and8.2Hz),7.31 (lH,d,J=8.2Hz).
Step E:
F
w 1 O N rN
~N~N W N I N
CFa
This product was prepared in an analogous fashion to that of Example 81,
except Intermediate 1
was replaced with the product described in Step D. The crude product was
purified by
preparative TLC (eluant: 10 % methanol: 89.5 % DCM: 0.5 % NHaOH) to yield
Example 31 as a
mixture of two cis isomers. LC-MS for C3~H36F3N6O calculated 584.29, found
[M+H]+ 585.
EXAMPLE 112
F
O
~N~N
O~
145

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
This product was prepared in an analogous fashion to that of Example 81,
except Intermediate 1
was replaced with commercially available 6,7- diethoxy-tetrahydroisoquinoline.
The crude
product was purified by preparative TLC (eluant: 5 % ethanol: 94 % DCM: 1.0 %
NH40H) to
yield Example 32 as a mixture of two cis isomer. LC-MS for C33H4sFNzO3
calculated 536.34,
found [M+H]+ 537.
EXAMPLE 113
F
O
N~ F
N
F
Step A
HN \ F
F
This product was prepared in a similar manner to Intermediate 1, except 2-
Fluoro-4-
trifluoromethyl phenylacetonitrile was replaced with 3,4-di-fluoromethyl
phenylacetonitrile.
LC-MS for C~H~F2N calculated 169.07, found [M+H]+ 170.1
Step B
F
O
N~ F
N
F
This product was prepared in an analogous fashion to that of Example 81,
except Intermediate 1
was replaced with the product described in Step A. The crude product was
purified by
preparative TLC (eluant: 6 % ethanol: 93 % DCM: 1.0 % NH40H) to yield Example
33 as a
mixture of two cis isomers.. LC-MS for CZ~H35F3N20 calculated 484.27, found
[M+H]+ 485.
EXAMPLE 114
146

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
OH
O
N CFs
N
This product was prepared in an analogous fashion to that of Example 82,
except Intermediate 8
was replaced with commercially available 4-hydroxy-4-phenylpiperidine. The
crude product was
purified by preparative TLC (eluant: 10 % methanol: 89 % DCM: 1.0 % NH40H) to
yield
Example 114 as a mixture of four isomers. LC-MS for C3oH3~F3N20z calculated
514.28, found
[M+H]+ 515.
EXAMPLE 115 and 116
F / 1 F
O ~ ~ O
N~,.~N ~ CF3 N~N ~ CF3
N N
EXAMPLE 115 EXAMPLE 116
A solution of Intermediate 5 (100 mg, 0.22 mmol), 4-fluorophenylpiperidine
hydrochloride (57
mg, 0.26 mmol), diisopropylethylamine (45 p.L, 0.26 mmol) and crushed
molecular sieves (4 A,
50 mg) in dichloroethane (5 mL) was treated with sodium triacetoxyborohydride
(233 mg, 1.10
mmol) and stirred at room temperature overnight. The reaction was quenched
with saturated
sodium bicarbonate (10 mL) and diluted with an additional 10 mL of DCE. The
organic layer
was separated and the aqueous layer was washed with dichloromethane (2 x 5
mL). The organics
were combined, dried over anhydrous sodium sulfate, filtered and evaporated.
The residue was
purified by preparative TLC (eluent: 0.5 % NH40H: 5 % MeOH : 94.5 % CHZC12) to
yield 72.3
mg (63 %) of the final product as a mixture of two diastereomers. The
separation was
accomplished by using a HPLC equipped with a preparatory ChiralCel OD column
eluting with
an eluant of 15 % ethanol and 85 % hexane with a flow rate of 9 mL/min. This
afforded the
undesired trans isomer (35 mg, 50 % ) and the desired cis isomer (25 mg, 36 %
). Total recovery
86 %. LC-MS for both: C29H3sN30Fa calculated 517.28, found [M+H]+ 518.3.
147

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example 115: 'H NMR (1s' isomer, undesired) (500 MHz, CDC13) b 8.73 (s, 1H),
7.69 (s, 1H),
7.20 (app dd, J = 5.5, 8.6 Hz, 2H) 6.98 (app t, J = 8.6 Hz, 2H), [4.88 (d, J =
17.5 Hz, 1H), 4.80
(d, J = 17.5 Hz, 1H) (ABx q)] 4.05-3.96 (m, 1H), 3.88 (app dt, J = 5.9, 13.1
Hz, 1H), 3.27 (br d, J
= 11.4 Hz, 1H), 3.12 (br t, J = 5.6 Hz, 3H), 2.83 (dd, J = 5.7, 11.9 Hz, 1H),
2.52-2.44 (m, 1H),
2.43-2.34 (m, 1H), 2.16-1.95 (m, 6H), 1.86-1.74 (m, 4H), 1.45 (br t, J = 10.0,
3H), 1.03 (d, J =
6.6 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H).
Example 116: 'H NMR (2°d isomer, desired) (500 MHz, CDCl3) 8 8.72 (s,
1H), 7.69 (s, 1H),
7.19 (app dd, J = 5.5, 8.6 Hz, 2H) 6.98 (app t, J = 8.6 Hz, 2H), [4.94 (br s,
1H), 4.69 (br d, J =
17.6 Hz, 1H) (ABx q)] 4.05-3.80 (m, 1H), 3.20-3.08 (m, 4H), 2.68 (dd, J = 6.6,
12.8 Hz, 1H),
2.52-2.43 (m, 2H), 2.28 (dd, J = 7.3, 12.8 Hz, 1H), 2.14-2.00 (m, 3H), 1.97-
1.87 (m, 2H), 1.83
(br d, J = 12.8 Hz, 2H) 1.75 (br d, 12.4 Hz, 2H), 1.56-1.48 (m, 1H), 1.42-1.34
(m, 1H), 1.01 (d, J
= 6.5 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H).
EXAMPLE 117
cN
o
C F3
~J
The hydrochloride salt of the pyrimidyl piperidine (Intermediate 8, 133 mg,
0.564 mmol)
was combined with Intermediate 5 (100 mg, 0.282 mmol), DIEA (240 ~tL, 1.40
mmol), and 4 A
powdered molecular sieves (200 mg) in DCM. After 15 minutes at room
temperature, sodium
triacetoxyborohydride (300 mg, 1.41 mmol) was added and the resulting mixture
was stirred for
3 days before being filtered through celite, diluted with DCM and washed with
saturated sodium
bicarbonate and brine. The organic layer was dried over NaZS04, filtered and
concentrated under
reduced pressure to give a crude oil that was purified by preparative TLC
(silica gel, 0.5 %
NH40H/ 4.5 % MeOH/ 95 % DCM) to give 126 mg of a colorless oil. Resolution of
the cis/trans
isomers was accomplished by HPLC using a ChiralPak OD column eluting with 20 %
ethyl
alcohol/ hexanes to give 57 mg of the trans isomer and 45mg of the cis isomer.
First peak 57 mg: ESI-MS calc. for C27H34F3N50: 501.27; found 502 (M+H).
Second peak 45 mg: ESI-MS calc. for C27H34F3N50: 501.27; found 502 (M+H).
148

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLES 118-129
R~ O
~ CF3
R2 i N
N
Several other examples where prepared in a similar fashion to Example 117,
utilizing different
piperidine intermediates. These Examples (118-129) are shown below.
Example R' R' Molecular Calculated Found
Formula [M] [M+H]
118 ~N~ H C27H34F3N5 501.27 502
IN / , O
119 N--N H C24H32F3N7 491.26 492
1
N~N~, O
120 -N H C26H34F3N5 489.27 490
I
C
N S' O
121 N-N H C25H33F3N6 490.27 491
~N
~ O
122 /N~ H C25H33F3N6 490.27 491
\\NiN .S O
149

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
123 ~ H C26H34F3N5 489.27 490
N\N ~ s' O
124 N--N H C25H34F3N7 505.28 506
~N'N~S' O
125 ~ I H C26H33F3N4 506.23 507
iv s' OS
126 co2Et H C32H43F3N3 574.33 575
03
127 co2H H C30H39F3N3 546.29 547
03
_,
128 S1N H C25H32F3N5 523.22 524
o I
H~s' 02S
129 H ~ ~N C26H35F3N6 504.28 505
N ~s' O
EXAMPLE 130
150

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
N
N
~N~ O
~N~~~ . CF
~N
HO N
Step A
O
O CFs
\~N
HO~ N
This ketone was obtained from the racemic Intermediate 6 by resolution on the
ChiraICel OD
preparative column, eluting with 15 % ethyl alcohol in hexanes at 9.0 mL/min.
The faster
eluting enantiomers retention time under analogous analytical conditions (1.0
mL/min) was
11.25 minutes. LC MS for C,~H,~F3N203 calculated 356.13, found 357.05 [M +
H]+.
Step B
N
~~N. N O
~N CF3
~N
HO N
The final compound was synthesized starting from the faster eluting ketone
described in Step A
of this example and Intermediate 10 according to the procedure described in
Example 19. The
respective cis- and traps- diastereoisomeric mixtures were separated by
preparative TLC. LC
MS for C24H3~F3N602 calculated 492.25, found 493.30 [M + H]+.
EXAMPLE 131
151

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
N
N
N ~ CF3
N
This compound was synthesized starting from the ketone preparation of which
was described in
Example 130, Step A and Intermediate 9 according to the procedure described in
Example 19.
LC MS for C26H32F3NsOZ calculated 503.25, found 504.25 [M + H]+.
EXAMPLE 132
Step A
O
V '- N W CFs
O N
F
~N
O
O;~ CFs
~'i' -N
O
N
This ketone was synthesized following procedures described in Intermediates 6,
except that
methoxymethyl chloride was used instead of acetaldehyde in Step C,
Intermediate 6. The
respective enantiomers were obtained by HPLC separation using a ChiralCel OD
preparative
column (eluent hexane : ethyl alcohol / 85 : 15, 9.0 mlJmin). LC MS for
C26H32FsNs02
calculated 503.25, found 504.25 [M + H]+.
Step B
152

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
F
0
N ~ CF3
N I W
O N
The final compound was prepared starting from the ketone from Step A and 4-(4-
fluorophenyl)piperidine according to the procedure described in Example 19.
The respective
isomers were obtained by preparative TLC (eluent ethyl acetate : ethyl alcohol
: ammonium
hydroxide/90 :9 : 1). LC MS for C2~H3zF3NsOz calculated 503.25, found 504.70
[M + H]+.
EXAMPLE 133
w ~ O
N ~ CF3
N
CF3
N
Step A
O
FaC O
To a mixture of 2-(triflurormethyl)acrylic acid (20.0 g, 143 mmol) and benzyl
alcohol (14.8 mL,
142 mmol) in DCM (150 mL), was added EDC (40.93 g, 214.2 mmol) in portions.
The reaction
mixture was stirred for 2 h, diluted by DCM, washed with water and brine,
dried over Na2S04,
filtered and concentrated. The residue was purified by flash column
chromatography (silica gel, 5
% EtOAc/hexane) to yield the product (13.7 g, 42 %) as a viscous oil. 'H-NMR
(400MHz,
CDC13) 8 7.36-7.43 (m, SH), 6.78 (d, 1H), 6.48 (d, 1H), 5.32 (s, 2H).
Step B
153

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
O
CF3
To a flamed dried flask was added 2-[(trimethylsilyl)methyl]-2-propen-1-yl
acetate (12.18 mL,
57.35 mmol) and the intermediate described in Step A, Example 52 (13.2 g, 57.4
mmol), and
tetrakis(triphenylphosphine)palladium(0) (13.3 g, 11.5 mmol) in THF (200 mL)
under nitrogen.
The reaction mixture was refluxed overnight, diluted by DCM (150 mL),
filtered, and
concentrated. The residue was purified by flash column chromatography (silica
gel, 100 %
hexane to 2.5 %EtOAc/hexane to 5 %EtOAc/hexane) to afford the product (11.68
g, 71.7 %).
1H-NMR (400MHz, CDC13) 8 7.33-7.42 (m, 5H), 5.23 (s, 2H), 4.93 (m, 2H), 3.03
(m, 1H), 2.78
(m, 1H), 2.36-2.52 (m, 3H), 2.12-2.24 (m, 1H).
Step C
O
CF3
A solution of the product described in Step B (11.6 g, 40.8 mmol) in DCM (150
mL) was cooled
to -78 °C and saturated with nitrogen. Ozone was bubbled into the
reaction mixture until the
solution became blue, then triphenylphosphine (12.8 g, 49.0 mmol) was added to
the mixture.
The reaction mixture was stirred overnight, and then evaporated under reduced
pressure. The
residue was purified by flash column chromatography (silica gel, 30
%EtOAc/hexane) to yield
the title compound (8.49 g, 72.7 %). 'H-NMR (400MHz, CDC13) b 7.33-7.42 (m,
5H), 5.26 (s,
2H), 2.92 (m, 1H), 2.65 (m, 1H), 2.35-2.54 (m, 4H).
Step D
O
OH
CF3
To a solution of the intermediate described in Step C (1.00 g, 3.49 mmol) in
ethanol (60 mL),
was added Pd-C (10 %, 100 mg). The reaction mixture was placed in a Pan-shaker
and shaken
154

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
under 50 1b pressure of HZ for 1.5 h. The solution was diluted by methanol,
filtered through
celite and evaporated under vacuum to afford the acid (692 mg, 100%) as a
yellow oil. LC-MS
calc. for C7H7F303: 196.03; Found: 197 (M+H).
Step E
O
O CFs
~~~-~'~ N
CF3 ~~J~~~
N
To a mixture of the product described in Step D (684 mg, 3.49 mmol), EDC (2.01
g, 10.5 mmol),
and Intermediate 2 (916 mg, 3.84 mmol) in DCM (30 mL) was added DIEA (670 ~,L,
3.84
mmol) and the resulting solution was stirred overnight at room temperature.
The reaction
mixture was diluted with DCM, washed by water and brine, dried over Na2S04,
filtered and
evaporated in vacuo. The residue was purified by column chromatography (silica
gel, 50 %
EtOAc/hexane) to afford the title compound. 1H-NMR (400MHz, CDC13) b 8.75 (s,
1H), 7.71
(s, 1H), 4.86 (d, J=5.5Hz, 2H), 3.91-4.08 (m, 2H), 3.18 (t, J=S.OHz, 2H), 2.98
(s, 2H), 2.64-2.85
(m, 2H), 2.43-2.56 (m, 2H). LC-MS calc. for C16H14F6N2O2: 380.10; Found: 381
(M+H).
Step F
i
0
N~ CF3
N
CF3 I
N
To a mixture of the compound described in Step E (100 mg, 0.263 mmol), 4-
phenylpiperidine
HCl salt (52 mg, 0.26 mmol), molecular sieve (4 ~, 180 mg), DIEA (46 NL, 0.26
mmol) in DCM
(5 mL), was added sodium triacetoxyborohydride (167 mg, 0.789 mmol) and the
resulting
mixture was stirred overnight at room temperature. The reaction was diluted
with DCM, filtered
through celite, and evaporated under reduced pressure. The residue was
purified by preparative
TLC (1000 micron, eluant: 0.4 % aqueous NH40H: 4 % MeOH: 95.6 % DCM) to yield
a
mixture of cis-and trans- isomers as a free base. The cis- and traps- isomers
were separated by
155

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
preparative chiral HPLC (chiral OD column, eluant: 5 %EtOH/hexane) to yield
the final product
of the title compound as the desired cis isomers. Its HCl salt (20.4 mg) was
formed by treatment
with 4 N HCl/dioxane. 1H-NMR (400MHz, CDCI3) 8 8.74 (s, 1H), 7.70 (s, 1H),
7.20-7.35 (m,
5H), 4.85 (m, 2H), 3.99 (m, 2H), 3.14-3.24 (m, 5H), 2.46-2.56 (m, 3H), 2.02-
2.22 (m, 5H), 1.70-
1.91 (m, 5H). LC-MS calc. for C27H29F6N30: 525.22; Found: 526 (M+H).
EXAMPLE 134
N O
N ~ CF3
N02
Step A
OHC~CHO
To a stirred, -78 °C solution of cyclohexene (15 mL) in 100 mL of
dichloromethane was bubbled
in ozone until light blue color appeared. Excessive ozone was removed by a
nitrogen flow, then
60 mL of dimethyl sulfide was added. The mixture was left overnight, dried
over sodium sulfate.
The solvent and DMS were removed under low vacuum. The crude product was used
in next
step without further purification.
Step B
O
N
N ~ CF3
N02
A mixture of Intermediate 27 (135 mg, 0.3 mmol), the 1,6-hexane-dialdehyde
from Step A
0
0100 mg), molecular sieve (4 A, 50 mg), DIEA (130 mg, 1.0 mmol) in DCM (10 mL
crude
material) was stirred for 5 min. Then sodium triacetoxyborihydride (424 mg,
2.0 mmol) was
added. The resulting mixture was stirred for 2 h, quenched with sat. aq.
NazC03, filtered,
washed with DCM. The filtrates were separated, the aq. solution was extracted
with DCM. The
156

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
combined DCM layers were dried over NaZS04, evaporated. The residue was
purified on
preparative TLC (1000 micron) (developed by 10% [aq. NH40H/MeOH 1/9]/DCM) to
yield the
final product of the title compound as a free base. Its HCl salt (42 mg) was
formed by treatment
with 4 M HCl/dioxane. ESI-MS calc. For C25H34F3N3O3: 481; Found: 482 (M+H).
EXAMPLE 135
O
N
N ~ CF3
NH2
A mixture of the Example 134 (35 mg), PdIC (5%, 5 mg) and methanol (20 mL) was
hydrogenated on a Parr Apparatus for one hour. The catalyst was removed by
filtration. The
filtrate was evaporated to afford the title product as a white solid (32 mg).
ESI-MS calc. For
C25H36F3N30: 451; Found: 452 (M+H).
EXAMPLE 136
O
N
N ~ CFa
N02
Step A
OHC CHO
To a stirred, -78 °C solution of cycloheptene (5 mL) in 50 mL of
dichloromethane was bubbled
in ozone until light blue color appeared. Excessive ozone was removed by a
nitrogen flow, then
20 mL of dimethyl sulfide was added. The mixture was left overnight, dried
over sodium sulfate.
157

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
The solvent and DMS were removed under low vacuum. The crude product was used
in next
step without further purification.
Step B
O
N
N ~ CF3
N02
A mixture of the Intermediate 27 (135 mg, 0.3 mmol), 1,7-heptane-dialdehyde
from Step A)
0100 mg), molecular sieve (4 A, 50 mg), DIEA (130 mg, 1.0 mmol) in DCM (10 mL
crude
material) was stirred for 5 min. Then sodium triacetoxyborohydride (424 mg,
2.0 mmol) was
added. The resulting mixture was stirred for 2 h, quenched with sat. aq.
Na2C03, filtered,
washed with DCM. The filtrates were separated, the aq. solution was extracted
with DCM. The
combined DCM layers were dried over Na2S04, evaporated. The residue was
purified on
preparative TLC (1000 micron) (developed by 10% [aq. NH40H/MeOH 1/9]/DCM) to
yield the
final product of the title compound as a free base. Its HCl salt (50 mg) was
formed by treatment
with 4 M HCl/dioxane. ESI-MS calc. For C26H36F3N3O3: 485; Found: 486 (M+H).
EXAMPLE 137
F3
NH2
Step A
BnOOC~
~~JI~/
5-Norbornene-2-carboxylic acid (5.4 g, 40 mmol), benzyl alcohol (4.3 g, 40
mmol), EDAC.HCI
(9.5 g, 50 mmol), DIEA (5.2 g, 40 mmol) were weighed into a flask. 50 mL of
dichloromethane
158

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
was added. The mixture was stirred overnight, washed with 2 M aq. HCI, water
and sat. aq.
sodium carbonate, dried over sodium sulfate, evaporated. The residue was
purified on MPLC
(10% EtOAc/Hexane). The title compound was obtained as a mixture of exo and
endo isomers
(5.2 g).
S tep B
BnOOC\ ~
ECHO
ECHO
To a stirred, -78 °C solution of benzyl 5-norbornene-2-carboxylate (1.2
g, 5 mmol) in 50 mL of
dichloromethane was bubbled in ozone until light blue color appeared.
Excessive ozone was
removed by a nitrogen flow, then 20 mL of dimethyl sulfide was added. The
mixture was left
overnight, dried over sodium sulfate. The solvent and DMS were removed under
low vacuum.
The crude product was used in next step without further purification.
Step C
BnOOC
O
N
N ~ \ CFa
N02
A mixture of the Intermediate 27 (86 mg, 0.2 mmol), the di-aldehyde ester from
Step B 0200
mg), molecular sieve (4 A, 500 mg), DIEA (130 mg, 1.0 mmol) in DCM (10 mL
crude material)
was stirred for 5 min. Then sodium triacetoxyborohydride (420 mg, 2.0 mmol)
was added. The
resulting mixture was stirred for 2 h, quenched with sat. aq. NaZC03,
filtered, washed with
DCM. The filtrates were separated, the aq. solution was extracted with DCM.
The combined
DCM layers were dried over NaZS04, evaporated. The residue was purified on
preparative TLC
(1000 micron) (developed by 10% [aq. NH40H/MeOH 1/9J/DCM) to yield the final
product of
the title compound as a free base. Its HCl salt (62 mg) was formed by
treatment with 4N
HC1/dioxane. ESI-MS talc. For C34H40F3N3O5: 627; Found: 428 (M+H).
Step D
159

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
HOOC
O
N
N \ CF3
NH2
A mixture of the amino ester from Step C (60 mg), Pd/C (5°l0, 100 mg)
and methanol (20 mL)
was hydrogenated on a Parr Aparatus under 50 lbs of hydrogen for one hour. The
catalyst was
removed by filtration. The filtrate was evaporated, the residue was purified
on preparative TLC
(developed by methanol) to afford the title product as a white solid (18 mg).
ESI-MS calc. For
C27H36F3N30: 507; Found: 508 (M+H).
EXAMPLE 138
O
~N CF3
N
O~O~
Step A
H O
Boc'N N I \ CF3
O~O~
A mixture of Intermediate 26 (as HCl salt, 1.2 g, 4.0 mmol), Intermediate 23
(1.1 g, 4.0 mmol),
PyBrOP (1.9 g, 4.0 mmol), DMAP (0.29 g, 2.4 mmol) and DIEA (2.8 mL, 16 mmol)
in 10 mL of
dichloromethane was stirred at room temperature overnight. The entire mixture
was applied to a
silica gel column and eluted with 20% ethyl acetate/hexane. The title compound
was obtained as
a white solid (1.7 g, 83%). LC-MS for C26H35F3N205 calculated 512, found [M+H-
100]+ 413.
Step B
160

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
O
H2N N \ CF3
O O~
The above amide from Step A (1.7 g, 3.3 mmol) was mixed with 20 mL of 4 M
HCI/dioxane.
The resulting solution was stirred for one hour, evaporated and dried under
high vacuum to yield
the title product as a white solid (1.45 g, 100%). LC-MS for C21H27F3N2O3
calculated 412,
found [M+H]+ 413.
Step C
O
~N CF3
N
O~O~
A mixture of the above intermediate from Step B (140 mg, 0.30 mmol), glutaric
dialdehyde
(50% H20, 120 mg, 0.60 mmol), molecular sieve (4 ~, 1500 mg), DIEA (52 mg,
0.40 mmol) in
DCM (10 mL) was stirred for 5 min. Then sodium triacetoxyborohydride (212 mg,
1.00 mmol)
was added. The resulting mixture was stirred for one hour , quenched with sat.
aq. NaZC03,
filtered, washed with DCM. The filtrates were separated, the aq. solution was
extracted with
DCM. The combined DCM layers were dried over NaZS04 and evaporated. The
residue was
purified on preparative TLC (1000 micron) (developed by 10% [aq. NH40H/MeOH
1/9]/DCM)
to yield the final product of the title compound as a free base. Its HCl salt
(80 mg) was formed
by treatment with 4N HCl/dioxane. ESI-MS calc. For C26H35F3N2O3: 480; Found:
481
(M+H).
EXAMPLE 139
O
CN CF3
N
O' ~OH
A mixture of Example 138 (45 mg, 0.090 mmol), lithium hydroxide monohydrate
(50 mg), water
(0.1 mL) and methanol (1.0 mL) was stirred at room tempearture overnight, the
entire mixture
161

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
was loaded on preparative TLC and developed with methanol. The title compound
as obtained
as white solid (34 mg). LC-MS for C25H33F3N2O3 calculated 466, found [M+H]+
467.
EXAMPLE 140
~ o
N N \ CF3
O O~
A mixture of the Intermediate from Example 138, Step B (140 mg, 0.30 mmol),
1,6-hexane
dialdehyde from Example 13.6, Step A 0100 mg), molecular sieve (4 ~, 500 mg),
DIEA (130
mg, 1.00 mmol) in DCM (20 mL) was stirred for 5 min. Then sodium
triacetoxyborohydride
(424 mg, 2.00 mmol) was added. The resulting mixture was stirred for one hour
, quenched with
sat. aq. Na2C03, filtered, washed with DCM. The filtrates were separated, the
aq. solution was
extracted with DCM. The combined DCM layers were dried over NaZS04,
evaporated. The
residue was purified on preparative TLC (1000 micron) (developed by 10% [aq.
NH40H/MeOH
1/9]/DCM) to yield the final product of the title compound as a free base. Its
HCl salt (75 mg)
was formed by treatment with 4 M HCI/dioxane. ESI-MS calc. For C27H37F3N2O3:
494;
Found: 495 (M+H).
EXAMPLE 141
1 0
N N \ CFs
O OH
A mixture of the Example 140 (20 mg, 0.04 mmol), lithium hydroxide monohydrate
(50 mg),
water (0.1 mL) and methanol (1.0 mL) was stirred at room temperature
overnight, the entire
mixture was loaded on preparative TLC and developed with methanol. The title
compound as
obtained as white solid (15 mg). LC-MS for C26H35F3N2O3 calculated 480, found
[M+H]+
481.
162

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 142
F
O
i
N _ N \ CFs
O O~
Step A
O
O N I \ CF3
O~O~
To a stirred solution of Intermediate 29 (190 mg, 1.1 mmol) in 1 mL of
dichloromethane was
added a solution of oxalyl chloride (2 M, 0.70 mL, 1.4 mmol) in
dichloromethane, then a trace of
DMF. The mixture was stirred at room temperature for 30 min. before being
evaporated to
remove the solvent and excessive reagent under vacuum. The residue was
dissolved in 1 mL of
dichloromethane and added into a solution of the Intermediate 2 (295 mg, 1.00
mmol) and DIEA
(260 mg, 2.0 mmol) in dichloromethane (2 mL). The reaction was stirred for 2
h.. The entire
mixture was loaded onto preparative TLC plate (1000 micron) and developed with
10°Io
MeOH/DCM. The title compound was obtained as yellow solid (300 mg). LC-MS for
C21H24F3N04 calculated 411, found [M+H]+ 412.
Step B
F
O
~N N \ CF3
O O~
163

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
A mixture of the above ketone from Step A (300 mg, 0.73 mmol), 4-
fluorophenylpiperidine
hydrochloride (214 mg, 1.00 mmol), DIEA (129 mg, 1.00 mmol), molecular sieves
(4 t~, 500
mg) and sodium triacetoxyborohydride (212 mg, 1.00 mmol) in 10 mL of
dichloromethane was
stirred at room temperature over the weekend, quenched with sat. aq. sodium
carbonate,
extracted with dichloromethane and purified on preparative TLC (1000 micron),
eluting with
10% MeOH/DCM. The title compound was obtained as a mixture of cis and trans
isomers (270
mg). LC-MS for C32H38F4N2O3 calculated 574, found [M+H)+ 575.
EXAMPLE 143
F
O
~N N \ CF3
O' ~OH
A mixture of the Example 142 (22 mg, 0.04 mmol), lithium hydroxide monohydrate
(30 mg) in
MeOH/H20 (9/1, 0.5 mL) was stirred at 60 °C for 2 h., the entire
mixture was loaded on a
preparative TLC plate and developed with methanol. The title compound as
obtained as white
solid (12 mg). LC-MS for C31H34F4N2O3 calculated 560, found [M+H]+ 561.
EXAMPLE 144
C02 Et
\ O
N N \ CFs
Step A:
O
O~~N \ CFs
164

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Intermediate 29 (100 mg, 0.588 mmol) was dissolved in DCM (20 mL) and treated
sequentially
with oxalyl chloride (153 pL, 1.76 mmol) and DMF (1 drop). The resulting
solution was stirred
at room temperature for 2 h, before being concentrated to dryness and dried
under high vacuum
for 30 min. The resulting residue was dissolved in DCM (5 mL) and added
dropwise to a stirred
solution of Intermediate 1 (177 mg, 0.882 mmol) in DCM (5 mL) and
triethylamine (5 mL).
The resulting reaction mixture was stirred at room temperature overnight,
before being diluted
with DCM and washed with bicarb, 1 N aqueous HCI, and brine. The organic layer
was dried
over MgS04, filtered, and concentrated under reduced pressure to give 230 mg
of the desired
crude product, which was used in the next step without further purification.
Step B:
C02 Et
\ O
i
N N \ CFs
A mixture of the product from the previous step (115 mg, 0.326 mmol), ethyl 3-
piperidin-4-
ylbenzoate hydrochloride (131 mg, 0.489 mmol), DIEA (83 p,L, 0.49 mmol),
molecular sieves (4
A, 100 mg) and sodium triacetoxyborohydride (346 mg, 1.63 mmol) in 10 mL of
dichloromethane was stirred at RT over weekend, quenched with sat. aq. sodium
bicarbonate,
extracted with dichloromethane and purified on preparative TLC (silica gel,
eluting with 40%
THF/hexanes). The title compound was obtained as a mixture of cis and trans
isomers (200 mg).
LC-MS calc. for C33H41F3N2O3: 570.3; found [M+H]+ 571.6. The individual
stereosiomers
were obtained by resolution on a ChiralCel OD column eluting with 10%
ethanol/hexanes:
Peak 1: LC-MS calc. for C33H41F3N2O3: 570.3; found [M+H]+ 571.6.
Peak 2: LC-MS calc. for C33H41F3N2O3: 570.3; found [M+H]+ 571.6.
EXAMPLE 145
165

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
C02H
\ O
N N \ CFs
A mixture of the Example 144 Peak 2 (80 mg,), lithium hydroxide monohydrate
(30 mg) in
EtOH/H20 (4/1, 4 mL) was stirred at room temperature overnight. The product
was purified by
reverse phase HPLC and converted to an HCl salt in the usual fashion. The
title compound as
obtained as white solid (45 mg). LC-MS calculated for C31H37F3N203: 542.28;
found [M+H]+
543.
EXAMPLE 146
C02H
\ O
i
N~,, N \ CF3
A mixture of the Example 144 Peak 1 (78 mg,), lithium hydroxide monohydrate
(30 mg) in
EtOH/H20 (4/1, 4 mL) was stirred at room temperature overnight. The product
was purified by
reverse phase HPLC and converted to an HCl salt in the usual fashion. The
title compound as
obtained as white solid (49 mg). LC-MS calculated for C31H37F3N2O3: 542.28;
found [M+H]+
543.
EXAMPLE 147
C02H
\ O
i
N N \ CFs
166

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
Example 147 is prepared according to the procedure described for Example 144
except that
Intermediate 30 is used in place of ethyl 3-piperidin-4-ylbenzoate
hydrochloride. The resulting 4
stereoisomers are separated by Chiral Chromatography.
EXAMPLE 148 .
C02H
O
~~~N CF3
N I \
Example 148 is prepared according to the procedure described for Example 145
except that one
of the stereoisomers from Example 147 is used in place of one of the products
from Example
144.
EXAMPLE 149
C02H
.
\ O
i
N N \ CF3
Example 149 is prepared according to the procedure described for Example 145
except that one
of the stereoisomers from Example 147 is used in place of one of the products
from Example
144.
EXAMPLE 150
C02H
i
O
i
N, N \ CF3
Example 150 is prepared according to the procedure described for Example 145
except that one
of the stereoisomers from Example 147 is used in place of one of the products
from Example
144.
167

CA 02521625 2005-10-05
WO 2004/094371 PCT/US2004/011463
EXAMPLE 151
C02H
O
i
N I ~ CF3
Example 151 is prepared according to the procedure described for Example 145
except that one
of the stereoisomers from Example 147 is used in place of one of the products
from Example
144.
168

Representative Drawing