Title of Invention

SUBSITUTED PIPERAZINES

Abstract The present invention provides compounds having formula (I) : wherein the variables are as defined in the specification. The compounds act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are useful in pharmaceutical compositions, methods for the treatment of CCR1 - mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists. The present invention provides alternative solutions in the treatment of diseases mediated by CCR1 signaling.
Full Text CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This is a continuation in part of U.S. Ser. No. 10/979,882, filed November 1,
2004, which is a continuation in part of U.S. Ser. No. 10/732,897, filed December 9,2003,
which is a continuation in part of U.S. Ser. No. 10/460,752, filed June 11,2003, which
claims the benefit of Provisional Application Serial No. 60/453,711, filed June 12,2002,
(originally USSN 10/171,398, filed June 12,2002) the contents of each being incorporated
herein by reference.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] NOT APPLICABLE

REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER
PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] The present invention provides compounds, pharmaceutical compositions
containing one or more of those compounds or their pharmaceutically acceptable salts, which
are effective in inhibiting the binding of various chemokines, such as M1P-1α, leukotactin,
MPJP-1 and RANTES, to the CCR1 receptor. As antagonists or modulators for the CCR1
receptor, the compounds and compositions have utility in treating inflammatory and immune
disorder conditions and diseases.
[0005] Human health depends on the body's ability to detect and destroy foreign pathogens
that might otherwise take valuable resources from the individual and/or induce illness. The
immune system, which comprises leukocytes (white blood cells (WBCs): T and B
lymphocytes, monocytes, macrophages granulocytes, NK cell, mast cells, dendritic cell, and
immune derived cells (for example, osteoclasts)), lymphoid tissues and lymphoid vessels, is
the body's defense system. To combat infection, white blood cells circulate throughout the

body to detect pathogens. Once a pathogen is detected, innate immune cells and cytotoxic T
cells in particular are recruited to the infection site to destroy the pathogen. Chemokines act
as molecular beacons for the recruitment and activation of immune cells, such as
lymphocytes, monocytes and granulocytes, identifying sites where pathogens exist.
[0006] Despite the immune system's regulation of pathogens, certain inappropriate
chemokine signaling can develop and has been attributed to triggering or sustaining
inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and others. For
example, in rheumatoid arthritis, unregulated chemokine accumulation in bone joints attracts
and activates infiltrating macrophages and T-cells. The activities of these cells induce
synovial cell proliferation that leads, at least in part, to inflammation and eventual bone and
cartilage loss (see, DeVries, M.E., et al., Semin Immunol 11(2):95-104 (1999)). A hallmark
of some demyelinating diseases such as multiple sclerosis is the chemokine-mediated
monocyte/macrophage and T cell recruitment to the central nervous system (see, Kennedy, et
al.,J. Clin. Immunol. 19(5):273-279 (1999)). Chemokme recruitment of destructive WBCs
to transplants has been implicated in their subsequent rejection. See, DeVries, M.E., et al.,
ibid. Because chemokines play pivotal roles in inflammation and lymphocyte development,
the ability to specifically manipulate their activity has enormous impact on ameliorating and
halting diseases that currently have no satisfactory treatment. In addition, transplant rejection
may be minimized without the generalized and complicating effects of costly
immunosuppressive pharmaceuticals.
[0007] Chemokines, a group of greater than 40 small peptides (7-10 kD), ligate receptors
expressed primarily on WBCs or immune derived cells, and signal through G-protein-coupled
signaling cascades to mediate their chemoattractant and chemostimulant functions.
Receptors may bind more than one ligand; for example, the receptor CCR1 ligates RANTES
(regulated on activation normal T cell expressed), MIP-1Α (macrophage inflammatory
protein), MPIF-l/CKβ8, and Leukotactin chemokines (among others with lesser affinities).
To date, 24 chemokine receptors are known. The sheer number of chemokines, multiple
ligand binding receptors, and different receptor profiles on immune cells allow for tightly
controlled and specific immune responses. See, Rossi, et al., Ann. Rev. Immunol.
18(1) :217-242 (2000). Chemokine activity can be controlled through the modulation of their
corresponding receptors, treating related inflammatory and immunological diseases and
enabling organ and tissue transplants.

[0008] The receptor CCR1 and its chemokine ligands, including, for example MlP-1α,
MPEF-1/CKβ8, leukotactin and RANTES, represent significant therapeutic targets (see Saeki,
et al., Current Pharmaceutical Design 9:1201-1208 (2003)) since they have been implicated
in rheumatoid arthritis, transplant rejection (see, DeVries, M.E., et al., ibid.), and multiple
sclerosis (see, Fischer, et al., J Neuroimmunol. 110(1-2): 195-208 (2000); Izikson, et al., J.
Exp. Med. 192(7):1075-1080(2000); and Rottman, etal.,Eur. J. Immunol 30(8):2372-
2377 (2000). In fact, function-blocking antibodies, modified chemokine receptor ligands and
small organic compounds have been discovered, some of which have been successfully
demonstrated to prevent or treat some chemokine-mediated diseases (reviewed in Rossi, et
al., ibid.). Notably, in an experimental model of rheumatoid arthritis, disease development is
diminished when a signaling-blocking, modified-RANTES ligand is administered (see Plater-
Zyberk, et al., Immunol Lett. 57(1-3):117-120 (1997)). While function-blocking antibody
and small peptide therapies are promising, they suffer from the perils of degradation,
extremely short half-lives once administered, and prohibitive expense to develop and
manufacture, characteristic of most proteins. Small organic compounds are preferable since
they often have longer half lives in vivo, require fewer doses to be effective, can often be
administered orally, and are consequently less expensive. Some organic antagonists of CCR1
have been previously described (see, Hesselgesser, et al.,J. Biol. Chem. 273(25): 15687-
15692 (1998); Ng, et al., J. Med. Chem. 42(22):4680-4694 (1999); Liang, et al., J. Biol.
Chem. 275(25): 19000-19008 (2000); and Liang, et al.,Eur. J. Pharmacol. 389(1):41-49
(2000)). In view of the effectiveness demonstrated for treatment of disease in animal models
(see, Liang, etal., J. Biol. Chem. 275(25):19000-19008 (2000)), the search has continued to
identify additional compounds that can be used in the treatment of diseases mediated by
CCR1 signaling.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides compounds having the formula:

or a pharmaceutically acceptable salt or N-oxide thereof. In the formula above, the subscript
n represents an integer of from 1 to 2, preferably 1. The subscript m represents an integer of

from 0 to 10, limited by the number of available substituents positions on the piperazine or
homopiperazine ring to which it is attached. For example, piperazine derivatives (n is 1) can
have from 0 to 8 R1 groups, preferably 0 to 4 R1 groups, and more preferably 0,1 or 2 R1
groups. Each R1 is a substituent independently selected from C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -SO2Ra,
-X1COR3, -XlCO2Ra, -XlCONRaRb, -X1NRaCORb, -X1SO2Ra, -X1SO2NRaRb, -X1NRaRb,
-X1ORa, wherein X1 is a member selected from the group consisting of C1-4 alkylene, C2-4
alkenyl ene and C2-4 alkynylene and each Ra and Rb is independently selected from the group
consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl and aryl-C1-4 alkyl, or
optionally Ra and Rb when attached to the same nitrogen atom can be combined with the
nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms
as ring members, and wherein the aliphatic portions of each of the R1 substituents is
optionally substituted with from one to three members selected from the group consisting of
-OH, -ORm, -OC(O)NHRm, -OC(O)N(Rm)2, -SH, -SRm, -S(O)Rm, -S(O)2Rm, -SO2NH2,
-S(O)2NHRm, -S(O)2N(Rm)2, -NHS(O)2Rm, -NRmS(O)2Rm, -C(O)NH2) -C(O)NHRm,
-C(O)N(Rm)2, -C(O)Rm, -NHC(O)Rm, -NRmC(O)Rm, -NHC(O)NH2, -NRmC(O)NH2,
-NRraC(O)NHRm, -NHC(O)NHRm, -NRmC(O)N(Rm)2, -NHC(O)N(Rm)2, -CO2H, -CO2Rm,
-NHCO2Rm, -NRmCO2Rm, -CN, -NO2, -NH2, -NHRm, -N(Rm)2, -NRmS(O)NH2 and
-NRmS(O)2NHRm, wherein each Rm is independently an unsubstituted C1-6 alkyl.
[0010] The symbol Ar1 represents an optionally substituted aryl or heteroaryl group.
Preferred aryl groups are phenyl and naphthyl. Preferred heteroaryl groups are those having
from 5 to 10 ring vertices, at least one of which is a nitrogen atom (e.g., pyridyl, pyridazinyl,
pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, purinyl and the like). Each of the
Ar1 rings is optionally substituted with from one to five R2 substituents independently
selected from halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CN, -NO2, -CO2Rc, -CONRcRd,
-C(O)R.c, -OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRc-C(O)NRcRd, -NH-C(NH2)=NH,
-NReC(NH2)=NH, -NH-C(NH2)=NRe, -NH-C(NHRe)=NH, -NReC(NHRe)=NH,
-NReC(NH2)=NRe, -NH-C(NHRc)=NRe, -NH-C(NReRe)=NH, -S(O)Re, -S(O)2Re, -
NRcS(O)2Re, -S(O)2NRcRd, -N3, -C(NORc)Rd, -C(NR°W)=NW, -N(W)C(R0)=NW,
-NRcC(S)NRcRd, -X2C(NORc)Rd, -X2C(NRcW)=NW, -X2N(W)C(Rc)=NW,
-X2NRcC(S)NRcRd, -X2ORc, -O-X2ORc, -X2OC(O)Rc, -X2NRcRd, -O-X2NRcRd -X2SRc, -
X2CN, -X2NO2, -X2CO2Rc, -O-X2CO2Rc, -X2CONRcRd, -O-X2CONRcRd, -X2C(O)Rc,
-X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd,
-X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, X2NH-C(NHRe)=NH, -

X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NR°Rd, -X2N3, -NRd-X2ORc,
-NRd-X2NRcRd, -NRd-X2CO2Rc,. and -NRd-X2CONRcRd, wherein W is selected from Rc,
-CN, -CO2Re and -NO2, and wherein X2 is a member selected from the group consisting of
C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and each Rc and Rd is independently
selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl,
aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, or optionally Rc and Rd when attached
to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-
membered ring having from 0 to 2 additional heteroatoms as ring members; and each R6 is
independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl,
C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, and each of
Rc, Rd and Re is optionally further substituted with from one to three members selected from
the group consisting of-OH, -ORn, -OC(O)NHRn, -OC(O)N(Rn)2, -SH, -SRn, -S(O)Rn,
-S(O)2Rn, -SO2NH2, -S(O)2NHRn, -S(O)2N(Rn)2, -NHS(O)2Rn, -NRnS(O)2Rn, -C(O)NH2,
-C(O)NHRn, -C(O)N(Rn)2, -C(O)Rn, -NHC(O)Rn, -NRnC(O)Rn, -NHC(O)NH2,
-NRnC(O)NH2, -NRnC(O)NHRn, -NHC(O)NHRn, -NRnC(O)N(Rn)2, -NHC(O)N(Rn)2,
-CO2H, -CO2Rn, -NHCO2Rn, -NRCO2Rn, -CN, -NO2, -NH2, -NHRn, -N(Rn)2, -NRnS(O)NH2
and -NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl.
Optionally, two R2 substituents on adjacent carbon atoms are combined to form a five or six-
membered ring having 0-3 heteroatoms as ting members.
[0011] The symbol HAr represents an optionally substituted heteroaryl group. The
heteroaryl groups for HAr can be the same or different from any of the heteroaryl groups
used for Ar1. Generally, the HAr groups are monocyclic, but can also be fused bicyclic
systems having from 5 to 10 ring atoms, at least one of which is a nitrogen atom. Certain
preferred heteroaryl groups are 5 or 6-membered rings having at least one nitrogen atom as a
ring vertex and fused ring systems having a 5-membered ring fused to a benzene ring, for
example pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
oxathiadiazolyl, pyrrolyl, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazolyl and
benzotriazolyl, each of which is substituted with from one to five R3 substituents
independently selected from the group consisting of halogen, -ORf, -OC(O)Rf, -NRfRg, -SRf,
-Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRfRg, -NR6C(O)Rf, -NRsC(O)2Rh,
-NRf-C(O)NRfRg, -NH-C(NH2)=NH, -NRhC(NH2)=NH, -NH-C(NH2)=NRh, -NH-
C(NHRh)=NH, -NRhC(NHRh)=NH, -NRhC(NH2)=NRh, -NH-C(NHRh)=NRh, -NH-
C(NRhRh)=NH, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg. -NRfS(O)2NR^8, -N3,

-C(NORf)Rg, -C(NRfWa)=NWa, -N(Wa)C(Rf)=NWa, -X3C(NORf)RB, -X3C(NRV)=NW2,
-X3N(Wa)C(Rf)=NWa, -NRfC(S)NRfRE,--X3NRfC(S)NRfRs, -X3ORf, -X3OC(O)Rf, -X3NRfR8,
-X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -
X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRf-C(O)NRfRg, -X3NH-C(NH2)=NH,
-X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -
X3NRfS(O)2Rh, -X3S(O)2NRfRg, -Y, -SO2Y, -C(O)Y, -X3Y, -X3N3, -O-X3ORf, -O-X5NRfRg,
-O-X3CO2Rf, -OX3CONRfRg, -NRg-X3ORf, -NRg-X3NRfRg, -NRg-X3CO2Rf, and
-NR6-X3CONRfRg, wherein Y is a five to ten-membered aryl, heteroaryl or heterocyclic ring,
optionally substituted with from one to three substitutents selected from the group consisting
of halogen, -ORf, -NRfRg, -Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfRg -C(O)Rf, -NRgC(O)Rf, -
S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -C(NORf)Rg, -C(NRfWa)=NWa,
-N(Wa)C(Rf)=NWa, -X3C(NORf)Rg, -X3C(NRfWa)=NWa, -X3N(Wa)C(Rf)=NWa, -X3ORf, -
X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg, and wherein Wa is selected from Rf, -CN,
-CO2Rh and -NO2, and wherein each X3 is independently selected from the group consisting
of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and each Rf and Rg is independently
selected from hydrogen, C1-8 alkyl, C1-8haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl,
aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, or when attached to the same nitrogen
atom can be combined with the nitrogen atom to form a five or six-membered ring having
from 0 to 2 additional heteroatoms as ring members, and each R is independently selected
from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8
alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, wherein the aliphatic
portions of Rf, Rg and Rh is optionally further substituted with from one to three members
selected from the group consisting of-OH, -ORo, -OC(O)NHRo, -OC(O)N(R°)2, -SH, -SR°,
-S(O)R°, -S(O)2Ro, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2R°, -NR°S(O)2R°,
-C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)Ro, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2,
-NRoC(O)NH2, -NRoC(O)NHR°, -NHC(O)NHR°, -NRoC(O)N(R°)2, -NHC(O)N(R°)2,
-CO2H, -CO2R°, -NHCO2R°, -NR°CO2Ro, -CN, -NO2, -NH2, -NHR°, -N(Ro)2, -NR°S(O)NH2
and -NRoS(O)2NHRo, wherein each R° is independently an unsubstituted C1-6 alkyl. Among
the most preferred HAr groups are substituted or unsubstituted pyrazoles and benzopyrazoles
as well as substituted or unsubstituted triazoles and benzotriazoles. Preferably, substituted or
unsubstituted pyrazoles and benzopyrazoles are attached to the remainder of the molecule via
a nitrogen atom of the pyrazole ring. Optionally, two R3 substituents on adjacent carbon
atoms are combined to form a five or six-membered ring having 0-3 heteroatoms as ring

members. In other embodiments, HAr can be a furanyl or thienyl ring (e.g., having no ring
nitrogen atom) and being optionally substituted as described above.
[0012] The symbol Ll represents a linking group having from one to three main chain
atoms selected from the group consisting of C, N, O and S and being optionally substituted
with from one to three substituents selected from the group consisting of halogen, phenyl,
-ORi, -OC(O)Rj, -NRjRj, -SRi, -Rk, -CN, -NO2, -CO2Ri, -CONRiRj, -C(O)Ri, -OC(O)NRiRj, -
NRjC(O)Ri -NRjC(O)2Rk, -X4ORi, -X4OC(O)Ri, -X4NRiRj, -X4SRi, -X4CN, -X4NO2, -
X4CO2Ri, --X4OCNRiRj, -X4C(O)Ri, -X4OC(O)NRiRj, -X4NRjC(O)Ri and -X4NRjC(O)2Rk,
wherein X4 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4
alkynylene and each R1 and Rj is independently selected from hydrogen, C1-8 alkyl, C1-8
haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and
aryloxy-C1-4 alkyl, and each Rk is independently selected from the group consisting of C1-8
alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4
alkyl, and arylox.y-C1-4 alkyl. In certain preferred embodiments, the linking groups are
unsubstituted, while in other preferred embodiments, substituents are present that can
increase partitioning into selected solvents or into selected tissues. For example, addition of a
hydroxy group to a propylene linkage will generally provide compounds having more
favorable solubility in water. Preferably, L1 is selected from -CH2-, -CH2CH2-,
-CH2CH2CH2-, -CH2O-, -CH2NH-, -CH2OCH2- and -CH2NHCH2-. Most preferably, L1 is
-CH2-.
[0013] In addition to the compounds provided herein, the present invention further provides
pharmaceutical compositions containing one or more of these compounds, as well as methods
for the use of these compounds in therapeutic methods, primarily to treat diseases associated
with CCR1 signalling activity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figures 1A through 1G provides selected and preferred Ar1 groups for compounds
of formulae I, II and III.
[0015] Figures 2A through 2Z, 2AA through 2HH and 3 provide selected and preferred
HAr groups for compounds of formulae I, II, III and IV.
[0016] Figures 4A-4C provide structures of selected commercially available starting
materials.

[0017] Figures 5A-5L provide generic formulae of preferred embodiments of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Abbreviation and Definitions
[0018] The term "alkyl", by itself or as part of another substituent, means, unless otherwise
stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms
designated (i.e. C1-8 means one to eight carbons). Examples of alkyl groups include methyl,
ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-
octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group having one or
more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having
one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-
propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl,
1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term "cycloalkyl"
refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-6cycloalkyl)
and being fully saturated or having no more than one double bond between ring vertices.
"Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for
example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.
[0019] The term "alkylene" by itself or as part of another substituent means a divalent
radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer
carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is
a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms.
Similarly, "alkenylene" and "alkynylene" refer to the unsaturated forms of "alkylene" having
double or triple bonds, respectively.
[0020] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their
conventional sense, and refer to those alkyl groups attached to the remainder of the molecule
via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for
dialkylamino groups, the alkyl portions can be the same or different and can also be
combined to form a 3-7 membered ring with the nitrogen atom to which each is attached.
Accordingly, a group represented as -NRaRb is meant to include piperidinyl, pyrrolidinyl,
morpholinyl, azetidinyl and the like.

[0021] The terms "halo" or "halogen," by themselves or as part of another substituent,
mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally,
terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For
example, the term "C1-4 haloalkyl" is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-
chlorobutyl, 3-bromopropyl, and the like.
[0022] The term "aryl" means, unless otherwise stated, a polyunsaturated, typically
aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings)
which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or
rings) that contain from one to five heteroatoms selected from N, O, and S, wherein the
nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. A heteroaryl group can be attached to the remainder of the molecule through a
heteroatom. Non-lirniting examples of aryl groups include phenyl, naphthyl and biphenyl,
while non-limiting examples of heteroaryl groups include 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,
1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-
oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-
furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,
5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-
isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each
of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable
substituents described below.
[0023] For brevity, the term "aryl" when used in combination with other terms (e.g.,
aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is
attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like).
[0024] The above terms (e.g., "alkyl," "aryl" and "heteroaryl"), in some embodiments, will
include both substituted and unsubstituted forms of the indicated radical. Preferred
substituents for each type of radical are provided below. For brevity, the terms aryl and
heteroaryl will refer to substituted or unsubstituted versions as provided below, while the
term "alkyl" and related aliphatic radicals is meant to refer to unsubstituted version, unless
indicated to be substituted.
[0025] Substituents for the alkyl radicals (including those groups often referred to as
alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from: -halogen,

-OR', -NR'R", -SR', -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R",
-NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-
C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and -NO2 in a number
ranging from zero to (2 m'+1), where m' is the total number of carbon atoms in such radical.
R', R" and R'" each independently refer to hydrogen, unsubstituted C1-8 alkyl, unsubstituted
heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-8 alkyl,
C1-8 alkoxy or C1-8 thioalkoxy groups, or unsubstituted aryl-C1-4 alkyl groups. When R' and
R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to
form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1 -
pyrrolidinyl and 4-morpholinyl.
[0026] Similarly, substituents for the aryl and heteroaryl groups are varied and are
generally selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R',
-CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', ,-NR'-C(O)NR"R"',
-NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R",
-NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging
from zero to the total number of open valences on the aromatic ring system; and where R', R"
and R'" are independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl,
C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C1-4 alkyl, and
unsubstituted aryloxy-C1-4 alkyl. Other suitable substituents include each of the above aryl
substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
[0027] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, wherein T and U
are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2.
Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are
independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an
integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be
replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)S-
X-(CH2)t-, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -
S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from
hydrogen or unsubstituted C1-6 alkyl.

[0028] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N),
sulfur (S) and silicon (Si).
[0029] The term "pharmaceutically acceptable salts" is meant to include salts of the active
compounds which are prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein. When compounds of the
present invention contain relatively acidic functionalities, base addition salts can be obtained
by contacting the neutral form of such compounds with a sufficient amount of the desired
base, either neat or in a suitable inert solvent. Examples of salts derived from
pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper,
ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the
like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary,
secondary and tertiary amines, including substituted amines, cyclic amines, naturally-
occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-
dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,
piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present
invention contain relatively basic functionalities, acid addition salts can be obtained by
contacting the neutral form of such compounds with a sufficient amount of the desired acid,
either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid
addition salts include those derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
the like, as well as the salts derived from relatively nontoxic organic acids like acetic,
propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included
are salts of amino acids such as arginate and the like, and salts of organic acids like
glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al,
"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific
compounds of the present invention contain both basic and acidic functionalities that allow
the compounds to be converted into either base or acid addition salts.

[0030] The neutral forms of the compounds may be regenerated by contacting the salt with
a base or acid and isolating the parent compound in the conventional manner. The parent
form of the compound differs from the various salt forms in certain physical properties, such
as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the
compound for the purposes of the present invention.
[0031] In addition to salt forms, the present invention provides compounds which are in a
prodrug form. Prodrugs of the compounds described herein are those compounds that readily
undergo chemical changes under physiological conditions to provide the compounds of the
present invention. Additionally, prodrugs can be converted to the compounds of the present
invention by chemical or biochemical methods in an ex vivo environment. For example,
prodrugs can be slowly converted to the compounds of the present invention when placed in a
transdermal patch reservoir with a suitable enzyme or chemical reagent.
[0032] Certain compounds of the present invention can exist in unsolvated forms as well as
solvated forms, including hydrated forms. In general, the solvated forms are equivalent to
unsolvated forms and are intended to be encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in multiple crystalline or
amorphous forms. In general, all physical forms are equivalent for the uses contemplated by
the present invention and are intended to be within the scope of the present invention.
[0033] Certain compounds of the present invention possess asymmetric carbon atoms
(optical centers) or double bonds; the racemates, diastereomers, geometric isomers,
regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be
encompassed within the scope of the present invention. The compounds of the present
invention may also contain unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. For example, the compounds may be radiolabeled
with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14
(14C). All isotopic variations of the compounds of the present invention, whether radioactive
or not, are intended to be encompassed within the scope of the present invention.
II. General
[0034] The present invention derives from the discovery that compounds of formula I (as
well as the subgeneric formulae II, III and IV) act as potent antagonists of the CCR1 receptor.

The compounds have in vivo anti-inflammatory activity. Accordingly, the compounds
provided herein are useful in pharmaceutical compositions, methods for the treatment of
CCR1 -mediated diseases, and as controls in assays for the identification of competitive
CCR1 antagonists.
III. Compounds
[0035] In one aspect, the present invention provides compounds having the formula:

or a pharmaceutically acceptable salt or N-oxide thereof.
[0036] In the formula above, the subscript n represents an integer of from 1 to 2, preferably
1. The subscript m represents an integer of from 0 to 10, limited by the number of available
substituents positions on the piperazine or homopiperazine ring to which it is attached. For
example, piperazine derivatives (n is 1) can have from 0 to 8 R1 groups, preferably 0 to 4 R1
groups, and more preferably 0, 1 or 2 R1 groups.
[0037] The symbol Ar1 represents an optionally substituted aryl or heteroaryl group.
Preferred aryl groups are phenyl and naphthyl. Preferred heteroaryl groups are those having
from 5 to 10 ring vertices, at least one of which is a nitrogen atom (e.g., pyridyl, pyridazinyl,
pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, purinyl and the like). Each of the
Ar1 rings is optionally substituted with from one to five R2 substituents independently
selected from halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CN, -NO2, -CO2Rc, -CONRcRd,
-C(O)Rc, -OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRc-C(O)NRcRd, -NH-C(NH2)=NH,
-NReC(NH2)=NH, -NH-C(NH2)=NRe, -NH-C(NHRe)=NH, -NReC(NHRe)NH,
-NReC(NH2)=NRe, -NH-C(NHRe)NR6, -NH-C(NReRe)=NH, -S(O)Re, -S(O)2Re, -
NRcS(O)2Re, -S(O)2NRcRd, -N3, -C(NORc)Rd, -C(NRcW)=NW, -N(W)C(Rc)=NW,
-NRcC(S)NRcRd, -X2C(NORc)Rd, -X2C(NRCW)=NW, -X2N(W)C(Rc)=NW,
-X2NRcC(S)NRcRd, -X2ORc, -O-X2ORc, -X2OC(O)Rc, -X2NRcRd, -O-X2NRcRd, -X2SRc, -
X2CN, -X2NO2, -X2CO2Rc, -O-X2CO2Rc, -X2CONRcRd, -O-X2CONRcRd, -X2C(O)RC,
-X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd,

-X2NH-C(NH2)=NHS -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X2NH-C(NHRe)=NH, -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd, -X2N3, -NRd-X2ORc,
-NRd-X2NRcRd, -NRd-X2CO2Rc, and -NRd-X2CONRcRd, wherein each W is selected from Rc,
-CN, -CO2R6 and -NO2, and wherein each X2 is a member selected from the group consisting
of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and each Rc and Rd is independently
selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl,
aryl, heteroaryl, aryl-C1-4alkyl, and aryloxy-C1-4 alkyl, or optionally Rc and Rd when attached
to the same nitrogen atom can. be combined with the nitrogen atom to form a five or six-
membered ring having from 0 to 2 additional heteroatoms as ring members; and each Re is
independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl,
C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, and each of
Rc, Rd and Re is optionally further substituted with from one to three members selected from
the group consisting of-OH, -OR", -OC(O)NHRn, -OC(O)N(Rn)2, -SH, -SRn, -S(O)Rn,
-S(O)2Rn, -SO2NH2, -S(O)2NHRn, -S(O)2N(Rn)2, -NHS(O)2Rn, -NRnS(O)2Rn, -C(O)NH2,
-C(O)NHRn, -C(O)N(Rn)2, -C(O)Rn, -NHC(O)Rn, -NRnC(O)Rn, -NHC(O)NH2,
-NRnC(O)NH2, -NRnC(O)NHRn, -NHC(O)NHRn, -NRnC(O)N(Rn)2, -NHC(O)N(Rn)2,
-CO2H, -CO2Rn, -NHCO2Rn, -NRnCO2Rn, -CN, -NO2, -NH2, -NHR", -N(Rn)2, -NRnS(O)NH2
and -NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl.
Optionally, two R2 substituents on adjacent carbon atoms are combined to form a five or six-
membered ring having 0-3 heteroatoms as ring members.
[0038] HAr is an optionally substituted heteroaryl group. The heteroaryl groups for HAr
can be the same or different from any of the heteroaryl groups used for Ar1. Generally, the
HAr groups are monocyclic, but can also be fused bicyclic systems having from 5 to 10 ring
atoms, at least one of which is a nitrogen atom. Certain preferred heteroaryl groups are 5 or
6-membered rings having at least one nitrogen atom as a ring vertex and fused ring systems
having a 5-membered ring fused to a benzene ring, for example pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathiadiazolyl, pyrrolyl, thiazolyl,
isothiazolyl, benzimidazolyl, toenzopyrazolyl and benzotriazolyl. Preferably, the fused
bicyclic HAr moiety, when present, is attached to the remainder of the molecule through the
5-member ring. Additionally, each of the HAr groups is substituted with from one to five R3
substituents independently selected from the group consisting of halogen, -ORf, -OC(O)Rf, -
NRfRg, -SRf, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRfRg, -NRgC(O)Rf, -
NRgC(O)2Rh, -NRf-C(O)NRfRg, -NH-C(NH2)=NH, -NRhC(NH2)=NH, -NH-C(NH2)=NRh, -

NH-C(NHRh)=NH, -NHhC(NHRh)=NH, -NRhC(NH2)=NRh, -NH-C(NHRh)=NRh, -NH-
C(NRhRh)=NH, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -NRfS(O)2NRfRg
-C(NORf)Rg, -C(NRfWa)=NWa, -N(Wa)C(Rf)=NWa, -N3, -X3ORf, -X3OC(O)Rf, -X3NRfRg, -
X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -
X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRf-C(O)NRfRg, -X3NH-C(NH2)=NH,
-X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -
X3NRfS(O)2Rh, -X3S(O)2NRfRg, -X3C(NORf)Rg, -X3C(NRfWa)=NWa, -X3N(Wa)C(Rf)=NWa,
-Y, -SO2Y, -C(O)Y, -X3Y, -X3N3, -O-X3ORf, -O-X3NRfR8, -O-X3CO2Rf, -O-X3CONRfR6,
-NR8-X3ORf, -NRg-X3NRfRg, -NRg-X3CO2Rf, and -NRg-X3CONRfRg, wherein Y is a five to
ten-membered aryl, heteroaryl or heterocyclic ring, optionally substituted with from one to
three substitutents selected from the group consisting of halogen, -ORf, -NRfRg, -Rh, -SRf,
-CN, -NO2, -CO2Rf, -CONRfR8, -C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh,
-S(O)2NRfRg, -C(NORf)Rg, -C(NRfWa)=NWa, -N(Wa)C(Rf)=NWa, -X3C(NORf)Rg,
-X3C(NRfWa)=NWa, -X3N(W)C(Rf)-NWa, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh and
-X3S(O)2NRfRg, wherein each Wa is selected from Rf, -CN, -CO2R11 and -NO2, and wherein
each X is independently selected from the group consisting of C1-4 alkylene, C2-4 alkenylene
and C2-4 alkynylene and each Rf and R8 is independently selected from hydrogen, C1-8 alkyl,
C1-8haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and
aryloxy-C1-4 alkyl, or when attached to the same nitrogen atom can be combined with the
nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms
as ring members, and each Rh is independently selected from the group consisting of C1-8
alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4
alkyl, and aryloxy-C1-4 alkyl, wherein the aliphatic portions of Rf, Rg and Rh is optionally
further substituted with from one to three members selected from the group consisting of
-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2Ro, -SO2NH2,
-S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2R°, -NR°S(O)2Ro, -C(O)NH2, -C(O)NHR°,
-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NRoC(O)R°, -NHC(O)NH2, -NR°C(O)NH2,
-NR°C(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2Ro,
-NHCO2R°, -NRoCO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and
-NRoS(O)2NHR°, wherein each R° is independently an unsubstituted C1-6 alkyl. Optionally,
two R3 substituents on adjacent carbon atoms are combined to form a five or six-membered
ring having 0-3 heteroatoms as ring members. Among the most preferred HAr groups are
substituted or unsubstituted pyrazoles and benzopyrazoles and substituted or unsubstituted

triazoles and benzotriazoles. Preferably, substituted or unsubstituted pyrazoles are attached
to the remainder of the molecule via a nitrogen atom of the pyrazole ring.
[0039] The symbol L1 represents a linking group having from one to three main chain
atoms selected from the group consisting of C, N, O and S and being optionally substituted
with from one to three substituents selected from the group consisting of halogen, phenyl,
-ORi, -OC(O)ORi, -NRiRj, -SRi, -Rk, -CN, -NO2, -CO2Ri, -CONRiRj, -C(O)Ri, -OC(O)NRiRj, -
NRjC(O)Ri, -NRjC(O)2Rk, -X4ORi, -X4OC(O)Ri, -X4NRiRj, -X4SRi, -X4CN, -X4NO2, -
X4CO2Ri, -X4CONRiRJ, -X4C(O)Ri, -X4CONRiRJ, -X4NRjC(O)Ri and-X4NRjC(O)2Rk,
wherein X4 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4
alkynylene and each Ri and Rj is independently selected from hydrogen, C1-8 alkyl, C1-8
haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and
aryloxy-C1-4 alkyl, and each Rk is independently selected from the group consisting of C1-8
alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4
alkyl, and aryloxy-C1-4 alkyl. In certain preferred embodiments, the linking groups are
unsubstituted, while in other preferred embodiments, substituents are present that can
increase partitioning into selected solvents or into selected tissues. For example, addition of a
hydroxy group to a propylene linkage will generally provide compounds having more
favorable solubility in water. Preferably, L1 is selected from -CH2-, -CH2CH2-,
-CH2CH2CH2-, -CH2O-, -CH2NH-, -CH2OCH2- and -CH2NHCH2-. More preferably, L1 is
-CH2-.
[0040] Returning to the piperazine or homopiperazine portion of the compounds, each R1 is
a substituent independently selected from C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8
alkenyl and C2-8 alkynyl, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -SO2Ra, -X'CORa,
-X1CO2Ra, -X1CONRaRb, -X1NRaCORb, -X1SO2Ra, -XlSO2NRaRb, -X1NRaRb,
-X1ORa,wherein X1 is a member selected from the group consisting of C1-4 alkylene, C2-4
alkenylene and C2-4 alkynylene and each Ra and Rb is independently selected from the group
consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl and aryl-C1-4alkyl, or
optionally Ra and Rb when attached to the same nitrogen atom can be combined with the
nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms
as ring members, and wherein the aliphatic portions of each of the R1 substituents is
optionally substituted with from one to three members selected from the group consisting of
-OH, -ORm, -OC(O)NHRm, -OC(O)N(Rm)2, -SH, -SRm, -S(O)Rra, -S(O)2Rm, -SO2NH2,
-S(O)2NHRm, -S(O)2N(Rm)2, -NHS(O)2Rm, -NRmS(O)2Rm, -C(O)NH2, -C(O)NHRm,

-C(O)N(Rm)2, -C(O)Rra, -NHC(O)Rm, -NRmC(O)Rm, -NHC(O)NH2, -NRraC(O)NH2,
-NRmC(O)NHRm, -NHC(O)NHRm, -NRmC(O)N(Rm)2; -NHC(O)N(Rm)2, -CO2H, -CO2Rm,
-NHCO2Rin, -NRmCO2Rm, -CN, -NO2, -NH2, -NHRm, -N(Rm)2, -NRmS(O)NH2 and
-NRmS(O)2NHRm, wherein each Rm is independently an unsubstituted C1-6 alkyl. In certain
preferred embodiments, R1, when present is selected from methyl, ethyl, isopropyl, -CH2OH,
-CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH(CH3)OH and -CH(CH3)OCH3, or more
preferably, methyl, -CH2OH and -CH2OCH3.
[0041] Excluded from the above generic formula, as well as each of the formulae below,
are those compounds that are either commercially available or known in the literature,
including: CAS Reg. No. 492422-98-7, 1-[4-bromo-5-methyl-3-(trifluoromethyl)-1H-
pyrazol-1-yl]acetyl]-4-(5-chloro-2-methylphenyl)-piperazine; CAS Reg. No. 351986-92-0,
1-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(4-fluorophenyl)-
piperazine; CAS Reg. No. 356039-23-1, 1-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]-
4-(4-fluorophenyl)-piperazine; l-(2-{4-nitro-3,5-dimethyl-1H-pyrazol-1-yl}propanoyl)-4-
phenylpiperazine; 2-(2,4-Dinitro-imidazol-1 -yl)-1 - [4-(4-fluorophenyl)-piperazin-1 -yl]-
ethanone; 2-(2,4-Dinitro-imidazol-1 -yl)-1 -(4-phenyl-piperazin-1 -yl)-ethanone; 2-(4-Nitro-
imidazol-1-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone; and CAS Reg. No. 492992-15-1,3-[3-
Fluoro-4-[4-[(l-pyrazolyl)acetyl]piperazine-1-yl]phenyl]-5-[[(isoxazol-3-
yl)amino]methyl]isoxazole.
[0042] A number of groups of embodiments can be outlined as follows.
[0043] In a first group of embodiments, the compounds are represented by formula I in
which Ar1 is selected from
(i) phenyl, substituted with from 1 to 5 R2 groups;
(ii) pyridinyl, substituted with from 1 to 4 R2 groups; and
(iii) pyrimidinyl, substituted with from 1 to 3 R2 groups;
(iv) pyrazinyl, substituted with from 1 to 3 R2 groups; and
(v) pyridazinyl, substituted with from 1 to 3 R2 groups;
wherein each R2 is a member independently selected from the group consisting of halogen,
-ORc, -OC(O)Rc, -NRcRd, -SR°, -Re, -CN, -NO2, -CO2Rc, -CONR°Rd, -C(O)Rc,
-OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRe-C(O)NRcRd, -C(NORc)Rd,
-C(NR°W)=NW, -N(W)C(Rc)=NW, -S(O)Re, -S(O)2Re, -NRcS(O)2Re, -S(O)2NRcRd and-N3,
wherein each Rc and Rd is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl,

C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each Re is independently selected from the
group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl,
wherein the aliphatic portions of Rc, Rd and Re are optionally further substituted with from
one to three members selected from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8
alkyl), CN, NO2, NH2, NH(C1-8 alkyl) and N(C1-8 alkyl)2. More preferably, Ar1 is phenyl
substituted with from 1 to 3 R2 groups. Some preferred embodiments are those in which the
Ar1 groups are represented by;

wherein Hal is F, Cl or Br and each R is independently C1-6 alkyl or C3-6 cycloalkyl.
[0044] In other preferred embodiments, L1 is -CH2- and is optionally substituted with
phenyl, -Rk, X4ORi, -X4OC(O)Ri, -X4NRiRj, -X4SRi, -X4CN or -X4NO2. In still other
preferred embodiments, HAr is selected from pyrazolyl and triazolyl, each of which is
optionally substituted with from one to three R3 groups independently selected from halogen,
phenyl, thienyl, -ORf, -OC(O)Rf, -NRfRg, -SRf, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg,
-C(O)Rf, -OC(O)NRfRg, -NR6C(O)Rf, -NRgC(O)2Rh, -NRf-C(O)NRfRg, -S(O)Rh, -S(O)2Rh,
-S(O)2NRfRg, -NRfS(O)2Rh, -NRfS(O)2NRfRg, -N3, -X3ORf, -X3OC(O)Rf, -X3NRfRg, -X3SRf,
-X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf. -
X3NRgC(O)2Rh, -X3NRf-C(O)NRfRg, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh,
-X3S(O)2NRfRg and -X3N3 wherein Rf and Rg are each independently selected from the group
consisting of H, C1-8 alkyl and C1-8 haloalkyl, and each Rh is independently selected from the
group consisting of C1-8 alkyl and C1-8 haloalkyl. In still other preferred embodiments, the
subscript n is 1, m is 0, 1 or 2, Ar1 is phenyl substituted with from one to three R2 groups,
HAr is pyrazolyl which is substituted with three R3 groups and Ll is -CH2-. In certain
preferred embodiments in this group, Ar1 is selected from those substituted phenyl moieties
provided in Figures 1A through 1G.
[0045J In a second group of embodiments, the compounds are represented by formula I in
which Ar1 is selected from
(i) phenyl, substituted with from 1 to 5 R2 groups;
(ii) pyridinyl, substituted with from 1 to 4 R2 groups; and
(iii) pyrimidinyl, substituted with from 1 to 3 R2 groups;
(iv) pyrazinyl, substituted with from 1 to 3 R2 groups; and

(v) pyridazinyl, substituted with from 1 to 3 R2 groups;
wherein each R2 is a member independently selected from the group consisting of halogen,
-X2ORc, -O-X2ORc, -X2OC(O)Rc, -X2NRcRds -O-X2NRcRd, -X2SRc, -X2CN, -X2NO2,
-X2CO2Rc, -O-X2CO2Rc, -X2CONRcRd, -O-X2CONRcRd, -X2C(O)Rc, -X2OC(O)NRcRd,
-X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd, -X2NH-C(NH2)=NH,
-X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X2NH-C(NHRe)=NH, -X2C(NORc)Rd,
-X2C(NRcW)=NW, -X2N(W)C(Rc)=NW, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re,
-X2S(O)2NRcRd and -X2N3.
[0046] In a third group of embodiments, the compounds are represented by formula I in
which HAr is a member selected from the group consisting of pyrazolyl and triazolyl, which
is optionally substituted with from one to three R3 groups independently selected from the
group consisting of halogen, -ORf, -OC(O)Rf, -NRfRB, -SRf, -Rh, -CN, -NO2, -CO2Rf,
-CONRfRg, -C(O)Rf, -OC(O)NRfRg, -NRgC(O)Rf, -NRgC(O)2Rh, -NRf-C(O)NRfRg,
-NH-C(NH2)=NH, -NRhC(NH2)=NH, -NH-C(NH2)=NRh, -NH-C(NHRh)=NH, -S(O)Rh, -
S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -NRfS(O)2Rh. -NRfS(O)2NRfR6, -N3, -X3ORf,
-X3OC(O)Rf, -X3NRfRe, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf,
-X3OC(O)NRfRg, -X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRf-C(O)NRfRg,
-X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -
X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfRg, -Y, -X3Yand -X3N3 wherein Y is a
five to ten-membered aryl, heteroaryl or heterocyclic ring, optionally substituted with from
one to three substitutents selected from the group consisting of halogen, -ORf, -NRfR8, -Rh,
-SRf, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh, -
NRfS(O)2Rh, -S(O)2NRfRg, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg, and
wherein each X3 is independently selected from the group consisting of C1-4 alkylene, C2-4
alkenylene and C2-4 alkynylene and each Rf and Rg is independently selected from hydrogen,
C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4
alkyl, and aryloxy-C1-4 alkyl, or when attached to the same nitrogen atom can be combined
with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional
heteroatoms as ring members, and each Rh is independently selected from the group
consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl,
heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, wherein the aliphatic portions of Rf, R8 and
Rh are optionally further substituted with from one to three members selected from the group
consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)Ro, -S(O)2Ro,
-SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2Ro, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°,

-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NRoC(O)R°, -NHC(O)NH2) -NR°C(O)NH2,
-NR°C(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2Ro,
-NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and
-NR°S(O)2NHR°, wherein R° is unsubstituted C1-6 alkyl. Within this group of embodiments,
preferred compounds are those in which n is 1, m is 0-2, Ar1 is phenyl substituted with from
one to three R2 groups, HAr is pyrazolyl which is substituted with two to three R3 groups,
more preferably three R3 groups and L1 is -CH2-. Optionally, two R2 groups on Ar1 are
combined as noted above to form a five or six-membered ring having from 0-2 heteroatoms
as ring members. Further preferred are those in which Ar1 is selected from the substituted
phenyl moieties provided in Figures 1A through 1G. In some preferred embodiments are
those compounds in which one of the R3 groups is selected from the group consisting of-Y
and -X3-Y. More preferably, those compounds wherein Y is selected from the group
consisting of thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl and oxadiazolyl,
which is optionally substituted, or phenyl or naphthyl which is substituted as set forth above,
or more preferably, with from one to three substituents independently selected from the group
consisting of halogen, -ORf, -NRfRg, -CORf, -CO2Rf, -CONRfRg, -NO2, -Rh, -CN, -X3-ORf,
-X3-NRfRg and -X5-NRfS(O)2Rh, wherein Rf and Rg are each independently selected from the
group consisting of H, C1-8 alkyl, C3-6 cycloalkyl and C1-8 haloalkyl, and each Rh is
independently selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl and C1-8
haloalkyl.
[0047] In another group of embodiments, the compounds are represented by formula II:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein each of R1a, R1b, R1c, R1d,
R1e, R1f, R1g and R1h represents a member independently selected from the group consisting
of H, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl. C2-8 alkenyl and C2-8 alkynyl, -CORa, -CO2Ra,
-CONRaRb, -NRaCORb, -SO2R1, -X1CORa, -X1CO2Ra, -X1CONRaRb, -X1NRaCORb,
-X1SO2R1, -X1SO2NRaRb, -X1NRaRb, -X1ORa,wherein X1 is a member selected from the
group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and each Ra and Rb is

independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl and aryl-C1-4alkyl, or optionally Ra and Rb when attached to the same nitrogen
atom can be combined with the nitrogen atom to form a five or six-membered ring having
from 0 to 2 additional heteroatoms as ring members, and wherein the aliphatic portions of
each of the R1 substituents is optionally substituted with from one to three members selected
from the group consisting of-OH, -ORm, -OC(O)NHRm, -OC(O)N(Rm)2, -SH, -SRm,
-S(O)Rm, -S(O)2Rm, -SO2NH2, -S(O)2NHRm, -S(O)2N(Rm)2, -NHS(O)2Rm, -NRmS(O)2Rm,
-C(O)NH2, -C(O)NHRm, -C(O)N(Rm)2j -C(O)Rm, -NHC(O)Rm, -NRmC(O)Rm, -NHC(O)NH2,
-NRmC(O)NH2, -NRmC(O)NHRm, -NHC(O)NHRm, -NRmC(O)N(Rm)2, -NHC(O)N(Rm)2,
-CO2H, -CO2Rm, -NHCO2Rm -NRmCO2Rm, -CN, -NO2, -NH2, -NHRm, -N(Rm)2,
-NRmS(O)NH2 and -NRmS(O)2NHRm, wherein each Rm is independently an unsubstituted C1-
6 alkyl. The remaining groups have the meanings provided above with reference to formula I
in their most complete interpretation. Preferably, Ar1 is phenyl, optionally substituted with
from one to five R2 substitutents; and HAr is pyrazolyl, substituted with from 1 to 3 R3
substituents. Still more preferably, L1 is -CH2-. Further preferred are those compounds in
which Ar1 is phenyl substituted with from one to three independently selected R2 substituents
and HAr is pyrazolyl substituted with one to three, more preferably three R3 substituents. In
still further preferred embodiments, Ar1 is a substituted phenyl selected from those provided
in Figures 1A through 1G. Even further preferred are those compounds in which HAr is
selected from the substituted pyrazoles provided in Figures 2A through 2Z, 2AA through
2CC and 3. Still more preferably, no more than two of R1a through R1h are other than H.
[0048] In yet another group of embodiments, compounds are provided having formula III:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein the subscript m is an
integer of from 0 to 2; each R1 is selected from the group consisting of -CO2H, C1-4 alkyl and
C1-4 haloalkyl, wherein the aliphatic portions are optionally substituted with -OH, -ORm,
-OC(O)NHRm, -OC(O)N(Rm)2, -SH, -SRm, -S(O)Rm, -S(O)2Rm, -SO2NH2, -S(O)2NHRm,

-S(O)2N(R)2, -NHS(O)2Rm, -NRmS(O)2Rm, -C(O)NH2, -C(O)NHRm, -C(O)N(Rm)2,
-C(O)Rm, -NHC(O)Rm, -NRmC(O)Rm, -NHC(O)NH2, -NRmC(O)NH2, -NRmC(O)NHRm,
-NHC(O)NHRm, -NRmC(O)N(Rm)2, -NHC(O)N(Rm)2, -CO2H, -CO2Rm, -NHCO2Rm,
-NRmCO2Rm, -CN, -NO2, -NH2, -NHRm, -N(Rm)2, -NRmS(O)NH2 and -NRmS(O)2NHRm,
wherein each Rm is independently an unsubstituted C1-6 alkyl. In certain preferred
embodiments, R1, when present is selected from methyl, ethyl, isopropyl, -CH2OH,
-CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH(CH3)OH and -CH(CH3)OCH3, or more
preferably, methyl, -CH2OH and -CH2OCH3. R2a, R2b, R2c, R2d and R2e are each members
independently selected from hydrogen, halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CN, -
NO2, -CO2Rc, -CONRcRd, -C(O)Rc, -OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRc-
C(O)NRcRd, -NH-C(NH2)=NH, -NReC(NH2)=NH, -NH-C(NH2)=NRe, -NH-C(NHRe)=NH, -
S(O)R6, -S(O)2Re, -NRcS(O)2Re, -S(O)2NRcRd, -N3, -C(NORc)Rd, -C(NRcW)=NW,
-N(W)C(Rc)=NW, -NRcC(S)NRcRd, -X2C(NORc)Rd, -X2C(NRcW)=NW,
-X2N(W)C(Rc)=NW, -X2NRcC(S)NRcRd, -X2ORc, -O-X2ORc, -X2OC(O)Rc, -X2NRcRd,
-O-X2NRcRd, -X2SRc, -X2CN, -X2NO2) -X2CO2Rc, -O-X2CO2Rc, -X2CONRcRd,
-O-X2CONRcRd, -X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re,
-X2NRcC(O)NRcRd, -X2NH-C(NH2)=NH, -X2NRcC(NH2)=NH, -X2NH-C(NH2)=NRe,
-X2NH-C(NHRc)=NH, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd, -X2N3,
-NRd-X2ORc, -NRd-X2NRcRd, -NRd-X2CO2Rc, and -NRd-X2CONRcRd, wherein each W is
selected from Rc, -CN, -CO2Re and -NO2, and wherein each X2 is a member selected from the
group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and each Rc and Rd is
independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl,
C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl, or optionally Rc and Rd
when attached to the same nitrogen atom can be combined with the nitrogen atom to form a
five or six-membered ring having from 0 to 2 additional heteroatoms as ring members; and
each Re is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl,
and each of Rc, Rd and Re is optionally further substituted with from one to three members
selected from the group consisting of-OH, -ORn, -OC(O)NHRn, -OC(O)N(Rn)2, -SH, -SRn,
-S(O)Rn, -S(O)2Rn, -SO2NH2, -S(O)2NHRn, -S(O)2N(Rn)2, -NHS(O)2Rn, -NRnS(O)2Rn,
-C(O)NH2, -C(O)NHRn, -C(O)N(Rn)2, -C(O)Rn, -NHC(O)Rn, -NRnC(O)Rn, -NHC(O)NH2,
-NRnC(O)NH2, -NRnC(O)NHRn, -NHC(O)NHRn, -KRnC(O)N(Rn)2, -NHC(O)N(Rn)2,
-CO2H, -CO2Rn, -NHCO2Rn, -NRnCO2Rn, -CN, -NO2, -NH2, -NHRn, -N(Rn)2, -NRnS(O)NH2
and -NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl, such that

at least one of R2a, R2b, R2c, R2d and R2e is other than H; R3a, R3b and R3c are each members
independently selected from hydrogen, halogen, -ORf, -OC(O)Rf, -NRfRg, -SRf, -Rh, -CN,
-NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRfRg, -NRgC(O)Rf, -NRgC(O)2Rh, -NRf-
C(O)NRfRg, -NH-C(NH2)=NH, -NRhC(NH2)=NH, -NH-C(NH2)=NRh, -NH-C(NHRh)=NH, -
S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -NRfS(O)2NRfRg, -N3, -C(NORf)Rg,
-C(NRfWa)=NWa, -N(Wa)C(Rf)=NWa, -X3C(NORf)Rg, -X3C(NRfWa)=NWa,
-X3N(Wa)C(Rf)=NWa, -X3ORf, -X3OC(O)Rf, -X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf,
-X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRf-
C(O)NRfRg, -X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-
C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfRg, -Y, -X3Y, -X3N3,
-O-X3ORf, -O-X3NRfRg, -O-X3CO2Rf, -O-X3CONRfRg, -NRg-X3ORf, -NR8-X3NRfRg,
NRg-X3CO2Rf3 and -NRg-X3CONRfRg, wherein Y is a five or six-membered aryl, heteroaryl
or heterocyclic ring, optionally substituted with from one to three substitutents selected from
the group consisting of halogen, -ORf, -NRfRg, -Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfRg,
-C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -C(NORf)Rg,
-C(NRfWa)=NWa, -N(Wa)C(Rf)=NWa, -X3C(NORf)Rg, -X3C(NRfWa)=NWa,
OC3N(Wa)C(Rf)=NWa, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg, wherein each
Wa is selected from Rf, -CN, -CO2Rh and -NO2, and wherein each X3 is independently
selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene and
each Rf and Rg is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl,
or when attached to the same nitrogen atom can be combined with the nitrogen atom to form
a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members, and
each Rh is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl,
wherein the aliphatic portions of Rf, Rg and Rh is optionally further substituted with from one
to three members selected from the group consisting of-OH, -ORo, -OC(O)NHR°,
-OC(O)N(Ro)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2,
-NHS(O)2Ro, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°, -NHC(O)Ro,
-NRoC(O)R°, -NHC(O)NH2, -NRoC(O)NH2, -NR°C(O)NHRo, -NHC(O)NHR°,
-NR°C(O)N(Ro)2, -NHC(O)N(Ro)2, -CO2H, -CO2Ro, -NHCO2Ro, -NR°CO2R°, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHRo, wherein each R° is
independently an unsubstituted C1-6 alkyl, such that at least one ofR3a,R3b and R3c is other
than H. Optionally, two of R3a, R3b and R3c, when attached to adjacent carbon atoms are

combined to form a five or six-membered ring having 0-3 heteroatoms as ring members and
which is further substituted with from 0-3 substituents provided for the aliphatic portions of
Rf above. Additionally, two of R2a, R2b, R2c, R2d and R2e, when attached to adjacent carbon
atoms are optionally combined to form a five or six-membered ring having 0-3 heteroatoms
as ring members and which is further substituted with from 0-3 substituents provided for the
aliphatic portions of Rc above.
[0049] Within the group of formula III above, certain groups of embodiments are
particularly preferred. In one group of particularly preferred embodiments, the subscript m is
0 or 1 and at least one of R2a or R2e is hydrogen. More preferably, at least one of R3a, R3b and
R3c is selected from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic portions are
optionally substituted as set forth above. Still more preferably, R2d is hydrogen and at least
two of R3a, R3b and R3c are selected from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the
aliphatic portions are optionally substituted as set forth above, with the remaining member
being other than hydrogen. In related, and preferred embodiments, m is 0 or 1 and at least
one of R2a or R2e is hydrogen, R2d is hydrogen, R2c is selected from F, Cl, Br, CN, NO2,
CO2CH3, C(O)CH3 and S(O)2CH3, and at least two of R3a, R3b and R3c are selected from
halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic portions are optionally
substituted as set forth above, with the remaining member being other than hydrogen. In
another group of particularly preferred embodiments, the subscript m is 0 or 1; and R2a and
R2e are both hydrogen. More preferably, at least one of R3a, R3b and R3c is selected from
halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic portions are optionally
substituted as set forth above. Still more preferably, at least one of R3a, R3b and R3c is
selected from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic portions are
optionally substituted as set forth above, and the remaining members of R3a, R3b and R3c are
other than hydrogen. In yet another group of particularly preferred embodiments, the
subscript m is 0 or 1; and R2b and R2e are both hydrogen. More preferably, at least one of R3a,
R3b and R3c is selected from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic
portions are optionally substituted as set forth above. Still more preferably, at least one of
R3a, R3b and R3D is selected from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic
portions are optionally substituted as set forth above, and the remaining members of R3a, R3b
and R3c are other than hydrogen.
[0050] In other groups of preferred embodiments of formula III, at least one of R3a, R3b and
R3c is selected from -Y and -X3-Y. Related embodiments are those in which m is 0 or 1 and

at least one of R2a and R2e is hydrogen. In still other embodiments, R3b is hydrogen, halogen
or cyano. Further preferred are those compounds in which R3b is halogen or cyano, and R1,
when present, is selected from the group consisting of -CO2H and C1-4 alkyl optionally
substituted with -OH, -ORm, -S(O)2Rm, -CO2H and -CO2Rm. In yet other embodiments, m is
0 or 1; at least one of R2a and R2c is hydrogen; and at least one of R3a, R3b and R3c is selected
from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic portions are optionally
substituted as set forth above. More preferably, R2d is hydrogen and at least two of R3a, R3b
and R3c are selected from halogen, C1-4 alkyl and C1-4 haloalkyl, wherein the aliphatic
portions are optionally substituted as set forth above. Still further preferred are those
compounds in which R2c is selected from F, Cl, Br, CN, NO2, CO2CH3, C(O)CH3 and
S(O)2CH3, and each of R3a, R3b and R3c is other than hydrogen.
[0051] In another group of preferred embodiments of formula III, m is 0 or 1 and each of
R2a and R2e are hydrogen. In still other embodiments, R3b is hydrogen, halogen or cyano.
Further preferred are those compounds in which R3b is halogen or cyano, and R1, when
present, is selected from the group consisting of C1-4 alkyl, optionally substituted with -OH,
-ORm, -S(O)2Rm, -CO2H and -CO2Rm. In yet other embodiments, m is 0 or 1; each of R2a and
R2e are hydrogen; and at least one of R3a, R3b and R3c is selected from halogen, C1-4 alkyl and
C1-4 haloalkyl, wherein the aliphatic portions are optionally substituted as set forth above.
More preferably, each of R3a, R3b and R3c is other than hydrogen. Still further preferred are
those compounds in which R2c is selected from F, Cl, Br, CN, NO2, CO2CH3, C(O)CH3 and
S(O)2CH3. In related embodiments, m is 0 or 1 and R2b and R2e are each hydrogen.
[0052] In other preferred groups of formula III, the compounds have a formula selected
from

wherein each of the substiruents has the meaning provided above with respect to formula HI.
In one group of embodiments, R3c and R3a are each independently selected from the group
consisting of C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl; and R3b is hydrogen, halogen or
cyano, more preferably halogen. In another group of embodiments, R3c and R3a are each

independently selected from the group consisting of halogen, -NRfRg, -SRf, -CO2Rf, -Y and
-Rh, wherein Rh is C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, wherein the aliphatic portions
optionally substituted with a member selected from the group consisting of -OH, -OR°,
-OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°,
-S(O)2N(Ro)2, -NHS(O)2Ro, -NRoS(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°,
-NHC(O)R°, -NRoC(O)R°, -NHC(O)NH2, -NRoC(O)NH2, -NRoC(O)NHR°, -NHC(O)NHR°,
-NR°C(O)N(R°)2, -NHC(O)N(Ro)2, -CO2H, -CO2R°, -NHCO2R°, -NRoCO2Ro, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHRo. In still other embodiments, m is
0. For embodiments in which m is 1 or 2, R1 is preferably-CO2H or C1-4 alkyl, optionally
substituted with -OH, -ORm, -S(O)2Rra, -CO2H and -CO2Rm. In certain preferred
embodiments, R1, when present is selected from methyl, ethyl, isopropyl, -CH2OH,
-CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH(CH3)OH and -CH(CH3)OCH3, or more
preferably, methyl, -CH2OH and -CH2OCH3.
[0053] In other preferred groups of formula III, the compounds have a formula selected
from

wherein each of the substituents has the meaning provided above with respect to formula III.
In one group of embodiments, R3c and R3a are each independently selected from the group
consisting of halogen, cyano, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRfRg, -SRf, -S(O)Rh, -
S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, where the
alkyl and cycloalkyl substituents can be optionally substituted with a member selected from
the group consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°,
-S(O)2R°, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2R°, -NRoS(O)2R°, -C(O)NH2,
-C(O)NHRo, -C(O)N(Ro)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2,
-NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°, -NR°C(O)NCR°)2, -NHC(O)N(R°)2,
-CO2H, -CO2R°, -NHCO2Ro, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2
and -NR°S(O)2NHR°; and R3b is hydrogen, halogen or cyano. Preferred groups for R3a are
halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -C(O)Rf, -NRfRg, -SRf, -S(O)2Rh,

-X3Y or Y wherein the aliphatic portions are optionally substituted as set forth above; while
preferred groups for R3c are halogen, cyano, -C(O)Rf, -S(O)2Rh, C1-6 alkyl, C1-6 haloalkyl or
C3-6 cycloalkyl, where the alkyl and cycloalkyl substituents can be optionally substituted as
noted above. In another group of embodiments, R3c and R3a are each independently selected
from the group consisting of C1-6 alkyl, optionally substituted with a member selected from
the group consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°,
-S(O)2Ro, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2Ro, -NR°S(O)2R°, -C(O)NH2,
-C(O)NHR°, -C(O)N(Ro)2, -C(O)R°, -NHC(O)R°, -NRoC(O)R°, -NHC(O)NH2,
-NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHRo, -NRoC(O)N(R°)2, -NHC(O)N(R°)2,
-CO2H, -CO2Ro, -NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2
and -NRoS(O)2NHRo. In some embodiments, R2c is other than hydrogen, and is preferably
selected from halogen, cyano and nitro; and R2b is selected from -SRc, -O-X2-ORc, -X2-ORc,
-Re, -ORc, -NRcRd, -NRdC(O)Rc and -NRcSO2Rd. In still other embodiments, m is 0. For
embodiments in which m is 1 or 2, Rl is preferably -CO2H or C1-4 alkyl, optionally
substituted with -OH, -ORm, -N(Rm)2, -S(O)2Rm, -CO2H and -CO2Rm.
[0054] Other preferred compounds of formula III are represented by the formula:

wherein R2a is other than hydrogen; R2c is halogen, cyano or nitro; R2d is -SRc, -O-X2-ORc,
-X2-ORc, -Re, -ORc, -NRcRd, -NRdC(O)Rc and -NRcSO2Rd; R3a is selected from the group
consisting of C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, optionally substituted with a
member selected from the group consisting of-OH, -ORo, -OC(O)NHRo, -OC(O)N(Ro)2,
-SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2R°,
-NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NR°C(O)Ro,
-NHC(O)NH2, -NR°C(O)NH2, -NRoC(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2,
-NHC(O)N(R°)2, -CO2H, -CO2Rc, -NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°,
-N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHR°; R3b is hydrogen, F, Cl, Br or cyano; and R3c is
selected from the group consisting of NH2, CF3, SCH3 and Y. Further preferred are those
compounds in which each R1, when present, is selected from the group consisting of -CO2H

and C1-4 alkyl, optionally substituted with a member selected from the group consisting of
-OH, -ORm, -S(O)2Rm, -CO2H and -CO2Rm.
[0055] Related embodiments are those compounds having the formula:

wherein R2a is other than hydrogen; R2c is halogen, cyano or nitro; R2d is -SRc, -O-X2-ORc,
-X2-ORc, -Re, -ORc, -NRcRd, -NRdC(O)Rc and -NRcSO2Rd; R3a is selected from the group
consisting of-NRfRg, -SRf, -SO2Rh, -Rh, -C(O)Rf, -Y and -X3Y, more preferably -NH2, -CF3,
-SCH3 and Y; R3b is hydrogen, F, Cl, Br or cyano; and R3c is selected from the group
consisting of C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, optionally substituted with a
member selected from the group consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2,
-SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2R°,
-NRoS(O)2Ro, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)Ro, -NHC(O)Ro, -NR°C(O)Ro,
-NHC(O)NH2, -NRoC(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2,
-NHC(O)N(R°)2, -CO2Hs -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°,
-N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHR°. Further preferred are those compounds in
which each R1, when present, is selected from the group consisting of -CO2H and C1-4 alkyl,
optionally substituted with a member selected from the group consisting of-OH, -ORm,
-S(O)2Rm,-CO2H and-CO2Rm. In other preferred embodiments, R3b is hydrogea In still
other related embodiments, two adjacent R3a, R3b or R3c groups are combined to form a five
or six-membered fused ring, preferably a carbocyclic ring or a heterocyclic ring having from
1-2 heteroatoms as ring members.
[0056] Still other preferred groups of formula III above, are:


[0057] Turning first to the compounds of formula IIIa, R3b is preferably hydrogen, halogen,
nitro or cyano, more preferably halogen and most preferably fluoro, chloro or bromo; R3c is
preferably C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl; R2c is halogen and R2b is -SRc,
-O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, -NRcS(O)2Re and -NRdC(O)Rc; wherein Rc and Rd
are selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8
alkynyl, and Re is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each of Rc, Rd and Re is optionally further
substituted as described above, or in some embodiments with from one to three members
selected from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8 alkyl), CN, NO2, NH2,
NH(C1-8 alkyl) and N(C1-8 alkyl)2.
[0058] For the compounds of formula IIIb, R3b is preferably hydrogen, halogen, nitro or
cyano, more preferably halogen and most preferably fluoro, chloro or bromo; R3a is
preferably C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl; R2c is preferably halogen and R2b is
preferably -SRc, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, -NRcS(O)2Re and -NRdC(O)Rc;
wherein Rc and Rd are selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8
alkenyl and C2-8 alkynyl, and Re is selected from the group consisting of C1-8 alkyl, C1-8
haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each of Rc, Rd and Re is
optionally further substituted as described above, or in some embodiments, with from one to
three members selected from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8 alkyl),
CN, NO2, NH2, NH(C1-8 alkyl) and N(C1-8 alkyl)2.

[0059] In one group of embodiments for the compounds of formula IIIc, each of R3a and
R3cis selected from halogen, cyano, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRfRg, -SRf,
-S(O)Rh5 -S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl,
where the alkyl and cycloalkyl substituents can be optionally substituted with a member
selected from the group consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°,
-S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2, -NHS(O)2Ro, -NRoS(O)2R°,
-C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°, -NHC(O)Ro, -NR°C(O)R°, -NHC(O)NH2,
-NR°C(O)NH2, -NRoC(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(Ro)2,
-CO2H, -CO2Ro, -NHCO2Ro, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2
and -NRoS(O)2NHRo. More preferably, R3a is selected from halogen, cyano, C1-6 alkyl, C1-6
haloalkyl, C3-6 cycloalkyl, -C(O)Rf, -NRfRg, -SRf, -S(O)2Rh, -X3Y and Y; still more
preferably R3ais halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -C(O)Rf or -SO2Rh
wherein the aliphatic portions are optionally substituted as set forth above. R3b is hydrogen,
F, Cl, Br or cyano. R3c is preferably halogen, cyano, -C(O)Rf, -SO2Rh, C1-6 alkyl, C1-6
haloalkyl or C3-6 cycloalkyl wherein the aliphatic portions are substituted as set forth above.
R2c is halogen, cyano or nitro; and R2b is selected from hydrogen, halogen, -ORc, -OC(O)Rc, -
NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -S(O)2Re5 -NRcS(O)2Re,
-NRdC(O)Rc, -X2ORc, -X2OC(O)Rc, -X2NR°Rd, -X2SR°, -X2CO2Rc, -X2CONReRd,
-X2C(O)Rc, -X20C(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd5 -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -O-X2-ORc, -X2S(O)2NRcRd and -X2N3, wherein X2
is C1-4 alkylene, and each Rc and Rd is independently selected from hydrogen, C1-8 alkyl, C1-8
haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each Re is independently selected
from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8
alkynyl, and each of Rc, Rd and Re is optionally further substituted as described above for
formula III, or with from one to three members selected from the group consisting of OH,
O(C1-8 alkyl), SH, S(C1-8 alkyl), CN, NO2, NH2, NH(C1-8 alkyl) and N(C1-8 alkyl)2. In some
preferred embodiments, R2c is halogen, cyano or nitro; R2b is -SR°, -O-X2-ORo, -X2-ORc, -Rc,
-ORc, -NRcRd, -NRcS(O)2Re and -NRdC(O)Rc; wherein Rc and Rd are selected from
hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and Re is
selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl
and C2-8 alkynyl, and each of Rc, Rd and Re is optionally further substituted with from one to
three members selected from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8 alkyl),
CN, NO2, NH2, NH(C1-8 alkyl) and N(C1-8 alkyl)2; R3a is C1-6 alkyl, C1-6 haloalkyl, C3-6
cycloalkyl, -C(O)Rf, -NRfR6, -SRf, -S(O)2Rh, -X3Y or Y; R3b is hydrogen, F, Cl, Br or cyano;

and R3c is halogen, cyano, -C(O)Rf, -SO2Rh, C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl
wherein the aliphatic portions are substituted as set forth above.
[0060] In related, and preferred embodiments, compounds of formula IIIc are provided
wherein R3c is selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl,
-C(O)Rf, -NRfRg, -SRf, -S(O)2Rh, -X3Y and Y; still more preferably R3cis halogen, cyano, C1-
6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -C(O)Rf or -SO2Rh wherein the aliphatic portions are
optionally substituted as set forth above. R3b is hydrogen, F, Cl, Br or cyano; R3a is
preferably halogen, cyano, -C(O)Rf, -SO2Rh, C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl
wherein the aliphatic portions are substituted as set forth above. R2c is halogen, cyano or
nitro, preferably halogen; and R2b is selected from hydrogen, halogen, -ORo, -OC(O)Ro, -
NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -S(O)2Re, -NRcS(O)2Re,
-NRdC(O)Rc, -X2ORc, -X2OC(O)Rc, -X2NRcRd, -X2SRc, -X2CO2R°, -X2CONRcRd,
-X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)R°, -X2NRdC(O)2Re, -X2NRcC(O)NRoRd, -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -O-X2-ORc, -X2S(O)2NRcRd and -X2N3, wherein X2
is C1-4 alkylene, and each R° and Rd is independently selected from hydrogen, C1-8 alkyl, C1-8
haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each Re is independently selected
from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8
alkynyl, and each of Rc, Rd and Re is optionally further substituted as described above for
formula III, or with from one to three members selected from the group consisting of OH,
O(C1-8 alkyl), SH, S(C1-8 alkyl), CN, NO2, NH2, NH(C1-8 alkyl) and N(C1-8 alkyl)2. In some
preferred embodiments, R2c is halogen, cyano or nitro; R2b is -SRc, -O-X2-ORc, -X2-OR°, -Re,
-ORc, -NRcRd, -NRcS(O)2Re or -NRdC(O)Rc; R3a is selected from the group consisting of C1-6
alkyl and C3-6 cycloalkyl; R3c is selected from the group consisting of NH2, CF3, SCH3 and Y;
and R3b is chloro or bromo.
[0061] For selected compounds of formula IIId, R3a and R3c are each independently
selected from halogen, cyano, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRfRg, -SRf, -S(O)Rh, -
S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl, where the
alkyl and cycloalkyl substituents can be optionally substituted with a member selected from
the group consisting of-OH, -OR°, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)Ro,
-S(O)2Ro, -SO2NH2, -S(O)2NHR°, -S(O)2N(Ro)2, -NHS(O)2Ro, -NRoS(O)2R°, -C(O)NH2,
-C(O)NHR°, -C(O)N(R°)2, -C(O)R°, -NHC(O)Ro, -NR°C(O)R°, -NHC(O)NH2,
-NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°, -NRoC(O)N(Ro)2, -NHC(O)N(R°)2,
-CO2H, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NRoS(O)NH2

and -NR°S(O)2NHRo. More preferably, R3a is selected from halogen, cyano, C1-6 alkyl, C1-6
haloalkyl, C3-6 cycloalkyl, -C(O)Rf, -NRfRg, -SRf, -S(O)2Rh, -X3Y and Y, and still more
preferably selected from NH2, CF3, SCH3, SO2CH3, CN, C(CH3)2OH and Y. R3b is
hydrogen, F, CI, Br or cyano; R3c is preferably C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl,
optionally substituted as for formula III; R2a is preferably other than hydrogen, and is selected
from halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -
S(O)2Re, -C(NORc)Rd, -C(NRcW)=NW, -N(W)C(Rc)=NW, -X2C(NORc)Rd,
-X2C(NRcW)=NW, -X2N(W)C(R°)=NW, -X2ORc, -X2OC(O)R°, -X2NR°Rd, -X2SRc, -
X2CO2Rc, -X2CONRcRd, -X2C(O)Re, -X2OC(O)NRcRd, -X2NRdC(O)R°, -X2NRdC(O)2Re,
-X2NRcC(O)NRcRd, -X2S(O)Re, -X2S(O)2Re. -X2NRcS(O)2Re, -X2S(O)2NRcRd and -X2N3; R2c
is hydrogen, halogen, cyano or nitro, preferably halogen; and R2d is selected from hydrogen,
halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -
S(O)2Re, -NRcS(O)2Re, -NRdC(O)Rc, -X2ORc, -X2OC(O)Rc, -X2NRcRd, -X2SRc, -X2CO2Rc,
-X2CONRcRd, -X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re,
-X2NRcC(O)NRcRd, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -O-X2-ORc, -X2S(O)2NRcRd
and -X2N3, wherein X2 is C1-4 alkylene, and each Rc and Rd is independently selected from
hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each Re
is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each of Rc, Rd and Re is optionally further
substituted as described above for formula III, or with from one to three members selected
from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8 alkyl), CN, NO2, NH2, NH(C1-8
alkyl) and N(C1-8 alkyl)2; and no more than one of R2a and R2d is hydrogen. Preferably, each
of R2a and R2d is other than hydrogen. In the most preferred embodiments, R2a is other than
hydrogen; R2c is halogen, cyano or nitro; R2d is -SRc, -O-X2-ORc, -X2-ORc, -Re, -ORc,
-NRcRd, -NRcS(O)2Re or -NRdC(O)Rc; R3c is selected from the group consisting of C1-6 alkyl
and C3-6 cycloalkyl; R3b is hydrogen, F, Cl, Br or cyano; and R3a is selected from the group
consisting of -NRfRg, -SO2Rh, -Rh, -C(O)Rf, -X3Y, SCH3 and Y, wherein Y is an
unsubstituted or substituted 5- or 6-membered heteroaryl group or heterocyclic group such as
pyridyl, pyrimidinyl, thienyl, furyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,
tetrazolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl and the like.
[0062] In related and preferred embodiments, compounds of formula IIId are provided
wherein R3a and R3c are each independently selected from halogen, cyano, -NO2, -CO2Rf,
-CONRfRg, -C(O)Rf, -NRfRg, -SRf, -S(O)Rh, -S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, C1-6 alkyl,

C1-6 haloalkyl or C3-6 cycloalkyl, where the alkyl and cycloalkyl substituents can be
optionally substituted with a member selected from the group consisting of-OH, -OR°,
-OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°,
-S(O)2N(R°)2, -NHS(O)2R°, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°,
-NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°,
-NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NRoS(O)2NHRo. More preferably, R3c is selected
from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -C(O)Rf, -NRfRg, -SRf, -
S(O)2Rh, -X3Y and Y, and still more preferably selected from NH2, CF3, SCH3, SO2CH3, CN,
C(CH3)2OH and Y. R3b is hydrogen, F, Cl, Br or cyano; and R3a is preferably C1-6 alkyl, C1-6
haloalkyl or C3-6 cycloalkyl. R2a is hydrogen, halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -
CO2Rc, -CONR°Rd, -C(O)Rc, -S(O)Re, -S(O)2Re, -C(NORc)Rd, -C(NRcW)=NW,
-N(W)C(Rc)=NW, -X2C(NORc)Rd, -X2C(NRcW)=NW, -X2N(W)C(R°)=NW, -X2ORc,
-X2OC(O)Rc, -X2NRcRd, -X2SRc, -X2CO2Rc, -X2CONRcRd, -X2C(O)Rc, -X2OC(O)NRcRd, -
X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd, -X2S(O)Re, -X2S(O)2Re, -
X2NRcS(O)2Re, -X2S(O)2NRcRd and -X2N3; R2c is hydrogen, halogen, cyano or nitro; and R2d
is selected from hydrogen, halogen, -ORc, -OC(O)R°, -NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd,
-C(O)Rc, -S(O)Re, -S(O)2Re, -NRcS(O)2Re, -NRdC(O)R°, -X2ORc, -X2OC(O)Rc, -X2NRcRd, -
X2SR°, -X2CO2R°, -X2CONRcRd, -X2C(O)R°, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -
X2NRdC(O)2Re, -X2NR°C(O)NRcRd, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -O-X2-ORc,
-X2S(O)2NRcRd and -X2N3, wherein X2 is C1-4 alkylene, and each Rc and Rd is independently
selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8
alkynyl, and each Re is independently selected from the group consisting of C1-8 alkyl, C1-8
haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each of Rc, Rd and Re is
optionally further substituted as described above for formula IE, or with from one to three
members selected from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8 alkyl), CN,
NO2, NH2, NH(C1-8 alkyl) and N(C1-8 alkyl)2; and no more than one of R2a and R2d is
hydrogen. Preferably, each of R2a and R2d is other than hydrogen. In some preferred
embodiments, R28 is other than hydrogen; R2c is halogen, cyano or nitro; R2d is -SRc,
-O-X2-OR°, -X2-ORc, -Re, -ORc, -NR°Rd, -NRcS(O)2Re or -NRdC(O)Rc; R3c is selected from
the group consisting of NH2, CF3, SCH3, C(CH3)2OH and Y; R3b is hydrogen, F, Cl, Br or
cyano; and R3a is selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl,
optionally substituted as described above.

[0663] Returning to formula III above, a particularly preferred group of compounds are
those in which m is 0 or 1; R1, when present, is C1-2 alkyl, optionally substituted with a
member selected from the group consisting of-OH, -ORm, -N(Rm)2, -S(O)2Rm, -CO2H and
-CO2Rm; R2a is selected from H, -CH3, halogen, -C(O)CH3, -CO2CH3, -CH2OH, -CH2OCH3,
-CH2NH2, -CH(CH3)OH, -CH2NHCH3, -CH2N(CH3)2, -CH2SO2CH3, -CH(CH3)NH2,
-C(=NOH)H, -C(=NOH)CH3, -C(=NOCH3)H and -C(=NOCH3)CH3; R2b is H; R2c is selected
from H, F, Cl and Br, R2d is selected from OCH3, OCH2CH3, NHCH3, CH2OCH3 and CH3;
R2e is H, such that at least one of R2a and R2° is other than H; R3b is hydrogen, F, Cl, Br or
cyano; one of R3a and R3c is cyclopropyl, CH3, CF3 or methyl optionally substituted with
NH2, NHCH3, N(CH3)2, OH, OCH3, SO2CH3 or NHSO2CH3, and the other of R3a and R3c is
selected from the group consisting of CF3, Br, methyl, ethyl, isopropyl, -CO2CH3, -CO2Et,
-SO2CH3, -C(O)CH3, -CH2OH, -CH(CH3)OH, -SCH3, -C(CH3)2OH, -NHCH3, -N(CH3)2,
-NH2, substituted phenyl and substituted or unsubstituted pyridyl, pyrimidinyl, thienyl, furyl,
oxadiazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, morpholinyl,
pyrrolidinyl, piperazinyl and piperidinyl.
[0064] Another particularly preferred group of embodiments of formula. III are those in
which m is 0 or1, preferably 0; R1, when present, is -CO2Ra, -X1-SO2Rn, or C1-6 alkyl,
optionally substituted with a member selected from the group consisting of-OH, -ORm,
-OC(O)NHRm, -OC(O)N(Rra)2, -SH, -SRm, -S(O)Rm, -S(O)2Rm, -SO2NH2, -S(O)2NHRm,
-S(O)2N(Rm)2, -NHS(O)2Rm, -NRmS(O)2Rm, -C(O)NH2, -C(O)NHRm. -C(O)N(Rm)2,
-C(O)Rm, -NHC(O)Rm, -NRmC(O)Rm, -NHC(O)NH2, -NRmC(O)NH2, -NRmC(O)NHRm,
-NHC(O)NHRm, -NRmC(O)N(Rm)2, -NHC(O)N(Rm)2, -CO2H, -CO2Rm, -NHCO2Rm,
-NRmCO2Rm, -CN, -NO2, -NH2, -NHRm, -N(Rm)2, -NRmS(O)NH2 and -MRmS(O)2NHRm,
wherein each Rm is independently an unsubstituted C1-6 alkyl; R2a, R2b and R2e are each
hydrogen; R2c is halogen or cyano; R2d is selected from -SRc, -O-X2-ORc, -X2-ORc, -Re,
-ORc, -NRcRd, -NRcS(O)2Re and -NRdC(O)Rc; R3b is hydrogen, F, Cl, Br or cyano; and R3a
and R3c are each independently selected from halogen, cyano, -NO2, -CO2;Rf, -CONRfRE,
-C(O)Rf, -NRfRE, -SRf, -S(O)Rh, -S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, C1-6 alkyl, C1-6
haloalkyl or C3-6 cycloalkyl, where the alkyl and cycloalkyl substituents can be optionally
substituted with a member selected from the group consisting of-OH, -ORo, -OC(O)NHR°,
-OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2Ro, -SO2NH2, -S(O)2NHRo, -S(O)2N(Ro)2,
-NHS(O)2Ro, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°, -NHC(O)R°,
-NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°,

-NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2R0, -NHCO2R°, -NR°CO2Ro, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHRo. Further preferred within this
group of embodiments are those compounds in which (a) at least one of R3a and R3c is C1-6
alkyl, optionally further substituted with from one to three members selected from the group
consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°,
-SO2NH2, -S(O)2NHRo, -S(O)2N(R°)2, -NHS(O)2R°, -NRoS(O)2Ro, -C(O)NH2, -C(O)NHR°,
-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2,
-NRoC(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2Ro,
-NHCO2Ro, -NRoCORo, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NRoS(O)NH2 and
-NRoS(O)2NHR°; (b) at least one of R3a and R3c is -NRfRg; (c) at least one of R3a and R3c is Y,
wherein when Y is phenyl, the phenyl group is substituted; (d) at least one of R3a and R3c is
Y, wherein Y is an unsubstituted or substituted 5- or 6-membered heteroaryl group or
heterocyclic group such as pyridyl, pyrimidinyl, thienyl, furyl, oxadiazolyl, oxazolyl,
thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl
and the like; or (e) at least one of R3a and R3c is -SO2Rh or -C(O)Rf. Any substituents not
particularly set forth are meant to have their most complete meaning with reference to
formula III. Additionally, all compounds are meant to include their pharmaceutically
acceptable salts, as well as any N-oxides thereof.
[0065] Yet another particularly preferred group of embodiments of formula III are those in
which m is 0 or1; R1, when present, is -CO2Ra, -X1-SO2Ra, or C1-6 alkyl, optionally
substituted with a member selected from the group consisting of-OH, -ORm3 -OC(O)NHRm,
-OC(O)N(Rm)2, -SH, -SRm, -S(O)Rm, -S(O)2Rm, -SO2NH2, -S(O)2NHRm, -S(O)2N(Rm)2,
-NHS(O)2Rm, -NR"S(O)2Rni, -C(O)NH2, -C(O)NHRm, -C(O)N(Rm)2, -C(O)Rm, -NHC(O)Rm,
-NRmC(O)Rm, -NHC(O)NH2, -NRmC(O)NH2, -NRmC(O)NHRm, -NHC(O)NHRm,
-NRmC(O)N(Rm)2, -NHC(O)N(Rm)2, -CO2H, -CO2Rm, -NHCO2Rm, -NRmCO2Rm, -CN, -NO2,
-NH2, -NHRm, -N(Rm)2, -NRmS(O)NH2 and -NRmS(O)2NHRm, wherein each Rm is
independently an unsubstituted C1-6 alkyl; R2a is hydrogen, halogen, -ORc, -OC(O)R°, -
NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -S(O)2Re, -C(NORc)Rd,
-C(NRcW)=NW, -N(W)C(Rc)=NW, -X2C(NOR°)Rd, -X2C(NRcW)=NW,
-X2N(W)C(Rc)=NW, -X2ORc, -X2OC(O)Rc, -X2NRcRd, -X2SRc, -X2CO2Rc, -X2CONRcRd,
-X2C(O)R°, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd, -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd or -X2N3; R2b is hydrogen; R2c is
halogen or cyano; R2d is selected from -SRC, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd,

-NRcS(O)2Re and -NRdC(O)Rc, or optionally is combined with R2e to form a five or six-
membered ring fused to the phenyl ring to which each is attached. R3b is hydrogen, F, Cl, Br
or cyano; and R3a and R3c are each independently selected from halogen, -NRfRg, -SRf,
-CO2Rf, -C(O)Rf, -SO2Rh, -X3Y, -Y and -Rh, wherein Rh is C1-6 alkyl, C1-6 haloalkyl and C3-6
cycloalkyl, wherein the aliphatic portions are optionally further substituted with from one to
three members selected from the group consisting of-OH, -ORo, -OC(O)NHR°,
-OC(O)N(Ro)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHRo, -S(O)2N(R°)2,
-NHS(O)2Ro, -NR°S(O)2Ro, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2; -C(O)Ro, -NHC(O)Ro,
-NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°,
-NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2Ro, -NHCO2R°, -NR°CO2Ro, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHRo. Further preferred within this
group of embodiments are those compounds in which (a) at least one of R3a and R3e is C1-6
alkyl, optionally further substituted with from one to three members selected from the group
consisting of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)Rc, -S(O)2R-°,
-SO2NH2, -S(O)2NHRo, -S(O)2N(Ro)2, -NHS(O)2R°, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°,
-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2. -NR°C(O)NH2,
-NR°C(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2R°,
-NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and
-NR°S(O)2NHR°; (b) at least one of R3a and R3c is -NRfRg; (c) at least one of R3a and R3c is Y, .
wherein when Y is phenyl, the phenyl group is substituted; (d) at least one of R3a and R3c is
Y, wherein Y is an unsubstituted or substituted 5- or 6-membered heteroaryl group or
heterocyclic group such as pyridyl, pyrimidinyl, thienyl, furyl, oxadiazolyl, oxazolyl,
thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl
and the like; or (e) at least one of R3a and R3c is -SO2Rh or -C(O)Rf.
[0066] In still another group of embodiments of formula III, two adjacent members of R3a,
R3b and R3c are joined together to form a five or six-membered ring fused to the pyrazole
moiety to which each is attached. The remaining member of (R3a or R3c) is selected from
-NRfRg, -SRf, -CO2Rf, -C(O)Rf, -SO2Rh, -X3Y, -Y and -Rh, wherein Rh is C1-6 alkyl, C1-6
haloalkyl and C3-6 cycloalkyl, wherein the aliphatic portions are optionally further substituted
with from one to three members selected from the group consisting of-OH, -ORo,
-OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°,
-S(O)2N(R°)2, -NHS(O)2Ro, -NR°S(O)2R°, -C(O)NH2, -C(O)NHRo, -C(O)N(R°)2, -C(O)Ro,
-NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHRo,

-NR°C(O)N(Ro)2, -NHC(O)N(R°)2, -CO2H, -CO2R°, -NHCO2Ro, -NR°CO2R°, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHR°.
[0067] Another particularly preferred group of embodiments of formula III are those in
which m is 0 or 1, preferably 0; R1, when present, is -CO2Ra, -X1-SO2Ra, or C1-6 alkyl,
optionally substituted with a member selected from the group consisting of-OH, -ORm,
-OC(O)NHRm, -OC(O)N(Rm)2, -SH, -SRm, -S(O)Rm, -S(O)2Rm, -SO2NH2, -S(O)2NHRm,
-S(O)2N(Rm)2, -NHS(O)2Rm, -NRm,S(O)2Rm, -C(O)NH2, -C(O)NHRm, -C(O)N(Rm)2,
-C(O)Rm, -NHC(O)Rm, -NRmC(O)Rm, -NHC(O)NH2j -NRmC(O)NH2, -NRmC(O)NHRm,
-NHC(O)NHRm, -NRmC(O)N(Rm)2, -NHC(O)N(Rm)2, -CO2H, -CO2Rm, -NHCO2Rm,
-NRmCO2Rm, -CN, -NO2, -NH2, -NHRm, -N(Rm)2, -NRmS(O)NH2 and -NRmS(O)2NHRm,
wherein each Rm is independently an unsubstituted C1-6 alkyl; R2b is selected from hydrogen,
halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -
S(O)2Re, -NRcS(O)2Re, -NRdC(O)R°, -X2OR°, -X2OC(O)Rc, -X2NRcRd, -X2SRc, -X2CO2Rc,
-X2CONRcRd, -X2C(O)R°, -X20C(O)NR°Rd, -X2NRdC(O)Rc, -X2NRdC(O)2Re,
-X2NRcC(O)NRcRd, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -O-X2-OR°, -X2S(O)2NRcRd
and -X2N3, wherein X2 is C1-4 alkylene, and each Rc and Rd is independently selected from
hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each Re
is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6
cycloalkyl, C2-8 alkenyl and C2-8 alkynyl, and each of Rc, Rd and Rc is optionally further
substituted as described above for formula III, or with from one to three members selected
from the group consisting of OH, O(C1-8 alkyl), SH, S(C1-8 alkyl), CN, NO2, NH2, NH(C1-8
alkyl) and N(C1-8 alkyl)2. More preferably R2b is hydrogen and R2c is hydrogen; R2a is
hydrogen, halogen, -CN, -C(O)Rc, -C(NORc)Rd, -C(NRcW)=NW, -N(W)C(Rc)=NW,
-X2C(NORc)Rd, -X2C(NRcW)=NW, -X2N(W)C(Rc)=NW, -X2NRcRd, or -Re; R2d is selected
from -SRC, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, -NRcS(O)2Re and -NRdC(O)Rc; R3b is
hydrogen, F, Cl, Br or cyano; and R3a and R3c are each independently selected from halogen,
cyano, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRfRg, -SRf, -S(O)Rh, -S(O)2Rh, -C(O)Y,
-SO2Y, -X3Y, Y, C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl, where the alkyl and cycloalkyl
substituents can be optionally substituted with a member selected from the group consisting
of-OH, -ORo, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2,
-S(O)2NHRo, -S(O)2N(R°)2, -NHS(O)2R°, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°,
-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2,
-NR°C(O)NHRo, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2R°,

-NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and
-NR°S(O)2NHR°. Further preferred within this group of embodiments are those compounds
in which (a) at least one of R3a and R3c is C1-6 alkyl, optionally further substituted with from
one to three members selected from the group consisting of-OH, -OR°, -OC(O)NHR°,
-OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°, -S(O)2N(R°)2,
-NHS(O)2R°, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°, -NHC(O)R°,
-NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°,
-NR°C(O)N(R°)2, -NHC(O)N(R°)2, -COzH, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHR°; (b) at least one of R3a and R3c is
-NRfR8; (c) at least one of R3a and R3° is Y, wherein when Y is phenyl, the phenyl group is
substituted; (d) at least one of R3a and R3c is Y, wherein Y is an unsubstituted or substituted
5- or 6-membered heteroaryl group or heterocyclic group such as pyridyl, pyrimidinyl,
thienyl, furyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,
morpholinyl, pyrrolidinyl, piperidinyl and the like; or (e) at least one ofR3a and R3c is-SO2Rh
or-C(O)Rf.
[0068] Still other preferred groups of formula III above, are formulae IIIe through IIIvvv,
wherein the substituents are as defined for formula III, with preferred embodiments provided
below. Formulae IIIe through IIIvvv are provided in Figure 5A through 5J. Turning first to
the compounds of formula IIIe, IIIg, IIIi, IIIk, IIIm, IIIo, IIIq, IIIs, IIIu, IIIw, IIIy, IIIaa, IIIcc,
IIIee, IIIgg, IIIii, IIIkk, IIImm, IIIoo, IIIqq, IIIss, IIIuu, IIIww, IIIyy, IIIaaa, IIIccc, IIIeee,
IIIggg, IIIiii, IIIkkk, IIImmm, IIIooo, IIIqqq, IIIsss, and IIIuuu, R2a is preferably hydrogen,
halogen, cyano, -NO2, -CO2Ro, -CONRcRd, -C(O)Rc, -S(O)Re, -S(O)2Re, -Rc, -C(NORc)Rd,
-C(NRcW)=NW, -N(W)C(R°)=NW, -X2C(NORc)Rd, -X2C(NRCW)=NW,
-X2N(W)C(Rc)=NW, -X2NRcRd, -X2SR°, -X2CN, -X2NO2, -X2CO2Ro, -X2CONR°Rd,
-X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NReC(O)NRoRd,
-X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X2NH-C(NHRe)=NH, -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd, or -X2N3; R2c is halogen, cyano or
nitro; R2d is -SRc, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, or -NRcSO2Rd; R3b is preferably
hydrogen, halogen, cyano, -NO2, -CO2Rf, -CONRfRe, -C(O)Rf, -S(O)Rh, -S(O)2Rh, -Rh, -
X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -
X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRfC(O)NRfRg, -X3NH-C(NH2)=NH,
-X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -
X3NRf(O)2Rh, -X3S(O)2NRfRg, -X3N3, Y, or -X3Y; R3c is preferably halogen, cyano, -NO2, -

CO2Rf, -CONRfRg, -C(O)Rf, NRfRg, SRf, -S(O)Rh, -S(0>2Rh, -C(O)Y, -SO2Y, -X3Y, Y, C1-6
alkyl, C1-6 haloalkyl or C3-6 cycloalkyl, where the alkyl and cycloalkyl substituents can be
optionally substituted with a member selected from the group consisting of-OH, -ORo,
-OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2, -S(O)2NHR°,
-S(O)2N(R°)2, -NHS(O)2Ro, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R°,
-NHC(O)Ro, -NRcC(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°,
-NRoC(O)N(R°)2, -NHC(O)N(R°)2, -CO2H, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHRo; R4 is preferably halogen, -ORf, -
NRfRg, -Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh,
-NRfS(O)2Rh, -S(O)2NRfRg, -C(NORf)Rg, -C(NRV)=NWa, -N(Wa)C(Rf)=NWa, -X3ORf, -
X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg; R5 is attached to a ring nitrogen and is
preferably hydrogen, -Rh, -S(O)2Rh, -X3ORf, -XJNRfRg, -X3NRfS(O)2Rh and-X3S(O)2NRfRg;
m is preferably 0-2; n is preferably 0-3. Further preferred are those compounds in which
each R1, when present, is selected from the group consisting of C1-4 alkyl, optionally
substituted with a member selected from the group consisting of-OH, -ORm, -S(O)2Rm,
-CO2H and -CO2Rm; when n is 1 or more, at least one R4 substituent is attached to a ring
carbon atom adjacent to a ring heteroatom. Even more preferably, R2a is hydrogen, halogen,
-CN, -C(O)Rc, -C(NORc)Rd, -C(NRCW)=NW, -N(W)C(Rc)=NW, -X2C(NORc)Rd,
-X2C(NRcW)=NW, -X2N(W)C(Rc)=NW, -X2NRcRd, or -Re; R2c is halogen or cyano; R5 is
hydrogen, C1-4************* alkyl, or C3-6 cycloalkyl. Still more preferably, m is 0 or 1, n is 0 or 1, and R1
when present is -CH3. In the most preferred embodiments, R2d is -SRC, -Re, or -OR0; R3b is
hydrogen, halogen, cyano, or -NO2; R3c is Q.6 alkyl, Ci^ haloalkyl or C3-6 cycloalkyl which
are optionally substituted as set forth above; and R4 when present is -CH3, -CF3 or -CN.
[0069] For compounds of formula Illf, Illh, nij, ffll, Hln, IIlp, Illr, lilt, IIIv, IIIx, IIIz, Dlbb,
mdd, Illff, Illhh, IIIjj, Hill, Illnn, IIIpp, Illrr, IHtt, IIIw, IIIxx, IIIzz, Illbbb, Illddd, Illfff,
IUhhh, IIIjjj, III111, Illnnn, IIIppp, nirrr, Illttt, and IIIwv, R2a is preferably hydrogen,
halogen, cyano, -NO2, -COzR0, -CONRcRd, -C(O)Rc, -S(O)Re, -S(0>2Re, -RC, -C(NORc)Rd,
-C(NRCW)=NW, -N(W)C(RC)=NW, -X2C(NORc)Rd, -X2C(NRCW)=NW,
-X2N(W)C(R°)=NW, -X2NRcRd, -X2SRC, -X2CN, -X2NO2, -X2CO2Rc, -X2CONRcRd,
-X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)R°, -X2NRdC(O)2Re, -X2NR°C(O)NRcRd,
-X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X2NH-C(NHRe)=NH, -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NR°Rd, or -X2N3; R2° is halogen, cyano or
nitro; R2d is -SRC, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, or -NRcSO2Rd; R3a is preferably

halogen, cyano, -NCb, -CO2Rf, -CONRfRg, -C(O)Rf, NRfRg, SRf, -S(O)Rh, -S(0>2Rh, -C(O)Y,
-SO2Y, -X3Y, Y, Cj-6 alkyl, Ci.6 haloalkyl or C3.6 cycloalkyl, where the alkyl and cycloalkyl
substituents can be optionally substituted with a member selected from the group consisting
of-OH, -OR0, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2,
-S(O)2NHR°, -S(O)2N(R°)2, -NHS^R0, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR0,
-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2,
-NR°C(O)NHR0, -NHC(O)NHR°, -NR0C(O)N(R°)2) -NHC(O)N(R°)2) -COjH, -CO2R°,
-NHCO2R°, -NR°CO2R0, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and
-NR°S(O)2NHR0; R3b is preferably hydrogen, halogen, cyano, -NO2, -CO2Rf, -CONRfRg,
-C(O)Rf, -S(O)Rh, -S(O)2Rh, -Rh, -X3NRfRs, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf,
-X3CONRfRg, -X3C(O)Rr, -X3OC(O)NRfRg, -X3NRgC(O)Rf. -X3NRgC(O)2Rh,
-X3NRfC(O)NRfRg, -X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh,
-X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfRB, -X3N3, Y,
or -X3Y; R4 is preferably halogen, -ORf, -NRfR6, -Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfRg,
-C(O)Rf, -NR8C(O)Rf, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh5 -S(O)2NRfRg, -C(NORf)R8,
-C(NRfWa)=NWa, -N(Wa)C(Rf)=NWa, -X3ORf, -X3NRfRs, -X3NRfS(O)2Rh and
-X3S(O)2NRfRg; R5 is attached to a ring nitrogen and is preferably hydrogen, -Rh, -S(O)2Rh,
-X3ORf, -X3NRfRB, -X3NRfS(O)2Rh and -X3S(O)2NRfRg; m is preferably 0-2; n is preferably
0-3. Further preferred are those compounds in which each R1, when present, is selected from
the group consisting of CM alkyl, optionally substituted with a member selected from the
group consisting of-OH, -ORm, -S(O)2Rm, -CO2H and -CO2Rm; when n is I or more, at least
one R4 substituent is attached to a ring carbon atom adjacent to a ring heteroatom. Even more
preferably, R2a is hydrogen, halogen, -CN, -C(O)Rc, -C(NORc)Rd, -C(NR*W)=NW,
-N(W)C(R°)=NW, -X2C(NOR°)Rd, -X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, or
-Re; R2c is halogen or cyano; R5 is hydrogen, CM alkyl, or C3-6 cycloalkyl. Still more
preferably, m is 0 or 1, n is 0 or 1, and R1 when present is -CH3. In the most preferred
embodiments, RM is -SRC, -Rc, or -OR0; R3a is halogen, cyano, Ci^ alkyl, Ci-g haloalkyl, C3^
cycloalkyl, -C(O)Rf or -SO2Rh wherein the aliphatic portions are optionally substituted as set
forth above; R3b is hydrogen, halogen, cyano, or -NO2; R4 when present is -CH3, -CF3, -CN,
-C(O)Rfor-SO2Rh.
N-linked heteroaryls

[0070] In other preferred groups of formula III, the compounds have a formula selected from
formulae IIIwww through Illdddd, Figure 5K, wherein the substituents have the meanings
provided with respect to formula III above. Turning first to the compounds of formula
IIIwww, Illyyy, Illaaaa and IIIcccc, R2a is preferably hydrogen, halogen, cyano, -NO2,
-CO2Rc, -CONReRd, -C(O)Rc, -S(O)Re, -S(O)2Re, -Rc, -C(NORc)Rd, -C(NR°W)=NW,
-N(W)C(R°)=NW, -X2C(NORc)Rd, -X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd,
-X2SR°, -X2CN, -X2NO2, -X2CO2Rc, -X2CONRcRd, -X2C(O)Rc, -X2OC(O)NRcRd,
-X2NRdC(O)R0, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd, -X2NH-C(NH2)=NH,
-X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X^H-CfNHR^NH, -X2S(O)Re, -X2S(O)2Rc,
-X2NR°S(O)2Re, -X2S(O)2NReRd, or -X2N3; R2c is halogen, cyano or nitro; RM is -SRc,
-O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, or -NRcSO2Rd; R3b is preferably hydrogen, halogen,
cyano, -NO2> -CO2Rf, -CONRfR8, -C(O)Rf, -S(O)Rh, -S(O)2Rh, -Rh, -X3NRfRg, -X3SRf, -
X3CN, -X3NO2, -X3CO2Rf, -X3CONRfR8, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf, -
X3NR8C(O)2Rh, -X3NRfC(O)NRfR8, -X3NH-C(NH2)=NH, -XWCCNH^NH, -X3NH-
C(NH2)=NRh, -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh,
-X3S(O)2NRfR8, -X3N3, Y, or -X3Y; R3c is preferably halogen, cyano, -NOz, -CO2Rf,
-CONRfRg, -C(O)Rf, -NRfRg, -SRf, -S(O)Rh, -S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, CW alkyl,
C1.6 haloalkyl or C3.6 cycloalkyl, where the alkyl and cycloalkyl substituents can be
optionally substituted with a member selected from the group consisting of-OH, -OR0,
-OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2) -S(O)2NHR°,
-S(O)2N(R°)2, -NHS(O)2R°, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2) -C(O)R°,
-NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2) -NR°C(O)NHR°, -NHC(O)NHR°,
-NR0C(O)N(R°)2, -NHC(O)N(R°)2) -CO2H, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2,
-NH2; -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR0S(O)2NHR°; R4 is preferably halogen, -ORf, -
NRfRg, -Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh,
-NRfS(O)2Rh, -S(O)2NRfR6, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg, and
two adjacent R4 groups can form a five or six-membered saturated or unsaturated ring having
from 0 to 2 additional heteroatoms as ring members; m is preferably 0-2; n is preferably 0-3.
Further preferred are those compounds in which each R1, when present, is selected from the
group consisting of CM alkyl, optionally substituted with a member selected from the group
consisting of-OH, -ORm, -S(O)2Rm, -CC^H and -CC^R"1; when n is 1 or more, at least one R4
substituent is attached to a ring carbon atom adjacent to a ring heteroatom. Even more
preferably, R2" is hydrogen, halogen, -CN, -C(O)Rc, -C(NORc)Rd, -C(NRCW)=NW,
-N(W)C(RC)=NW, -X2C(NORc)Rd, -X2C(NRCW)=NW, -X2N(W)C(R°)=NW, ^NR'R", or

-R^; R2c is halogen or cyano. Still more preferably, m is 0 or 1, n is 0 or 1, and R1 when
present is -CH3. In the most preferred embodiments, R2d is -SRC, -Re, or -OR0; R3b is
hydrogen, halogen, cyano, or -NO2; R3c is halogen, cyano, -C(O)Rf, -SO2Rh, CW alkyl, Ci.6
haloalkyl or C3.6 cycloalkyl wherein the aliphatic portions are substituted as set forth above;
and R4 when present is -CH3, -CF3 or-CN.
[0071] For compounds of formula IIIxxx, IIIzzz, Illbbbb, Illdddd, R2a is preferably hydrogen,
halogen, cyano, -NO2, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -S(O)2Re, -RC, -C(NORc)Rd,
-C(NRCW)=NW, -N(W)C(R>NW, -X2C(NORc)Rd, -X2C(NRCW)=NW,
-X2N(W)C(RC)=NW, -X2NRcRd, -X2SRC, -X2CN, -X2NO2, -X2CO2Rc, -X2CONRcRd,
-X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd,
-X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X2NH-C(NHRe)=NH, -
X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd, or -X2N3; R2c is halogen, cyano or
nitro; Ru is -SRC, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NR°Rd, or -NRcSO2Rd; R3a is preferably
halogen, cyano, -NO2, -CO2Rf, -CONRfR8, -C(O)Rf, -NRfRg, -SRf, -S(O)Rh, -S(0;hR-C(O)Y, -SO2Y, -X3Y, Y, C1.6 alkyl, d-6 haloalkyl or C3^ cycloalkyl, where the alkyl and
cycloalkyl substituents can be optionally substituted with a member selected from the group
consisting of-OH, -OR0, -OC(O)NHR°, -0C(O)N(R0)2, -SH, -SR°, -S(O)R°, -S(O)2R°,
-SO2NH2, -S(O)2NHR0, -S(O)2N(R°)2, -NHSCO^R0, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°,
-C(O)N(R°)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2,
-NR°C(O)NHR°, -NHC(O)NHR°, -NR°C(O)N(R°)2, -NHC(O)N(R°)2, -COjii, -COzR0,
-NHCO2R0, -NR°CO2R0, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and
-NR°S(O)2NHR°; R3b is preferably hydrogen, halogen, cyano, -NO2, -CO2Rf; -CONRfRg,
-C(O)Rf, -S(O)Rh, -S(O)2Rh, -Rh, -X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf,
-X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf, -X3NRgC(O)2Rh,
-X3NRfC(O)NRfRg, -X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRhJ
-X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfRg, -X3N3, Y,
or -X3Y; R4 is preferably halogen, -ORf, -NRfRg, -Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfRg,
-C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -X3ORf, -X3NRfRE, -
X3NRfS(O)2Rh and -X3S(O)2NRfRg, and two adjacent R4 groups can form a five or six-
membered saturated or unsaturated ring having from 0 to 2 additional heteroatoms as ring
members; m is preferably 0-2; n is preferably 0-3. Further preferred are those compounds in
which each R1, when present, is selected from the group consisting of CM alkyl, optionally
substituted with a member selected from the group consisting of-OH, -ORm, -S(O)2Rm,
-CO2H and -CO2Rm; when n is 1 or more, at least one R4 substituent is attached to a ring

carbon atom adjacent to a ring heteroatom. Even more preferably, R2a is hydrogen, halogen,
-CN, -C(O)R0, -C(NOR°)Rd, -C(NRcW)=>fW, -N(W)C(RC)=NW, -X2C(NORc)Rd,
-X2C(NRCW)=NW, -X2N(W)C(R°)=NW, -X2NRcRd, or -Re; R2c is halogen or cyano. Still
more preferably, m is 0 or 1, n is 0 or 1, and R1 when present is -CH3. In the most preferred
embodiments, R2d is -SRC, -Rc, or -ORc; R3a is halogen, cyano, -C(O)Rf, -S(O)2Rh, Cu6 alkyl,
C]_6 haloalkyl or C3.6 cycloalkyl, where the alkyl and cycloalkyl substituents can be
optionally substituted as noted above; R3b is hydrogen, halogen, cyano or -NO2; R4 when
present is -CH3, -CF3 or -CN.
5-membered C- and N-Iinked Heterocycles:
[0072] In other preferred groups of formula III, the compounds have a formula selected from
formulae Illeeee and Illffff, Figure 5L, wherein the substituents have the meanings provided
with respect to formula III above. Turning first to the compounds of formula Illeeee, R2a is
preferably hydrogen, halogen, cyano, -NO2, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -
S(O)2Re, -Rc,(-C(NORc)Rd, -C(NRcW)=NW, -N(W)C(RC)=NW, -X2C(NORc)Rd,
-X2C(NR°W>=NW, -X2N(W)C(R°)=NW, -X2NRcRd, -X2SRC, -X2CN, -X2NO2, -X2CO2Rc,
-X2CONRcRd, -X2C(O)Rc, -X2OC(O)NR0Rd, -X2NRdC(O)R0, -X2NRdC(O)2Re,
-X2NR°C(O)NRcRd, -X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe,
-X2NH-C(NHRe)=NH, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd, or -X2N3;
R2c is halogen, cyano or nitro; RM is -SR°, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, or
-NRcSO2Rd; R3b is preferably hydrogen, halogen, cyano, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf,
-S(O)Rh, -S(O)2Rh, -Rh, O^NR^, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg,
-X3C(O)Rr, -X30C(O)NRfRB,-X3NR8C(O)Rf, -X3NR6C(O)2Rh, -X3NRfC(O)NRfRB,
-X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -
X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfR6, -X3N3, Y, or -X3Y; R3c is
preferably halogen, cyano, -NO2, -CO2Rf, -CONRfR8, -C(O)Rf, -NRfR6, -SRf, -S(O)Rh, -
S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, Cw alkyl, C w haloalkyl or C3^ cycloalkyl, where the
alkyl and cycloalkyl substituents can be optionally substituted with a member selected from
the group consisting of-OH, -OR0, -OC(O)NHR0, -OC(O)N(R0)2, -SH, -SR°, -S(O)R°,
-S(O)2R°, -SO2NH2, -S(O)2NHR0, -S(O)2N(R0)2, -NHS(O)2R0, -NR°S(O)2R°, -C(O)NH2,
-C(O)NHR°, -C(O)N(R°)2) -C(O)R°, -NHC(O)R°, -NRDC(O)R°, -NHC(O)NH2,
-NR0C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR°, -NR0C(O)N(R°)2, -NHC(O)N(R°)2,
-CO2H, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2

and -NR°S(O)2NHR0; R4 is preferably halogen, -ORf, -NRfRg, -Rh, -SRf, -CN, -NO2j -CO2Rf,
-CONRfRg, -C(O)Rf, -NR8C(O)Rf, -S(O)Rh, -S(O)2Rh, -NRfS(0>2Rh, -S(O)2NRfRg, -X3ORf, -
X3NRfRg, -X3NRfS(O)2Rh, -X3S(O)2NRfR8, and two adjacent R4 groups can form a five or
six-membered saturated or unsaturated ring having from 0 to 2 additional heteroatoms as ring
members; m is preferably 0-2; n is preferably 0-3; a, b, and c can be N, NR5, S, SO, SO2,0,
or C(R4)0, where o can be 0-2; R5 is preferably hydrogen, -Rh, -S(O)2Rh, -X3ORf, -X3NRfR8, -
X3NRfS(O)2Rh and -X3S(O)2NRfRg, -CO2Rf, -CONRfRg, or -C(O)Rf. Further preferred are
those compounds in which each R1, when present, is selected from the group consisting of C\.
4 alkyl, optionally substituted with a member selected from the group consisting of-OH,
-ORm, -S(O)2Rm, -CC^H and -CO2Rm; when a and c are other than C(R4)0, b must be C(R4)0
or SO2; when a and b are other than C(R4)0, then c must be C(R4)0 or SO2. Even more
preferably, R2a is hydrogen, halogen, -CN, -C(O)Rc, -C(NORc)Rd, -C(NRCW)=NW,
-N(W)C(RC)=NW, -X2C(NORc)Rd, -X2C(NReW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, or
-Re; R2c is halogen or cyano. Still more preferably, m is 0 or 1, n is 0 or 1, and Rl when
present is -CH3. In the most preferred embodiments, R2d is -SR°, -Re, or -ORc; R3b is
hydrogen, halogen, cyano or -NO2; R3c is halogen, cyano, -C(O)Rf, -SO2Rh, C^ alkyl, Ci-6
haloalkyl or C3.6 cycloalkyl wherein the aliphatic portions are substituted as set forth above.
[0073] For compounds of Formula Illffff, R2a is preferably hydrogen, halogen, cyano, -NO2,
-CO2Rc, -CONR°Rd, -C(O)Rc, -S(O)Re, -S(O)2Re, -RC, -C(NORc)Rd, -C(NRcW)-NW,
-N(W)C(R>NW, -X2C(NORc)Rd, -X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd,
-X2SR°, -X2CN, -X2NO2, -X2CO2Rc, -X2CONRcRd, -X2C(O)R°, -X2OC(O)NRcRd,
-X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NR°Rd, -X2NH-C(NH2)=NH,
-X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X^H-CCNHR^NH, -X2S(O)Re, -X2S(O)2Re,
-X2NRcS(O)2Re, -X2S(O)2NRcRd, or -X2N3; R20 is halogen, cyano or nitro; RM is -SRc,
-O-X2-OR°, -X2-ORc, -Re, -ORc, -NRcRd, or -NRcSO2Rd; R3a is preferably halogen, cyano,
-NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -NRfRB, -SRf, -S(O)Rh, -S(O)2Rh, -C(O)Y, -SO2Y, -X3Y,
Y, Ci^s alkyl, Cu6 haloalkyl or C3.6 cycloalkyl, where the alkyl and cycloalkyl substituents
can be optionally substituted with a member selected from the group consisting of-OH,
-OR0, -OC(O)NHR0, -OC^NCR0^, -SH, -SR°, -S(O)R°, -S(O)2R°, -SO2NH2> -S(O)2NHR°,
-S(O)2N(R°)2( -NHS(O)2R°, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -C(O)N(R°)2, -C(O)R0,
-NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2, -NR°C(O)NH2, -NR0C(O)NHR°, -NHC(O)NHR0,
-NR°C(O)N(R0)2, -NHC(O)N(R°)2, -COzH, -CO2R°, -NHCO2R°, -NR°CO2R0, -CN, -NOz,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR°S(O)2NHR0; R3b is preferably hydrogen,
halogen, cyano, -NO2, -CO2Rf, -CONRfRe, -C(O)Rf, -S(O)Rh, -S(O)2Rh, -Rh, -X3NRfRg, -

X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfR8, -X3C(O)Rf, -X3OC(O)NRfRg, -
X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRfC(O)NRfRg, -X3NH-C(NH2)=NH,
-X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -
X'NR^O^, -X3S(O)2NRfRg, -X3N3, Y, or -X3Y; R4 is preferably halogen, -ORf, -NRfRg,
-R\ -SRf, -CN, -NO2, -CO2Rf, -CONRfR£, -C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh, -
NRfS(O)2R\ -S(O)2NRfRg, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg, and two
adjacent R4 groups can form a five or six-membered saturated or unsaturated ring having
from 0 to 2 additional heteroatoms as ring members; m is preferably 0-2; n is preferably 0-3;
a, b, and c can be N, NR5, S, SO, SO2, O, or C(R4)0, where o can be 0-2; R5 is preferably
hydrogen, -Rh, -S(O)2Rh, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh, -X3S(O)2NRfRg, -CO2Rf,
-CONRfRg, or -C(O)Rf. Further preferred are those compounds in which each R1, when
present, is selected from the group consisting of CM alkyl, optionally substituted with a
member selected from the group consisting of-OH, -ORm, -S(O)2Rm, -CO2H and -CO2Rm;
when a and c are other than C(R4)0, b must be C(R4)0 or SO2; when a and b are other than
C(R )0, then c must be C(R4)0 or SO2. Even more preferably, R2a is hydrogen, halogen, -CN,
-C(O)Rc, -C(NORc)Rd, -C(NRcW)=NW, -N(W)C(Rc)=NW, -X2C(NORc)Rd,
-X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, or -Re; R20 is halogen or cyano. Still
more preferably, m is 0 or 1, n is 0 or 1, and R1 when present is -CH3. In the most preferred
embodiments, R2d is -SRC, -Re, or -0RC; R3a is halogen, cyano, -C(O)Rf, -S(O)2Rh, Ci.6 alkyl,
C1-6 haloalkyl or C3-6 cycloalkyl, where the alkyl and cycloalkyl substituents can be
optionally substituted as noted above; and R3b is hydrogen, halogen, cyano or -NO2.
6-membered C- and NT-linked Heterocycles:
[0074] In other preferred groups of formula III, the compounds have a formula selected from
formulae Illgggg and Illhhhh, Figure 5L, wherein the substituents have the meanings
provided with respect to formula III above. Turning first to the compounds of formula
Illgggg, R2a is preferably hydrogen, halogen, cyano, -NO2, -CO2Rc, -CONRcRd, -C(O)Rc, -
S(O)Re, -S(O)2Re, -RC, -C(NOR°)Rd, -C(NRcW)=NW, -N(W)C(R°)=NW, -X2C(NORc)Rd,
-X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, -X2SR°, -X2CN, -X2NO2, -X2CO2Rc,
-X2CONR°Rd, -X2C(O)RC, -X2OC(O)NR°Rd, -X2NRdC(O)Rc, -X2NRdC(O)2Re,
-X2NRGC(O)NRcRd, -X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe,
-X^H-CCNHR^NH, -X2S(O)Re, -X2S(O)2Re, -X2NRcS(O)2Re, -X2S(O)2NRcRd, or-X2N3;
R2c is halogen, cyano or nitro; R2d is -SRC, -O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, or
-NRcSO2Rd; R3b is preferably hydrogen, halogen, cyano, -NO2, -CO2Rf, -CONRfR8, -C(O)Rf,

-S(O)Rh, -S(O)2Rh, -Rh, -X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRE,
-X3C(O)Rf, -X3OC(O)NRfRE, -X3NReC(O)Rf, -X3NRgC(O)2R\ -X3NRfC(O)NRfR6,
-X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -
X3S(O)Rh, -X3S(O)2R\ -X3NRfS(O)2Rh, -X3S(O)2NRfRg, -X3^, Y, or -X3Y; R3c is
preferably halogen, cyano, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, NRfRg, SRf, -S(O)Rh, -
S(O)2Rh, -C(O)Y, -SO2Y, -X3Y, Y, CM alkyl, Cw haloalkyl or C3-6 cycloalkyl, where the
alkyl and cycloalkyl substituents can be optionally substituted with a member selected from
the group consisting of-OH, -OR°, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°,
-S(O)2R°3 -SO2NH2) -S(O)2NHR°, -S(O)2N(R0)2j -NHS(O)2R°, -NR0S(O)2R°, -C(O)NH2,
-C(O)NHR°, -C(O)N(R0)2, -C(O)R°, -NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2,
-NR0C(O)NH2) -NR°C(O)NHR°, -NHC(O)NHR°, -NR0C(O)N(R°)2, -NHC(O)N(R°)2,
-CO2H, -CO2R°, -NHCO2R0, -NR°CO2R°, -CN, -NO2, -NH2, -NHR°, -N(R°)2, -NR°S(O)NH2
and -NR°S(O)2NHR0; R4 is preferably halogen, O, -ORf, -NRfRg, -Rh, -SRf, -CN, -NCh, -
CO2Rf, -CONRfRs, -C(O)Rf, -NR8C(O)Rf, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg,
-X3ORf, -X3NRfRg, -X3NRfS(O)2Rh, -X3S(O)2NRfRg, and two adjacent R4 groups can form a
five or six-membered saturated or unsaturated ring having from 0 to 2 additional heteroatoms
as ring members; m is preferably 0-2; n is preferably 0-3; a, b, c, and d can be N, NR5, S, SO,
SO2) O, or C(R4)0, where 0 can be 0-2; R5 is preferably hydrogen, -Rh, -S(O)2Rh, -X3ORf, -
X3NRfRg, -XWSCO^R11 and -X3S(O)2NRfRg, -CO^, -CONRFRg, or -C(O)Rf. Further
preferred are those compounds in which each R1, when present, is selected from the group
consisting of CM alkyl, optionally substituted with a member selected from the group
consisting of-OH, -ORm, -SCO^R"1, -CO2H and -CO2Rm; when b and d are other than C(R4)0)
c must be C(R4)0 or SO2; when b and c are other than C(R4)0, then d must be C(R4)0 or SO2;
when a and d are other than C(R4)0, then at least one of a and b must be C(R4)0 or SO2. Even
more preferably, R2a is hydrogen, halogen, -CN, -C(O)Rc, -C(NORc)Rd, -C(NRCW)=NW,
-N(W)C(R>NW, -X2C(NORc)Rd, -X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, or
-Re; R2c is halogen or cyano. Still more preferably, m is 0 or 1, n is 0 or 1, and R1 when
present is -CH3. In the most preferred embodiments, RM is -SRC, -Re, or -ORc; R3b is
hydrogen, halogen, cyano, or -NO2; R3c is halogen, cyano, -C(O)Rf, -SC^R11, C].6 alkyl, Ci.6
haloalkyl or C3.6 cycloalkyl wherein the aliphatic portions are substituted as set forth above.
[0075] For compounds of Formula Illhhhh, R2a is preferably hydrogen, halogen, cyano, -
NO2, -CO2Rc, -CONRcRd, -C(O)Rc, -S(O)Re, -S(O)2Re, -Rc, -C(NORc)Rd, -C(NRCW)=NW,
-N(W)C(RC)=NW, -X2C(NORc)Rd, -X2C(NRCW)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, -

X2SRC, -X2CN, -X2NO2, -X2CO2Rc, -X2CONR°Rd, -X2C(O)Rc, -X2OC(O)NRcRd, -
X2NRdC(O)Rc, -X2NRdC(O)2Re, -X2NRcC(O)NRcRd, -X2NH-C(NH2)=NH,
-X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe, -X^H-CCNHR^NH, -X2S(O)Re, -X2S(O)2Re, -
X2NRcS(O)2Re, -X2S(O)2NRcRd, or -X2N3; R2c is halogen, cyano or nitro; R2d is -SRC,
-O-X2-ORc, -X2-ORc, -Re, -ORc, -NRcRd, or -NRcSO2Rd; R3a is preferably halogen, cyano,
-NO2, -CChR1, -CONRfRg, -C(O)Rf, NRfRg, SRr, -S(O)Rh, -S(O)2R\ -C(O)Y, -SO2Y, -X3Y,
Y, C1.6 alkyl, C1-6 haloalkyl or C3.6 cycloalkyl, where the alkyl and cycloalkyl substituents
can be optionally substituted with a member selected from the group consisting of-OH,
-OR0, -OC(O)NHR°, -OC(O)N(R°)2, -SH, -SR°, -S(O)R°, -SCO^R0, -SO2NH2, -S(O)2NHRc,
-SCO^NCR0^, -NHS(O)2R0, -NR°S(O)2R°, -C(O)NH2, -C(O)NHR°, -0(O)^°^, -C(O)R°,
-NHC(O)R°, -NR°C(O)R°, -NHC(O)NH2) -NR°C(O)NH2, -NR°C(O)NHR°, -NHC(O)NHR0,
-NR°C(O)N(R0)2) -NHC(O)N(R0)2, -C^H, -CO2R°, -NHCO2R°, -NR°CO2R°, -CN, -NO2,
-NH2, -NHR°, -N(R°)2, -NR°S(O)NH2 and -NR^O^NHR0; R3b is preferably hydrogen,
halogen, cyano, -NO2, -CO2Rf, -CONRfR8, -C(O)Rf, -S(O)Rh, -S(O)2Rh, -Rh, -X3NRfRg, -
X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -
X3NRBC(O)Rf, -X3NR8C(O)2Rh, -X3NRfC(O)NRfRg, -X3NH-C(NH2)=NH,
-X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh, -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -
X3NRfS(O)2Rh, -X3S(O)2NRfRg, -X3^, Y, or -X3Y; R4 is preferably halogen, -ORf, -NRfRE,
-Rh, -SRf, -CN, -NO2, -CO2Rf, -CONRfR8, -C(O)Rf, -NRgC(O)Rf, -S(O)Rh, -S(O)2Rh, -
NRfS(O)2Rh, -S(O)2NRfRg, -X30Rf, -X3NRfRg, -X3NRfS(O)2Rh and -X3S(O)2NRfRg, and two
adjacent R4 groups can form a five or six-membered saturated or unsaturated ring having
from 0 to 2 additional heteroatoms as ring members; m is preferably 0-2; n is preferably 0-3;
a, b, c, and d can be N, NR5, S, SO, SO2, O, or C(R4)0, where o can be 0-2; R5 is preferably
hydrogen, -Rh, -S(O)2Rh, -X3ORF, -X3NRfRg, -X3NRfS(O)2Rh, -X3S(O)2NRfR8, -CO^,
-CONRfRg, or -C(O)Rf. Further preferred are those compounds in which each R1, when
present, is selected from the group consisting of CM alkyl, optionally substituted with a
member selected from the group consisting of-OH, -ORm, -S(O)2Rm, -CO2H and -CO2Rm;
when b and d are other than C(R4)0, c must be C(R4)0 or SO2; when b and c are other than
C(R4)0, then d must be CCR4),, or SO2; when a and d are other than C(R4)0, then at least one of
b and c must be C(R4)0 or SO2. Even more preferably, R2a is hydrogen, halogen, -CN,
-C(O)Rc, -C(NOR°)Rd, -C(NRCW)=NW, -N(W)C(Rc)=NW, -X2C(NORc)Rd,
-X2C(NR°W)=NW, -X2N(W)C(RC)=NW, -X2NRcRd, or -Re; R20 is halogen or cyano. Still
more preferably, m is 0 or 1, n is 0 or 1, and R1 when present is -CH3. In the most preferred
embodiments, R2d is -SRC, -Re, or -ORc; R3a is halogen, cyano, Cw alkyl, Cw haloalkyl, C3-6

cycloalkyl, -C(O)Rf or -SO2Rh wherein the aliphatic portions are optionally substituted as set
forth above; R3b is hydrogen, halogen, cyano, or -NO2.
[0076] For each of the groups of embodiments of formula III (e.g., Ilia through Hlhhhh)
additional preferred embodiments of the invention are those in which two adjacent R3a, R3b or
R3c substituents are combined to form a fused five or six-membered ring, having from 0-3
additional heteroatoms as ring members. Further preferred are those embodiments in which
the ring is a fused six-membered ring, preferably a fused benzene, pyridine or piperidine ring.
[0077] Any substituents not particularly set forth above for the various embodiments of
formula III (e.g., nia through Hlhhhh) are meant to have their most complete meaning with
reference to formula III. Additionally, all compounds are meant to include their
pharmaceutically acceptable salts, as well as any N-oxides thereof.

[00*78] In yet another group of preferred embodiments, the compounds are selected from
formulae IVa-IVe:

wherein R1 and the subscript m have the meaning provided above for formula III, and each of
R2a, R2b, R2" and R2d are substituents independently selected from hydrogen, halogen, -ORc,
-OC(O)Rc, -NRcRd, -SRC, -Re, -CN, -NO2, -CO2Rc, -CONRcRd, -C(O)R°, -OC(O)NRcRd,
-NRdC(O)R\ -NRdC(O)2Re, -NRc-C(O)NR°Rd, -NH-C(NH2)=NH, -NReC(NH2)=NH,
-NH-C(NH2)=NRe, -NH-C(NHRe)=NH, -S(O)Re, -S(O)2Re, -S(O)2NRcRd, -NRcS(O)2Re,
-NR0S(O)2NRcRd, -N3, -X2OR°, -X2OC(O)Rq, -X2NR°Rd, -X2SR°, -X2CN, -X2NO2,
-X2CO2Rc, -X2CONR°Rd, -X2C(O)Rc, -X2OC(O)NRcRd, -X2NRdC(O)Rc, -X2NRdC(O)2Re,
-X2NRcC(O)NRcRd, -X2NH-C(NH2)=NH, -X2NReC(NH2)=NH, -X2NH-C(NH2)=NRe,
-X^H-CCNHR^^NH, -X2S(O)R0, -X2S(O)2Re, -X2S(O)2NRcRd, -X2NRcS(O)2Re, -X'N3, aryl
and heteroaryl, wherein X2, Re, Rd and Re have the meanings provided above with respect to
the compounds of formula I. Similarly, each of R3a, R3b and R3° represents a substituent
independently selected from hydrogen, halogen, phenyl, thienyl, furanyl, pyridyl,

pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, -ORf, -OC(O)Rf, -NRfRg, -SRf, -Rh, -CN, -NOz,
-CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRrRB) -NRgC(O)Rf, -NR6C(O)2Rh, -NRf-C(O)NRfR8,
-NH-C(NH2)=NH, -NRhC(NH2)=NH, -NH-C(NH2)=NRh, -NH-C(NHRh)=NH, -S(O)Rh, -
S(O)2Rh, -S(O)2NRfRg, -NRfS(O)2Rh, -NRfS(O)2NRfR8, -N3) -X3ORf, -X3OC(O)Rf, -
X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfR£, -X3C(O)Rf, -X30C(O)NRfRg, -
X3NRgC(O)Rf, -X3NReC(O)2Rh, -X3NRf-C(O)NRfRg, -X3NH-C(NH2)=NH,
-X3NRhC(NH2)=NH, -X3NH-C(NH2)=NRh) -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh,
-X3S(O)2NRfRE, -X3NRfS(O)2Rh and -X3^ wherein X3, Rf, RE and Rh have the meaning
provided above with respect to the compounds of formula I, and wherein no more than two of
R3a, R3b and R3c are hydrogen, preferably, no more than one of R3a, R3b and R3c is hydrogen,
and still more preferably, each of R3a, R3b and R3c is other than hydrogen.
[0079] Turning first to the compounds of formula IVa, in one group of particularly
preferred embodiments, at least one of R3a, R3b and R3c is selected from halogen and CM
haloalkyl. Still more preferably, at least one of R2b and R2d is hydrogen and at least two of
R3a, R3b and R3c are selected from halogen and CM haloalkyl. In related, and preferred
embodiments, R2c is selected from F, CI, Br, CN, NO2, CO2CH3, C(O)CH3 and SCOTCH;,,
and at least two of R3a, R3b and R3c are selected from halogen and CM haloalkyl with the
remaining member being other than hydrogen.
[0080] Similarly, certain compounds of formula IVb are preferred. Particularly preferred
are those compounds of formula IVb in which at least one of R3a, R3b and R3c is selected from
halogen and C M haloalkyl. Still more preferably, at least one of R2b and R2*1 is hydrogen and
at least two of R3a, R3b and R3c are selected from halogen and CM haloalkyl. In related, and
preferred embodiments, R2c is selected from F, CI, Br, CN, NO2) CO2CH3, C(O)CH3 and
S(O)2CH3, and at least two of R3a, R3b and R3c are selected from halogen and CM haloalkyl
with the remaining member being other than hydrogen.
[0081] Turning next to the compounds of formula IVc, preferred embodiments are those in
which at least one of R2a, R2c and R2d, preferably R2c is selected from F, CI, Br, CN, NO2,
CO2CH3, C(O)CH3 and S(O)2CH3; and at least two of R3a, R3b and R3c are selected from
halogen and CM haloalkyl with die remaining member being other than hydrogen. In other
preferred embodiments, one of R2c and R2d is selected from F, CI, Br, CN, NO2, CO2CH3,
C(O)CH3 and S(O)2CH3, and the other is an aryl or heteroaryl group, for example, phenyl,
thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, and at least two of R a, R3b

andR3c are selected from halogen and Ci _4 haloalkyl with the remaining memher being other
than hydrogen.
[0082] For the compounds of formula IVd, preferred embodiments are those in which at
least one of R2a, R2b and R24 is selected from F, CI, Br, CN, NO2, CO2CH3) C(O)CH3 and
S(O)2CH3, and at least two of R3a, R3b and R3c are selected from halogen and CMhaloalkyl
with the remaining member being other than hydrogen. In other preferred embodiments, one
of R2b and R2d is selected from F, CI, Br, CN, NOz, CO2CH3) C(O)CH3 and S(O)2CH3, and
the other is an aryl or heteroaryl group, for example, phenyl, thienyl, furanyl, oxazolyl,
isoxazolyl, thiazolyl and isothiazolyl, and at least two of R3a, R3b and R3c are selected from
halogen and Cj-4 haloalkyl with the remaining member being other than hydrogen.
[0083] For the compounds of formula IVe, preferred embodiments are those in which at
least one of R2*, R2b and R2c is selected from F, CI, Br, CN, NO2, CO2CH3, C(O)CH3 and
S(O)2CH3, and at least two of R3a, R3b and R3G are selected from halogen and CMhaloalkyl
with the remaining member being other than hydrogen. In other preferred embodiments, one
of R2b and R2c is selected from F, CI, Br, CN, NO2, CO2CH3) C(O)CH3 and S(O)2CH3, and
the other is an aryl or heteroaryl group, for example, phenyl, thienyl, furanyl, oxazolyl,
isoxazolyl, thiazolyl and isothiazolyl, and at least two of R3a, R3b and R3c are selected from
halogen and CMhaloalkyl with the remaining member being other than hydrogen.

[0084] In yet another group of preferred embodiments, the compounds are selected from
formulae IVf-IVi:

wherein R1 and the subscript m have the meaning provided above for formula III, and each of
R2*, R2b, R2c, R2d, R3a, R3b and R3e have the meaning provided above for formulae IVa-IVe.
Additionally, R2e represents a substituent selected from the groups provided for R2" in
formulae IVa-IVe above.
[0085] In still other embodiments, compounds are provided having formulae Va and Vb:

wherein each of R1, the subscript m, R2*, R2b, R2c, R2d, R3a, R3b and R3c have the meaning
provided above for formulae IVa-IVe.
Preparation of Compounds
[0086] As provided in the examples below, the compounds of the present invention can be
prepared by one of skill in the art in a component assembly manner. A number of
compounds are prepared beginning with preparation of a suitably substituted pyrazole (or

other HAr component). Schemes la - Ik illustrate a variety of methods for the preparation of
substituted pyrazoles. In each of these schemes, non-interferring substituents are provided as
-R,-Rw,-Rx,-RyandRz.








IV. Pharmaceutical Compositions
[0087] In addition to the compounds provided above, compositions for modulating CCR1
activity in humans and animals will typically contain a pharmaceutical carrier or diluent.
[0088] 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.
[00891 The pharmaceutical compositions for the administration of the compounds of this
invention may conveniently be presented in unit dosage form and may be prepared by any of
the methods well known in the art of pharmacy and drug delivery. 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 carrier
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.
[0090] 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 and self emulsifications as described in U.S.
Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal
patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets.
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, antioxidants 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 cellulose, silicon
dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,
lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for
example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG,
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, enterically or otherwise, 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. Pat. Nos. 4,256,108; 4,166,452; and
4,265,874 to form osmotic therapeutic tablets for control release.
[0091] 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.
Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils
and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
[0092] 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 polyoxy-
ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, 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 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.

[0093] 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.
[0094] 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.
[0095] 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-
occurring 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.
[0096] 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. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and surfactants.
[0097] 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 maybe
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.
[0098] 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 include cocoa butter and polyethylene glycols.
Additionally, the compounds can be administered via ocular delivery by means of solutions
or ointments. Still further, transdermal delivery of the subject compounds can be
accomplished by means of iontophoretic patches and the like. For topical use, creams,
ointments, jellies, solutions or suspensions, etc., containing the compounds of the present
invention are employed. As used herein, topical application is also meant to include the use
of mouth washes and gargles.
V. Methods of Treating Diseases Modulated by CCR1
[0099] In yet another aspect, the present invention provides methods of treating CCR1 -
mediated conditions or diseases by administering to a subject having such a disease or
condition, a therapeutically effective amount of a compound of formula I above. The
"subject" is defined herein to include animals such as mammals, including, but not limited to,
primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like.
[0100] CCR1 provides a target for interfering with or promoting specific aspects of
immune cell functions, or more generally, with functions associated with CCR1 expression
on a wide range of cell types in a mammal, such as a human. Compounds that inhibit CCR1,
are particularly useful for modulating monocyte, macrophage, lymphocyte, granulocyte, NK
cell, mast cells, dendritic cell, neutrophils, and certain immune derived cell (for example,
osteoclasts) function for therapeutic purposes. Accordingly, the present invention is directed
to compounds which are useful in the prevention and/or treatment of a wide variety of
inflammatory and immunoregulatory disorders and diseases (see Saeki, et ah, Current
Pharmaceutical Design 9:1201-1208 (2003)).

[Q101] For example, an instant compound that inhibits one or more functions of CCR1 may
be administered to inhibit (i.e., reduce or prevent) inflammation or cellular infiltration
associated with an immune disorder. As a result, one or more inflammatory processes, such
as leukocyte emigration or infiltration, chemotaxis, exocytosis (e.g., of enzymes, histamine)
or inflammatory mediator release, can be inhibited. For example, monocyte infiltration to an
inflammatory site (e.g., an affected joint in arthritis, or into the CNS in MS) can be inhibited
according to the present method.
[0102] Similarly, an instant compound that promotes one or more functions of CCR1 is
administered.to stimulate (induce or enhance) an inflammatory response, such as leukocyte
emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator
release, resulting in the beneficial stimulation of inflammatory processes. For example,
monocytes can be recruited to combat bacterial infections.
[0103] Diseases and conditions associated with inflammation, immune disorders and
infection can be treated using the method of the present invention. In a preferred
embodiment, the disease or condition is one in which the actions of immune cells such
monocyte, macrophage, lymphocyte, granulocyte, NK cell, mast cell, dendritic cell, or certain
immune derived cell (for example, osteoclasts) are to be inhibited or promoted, in order to
modulate the inflammatory or autoimmune response.
[0104] In one group of embodiments, diseases or conditions, including chronic diseases, of
humans or other species can treated with modulators of CCR1 function. These diseases or
conditions include: (1) allergic diseases such as systemic anaphylaxis or hypersensitivity
responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel
diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis,
(4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis,
allergic contact dermatitis, urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies,
(7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic
rhinitis, hypersensitivity lung diseases and the like, (9) autoimmune diseases, such as
fibromyalagia, scleroderma, ankylosing spondylitis, juvenile RA, Still's disease, polyarticular
juvenile RA, pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoid arthritis,
psoriatic arthritis, osteoarthritis, polyarticular arthritis, multiple sclerosis, systemic lupus
erythematosus, type I diabetes, type II diabetes, glomerulonephritis, and the like, (10) graft
rejection (including allograft rejection and graft-v-host disease), and (11) other diseases in

which undesired inflammatory responses or immune disorders are to be inhibited, such as
cardiovascular disease including atherosclerosis, myositis, neurodegenerative diseases (e.g.,
Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic
conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome and
gout and (12) immune mediated food allergies such as Celiac disease.
[0105] In another group of embodiments, diseases or conditions can be treated with
modulators of CCR1 function. Examples of diseases to be treated with modulators of CCR1
function include cancers, cardiovascular diseases, diseases in which angiogenesis or
neovascularization play a role (neoplastic diseases, retinopathy and macular degeneration),
infectious diseases (viral infections, e.g., HIV infection, and bacterial infections) and
immunosuppressive diseases such as organ transplant conditions and skin transplant
conditions. The term "organ transplant conditions" is meant to include bone marrow
transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas or combination
thereof) transplant conditions.
[0106] The compounds of the present invention are accordingly useful in the prevention
and treatment of a wide variety of inflammatory and immunoregulatory disorders and
diseases.
[0107] Depending on the disease to be treated and the subject's condition, 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.
[0108] In the treatment or prevention of conditions which require chemokine receptor
modulation an appropriate dosage level will generally be about 0.001 to 100 mg per kg
patient body weight per day which can be administered in single or multiple doses.
Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably
about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25
mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this
range the dosage may be 0.005 to 0.05,0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral
administration, the compositions are preferably provided in the form of tablets containing 1.0

to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,10.0,15.0. 20.0,25.0, 50.0,
75.0, 100.0, 150.0, 200.0,250.0, 300.0,400.0,500.0, 600.0, 750.0, 800.0,900.0, and 1000.0
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.
[0109] 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, hereditary characteristics, general health, sex and
diet of the subject, as well as the mode and time of administration, rate of excretion, drug
combination, and the severity of the particular condition for the subject undergoing therapy.
[0110] Diseases and conditions associated with inflammation, immune disorder, infection
and cancer can be treated or prevented with the present compounds, compositions, and
methods.
[0111] The compounds and compositions of the present invention can be combined with
other compounds and compositions having related utilities to prevent and treat the condition
or disease of interest, such as inflammatory or autoimmune disorders, conditions and
diseases, including inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriatic
arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic
dermatitis and asthma, and those pathologies noted above.
[0112] For example, in the treatment or prevention of inflammation or autimmunity or for
example arthritis associated bone loss, the present compounds and compositions may be used
in conjunction with an anti-inflammatory 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 anti-inflammatory agent, or a cytokine-suppressing anti-
inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine,
fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a
steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant
compounds and compositions may be administered with an analgesic listed above; a
potentiator such as caffeine, an H2 antagonist (e.g., ranitidine), simethicone, aluminum or

magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine,
pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline,
propylhexedrine, or levo desoxy ephedrine; an antitussive such as codeine, hydrocodone,
caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non sedating
antihistamine.
[0113] Likewise, compounds and compositions 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 and compositions 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 or
composition of the present invention. When a compound or composition 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 or composition of the
present invention is preferred. Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active ingredients or therapeutic
agents, in addition to a compound or composition of the present invention. Examples of
other therapeutic agents that may be combined with a compound or composition of the
present invention, either administered separately or in the same pharmaceutical compositions,
include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids, such as
beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone,
dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol,
salmeterol, salbutamol, formeterol; (c) immunosuppressants such as cyclosporine
(cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin
(sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate,
e.g., mycophenolate mofetil (CellCept®); (d) antihistamines (Hl-histamine antagonists) such
as bromopheniramine, chlorpheniramine, dexchloipheniramine, triprolidine, clemastine,
diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,
promeuiazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,
astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and
the like; (e) non steroidal anti asthmatics (e.g., terbutaline, metaproterenol, fenoterol,
isoetharine, albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium, atropine,
ipratropium bromide, leukotriene antagonists (e.g., zafmlukast, montelukast, pranlukast,
iralukast, pobilukast and SKB-106,203), leukotriene biosynthesis inhibitors (zileuton,

BAV-1005); (f) non steroidal anti-inflammatory agents (NSAIDs) such as propionic acid
derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen,
fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, rniroprofen, naproxen,
oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid
derivatives (e.g, indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac,
fericlozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin,
zidometacin and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic
acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives
(e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam and
tenoxican), salicylates (e.g., acetyl salicylic acid and sulfasalazine) and the pyrazolones (e.g.,
apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone);
(g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib
(Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDEIV); (i) gold compounds such as
auranofin and aurothioglucose, (j) etanercept (Enbrel®), (k) antibody therapies such as
orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab
(Remicade®), (1) other antagonists of the chemokine receptors, especially CCR5, CXCR2,
CXCR.3, CCR2, CCR3, CCR4, CCR7, CX3CR1 and CXCR6; (m) lubricants or emollients
such as petrolatum and lanolin, (n) keratolytic agents (e.g., tazarotene), (O) vitamin D3
derivatives, e.g., calcipotriene or calcipotriol (Dovonex®), (p) PUVA, (q) anthralin
(Drithrocreme®), (r) etretinate (Tegison®) and isotretinoin and (s) multiple sclerosis
therapeutic agents such as interferon P-ip (Betaseron®), interferon (P-la (Avonex®),
azathioprine (Imurek®, Imuran®), glatiramcr acetate (Capoxonc®), a glucocorticoid (e.g.,
prednisolone) and cyclophosphamide (t) DMARDS such as methotrexate (u) other
compounds such as 5-aminosalicylic acid and prodrugs thereof; hydroxychloroquine;
D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurine and methotrexate;
DNA synthesis inhibitors such as hydroxyurea and microtubule disrupters such as colchicine.
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 NSA1D the weight ratio of the compound of the present
invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably
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.
VI. EXAMPLES
[0114] The following examples are offered to illustrate, but not to limit the claimed
invention.
[0115] Reagents and solvents used below can be obtained from commercial sources such as
Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 'H-NMR were recorded on a Varian
Mercury 400 MHz NMR spectrometer. Significant peaks are provided relative to TMS and
are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet)
and number of protons. Mass spectrometry results are reported as the ratio of mass over
charge, followed by the relative abundance of each ion (in parenthesis). In tables, a single
m/e value is reported for the M+H (or, as noted, M-H) ion containing the most common
atomic isotopes. Isotope patterns correspond to the expected formula in all cases.
Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-
Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery.
Normally the analyte was dissolved in methanol at 0.1 mg/mL and 1 microlitre was infused
with the delivery solvent into the mass spectrometer, which scanned from 100 to 1500
daltons. All compounds could be analyzed in the positive ESI mode, using acetonitrile /
water with 1 % formic acid as the delivery solvent. The compounds provided below could
also be analyzed in the negative ESI mode, using 2 raM NH4OAc in acetonitrile / water as
delivery system.
[0116] Compounds within the scope of this invention can be synthesized as described
below, using a variety of reactions known to the skilled artisan. A sample of useful routes to
both the arylpiperazine subunits and to the heteroaromatic subunit are provided below. In the
descriptions of the syntheses that follow, some of the arylpiperazine and pyrazole precursors
were obtained from commercial sources. These commercial sources include Aldrich
Chemical Co., Acros Organics, Ryan Scientific Incorporated, Oakwood Products
Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-
America, Alfa Aesar, Davos Chemicals, and GFS Chemicals. Some examples of these
commercially available compounds are shown in the Figures 4A-4C. Also, standard

chemistries have been employed to link the arylpiperazine and heteroaromatic subunits
(whether commercially obtained or prepared by the methods below) using a suitably
optimized linker, such as the acetyl unit described in the body of this invention.
[0117] One skilled in the art will also recognize that alternative methods may be employed
to synthesize the target compounds of this invention, and that the approaches described
within the body of this document are not exhaustive, but do provide broadly applicable and
practical routes to compounds of interest.
[0118] Certain molecules claimed in this patent can exist in different enantiomeric and
diastereomeric forms and all such variants of these compounds are claimed.
[0119] Regioisomerism is a common property in organic chemistry, and is especially
common with regards to certain structural types provided herein. Those skilled in the art will
recognize, with respect to the compounds described herein, that the coupling reactions with
the heteroaromatic ring systems can lead to either one of or a mixture of detectable
regioisomers.
[0120] The, detailed description of the experimental procedures used to synthesize key
compounds in this text lead to molecules that are described by the physical data identifying
them as well as by the structural depictions associated with them.
[0121] Two regioisomers can sometimes exist for certain compounds of the invention. For
example, compounds such as those of formula III can be prepared wherein the pyrazole
moiety is linked to the remainder of the molecule via either of the nitrogen atoms in the
pyrazole ring. In these cases, both regioisomeric types have demonstrated biological
properties and are meant to be within the scope of all the appended claims, whether explicitly
drawn or not.
[0122] Those skilled in the art will also recognize that during standard work up procedures
in organic chemistry, acids and bases are frequently used. Salts of the parent compounds are
sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the
experimental procedures described within this patent.

EXAMPLE 1
[0123] The piperazine ring can be formally attached to the terminal aryl unit in a number of
ways: by aromatic nuclephilic displacement reactions, metal catalyzed coupling reactions
(arylation reactions of secondary amines), ring expansion, rearrangement and cyclization
reactions and the like. Also, different protection / deprotection strategies can be utilized.
Hence, either all or only part of the final molecular architecture can be present during the key
aryl coupling step. Examples for a variety of such aryl coupling strategies are listed below.
PROTOCOL A; Metal catalysed arylation reactions of secondary amines
Synthesis of (5-Chloro-2-piperazin-1-yl-phenyl)-phenyI-methanone

[0124] Piperazine (3.6 g, 42.5 mmol), Pd(II)acetate (0.007 g, 0.043 mmol), sodium t-
butoxide (0.22 g, 2.4mmol) and BINAP (0.042 g, 0.068 mmol) were stirred at room
temperature in 10 mL dry toluene for 15 min. (2-Bromo-5-chloro-phenyl)-phenyl-methanone
(0.5 g, 1.7 mmol) in 10 mL dry toluene was then added into the reaction mixture. The
reaction mixture was refluxed at 110° C for 20 hrs, filtered through a celite bed, washed with
toluene, concentrated, taken in ethyl acetate and extracted with 1.5 (N) HC1 solution three
times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was
neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl
acetate three times. The combined ethyl acetate layers were washed with water and saturated
brine solution, dried over anhydrous sodium sulfate and concentrated. Purification by flash
chromatography (eluted with CHCl3-MeOH) afforded the title compound as product.
Synthesis of l-(4-Trifluoromethoxy-phenyl)-piperazine


[0i25] Piperazine (0.588 g, 6.84mmol), Pd(H)acetate (0.027 g, 0.123 mmol), sodium t-
butoxide (0.837 g, 10.06 mmol) and BINAP (0.154 g, 0.286 mmol) were stirred at room
temperature in 10 mL dry toluene for 15 min. 4-trifluoromethoxy bromo benzene (1.5 g,
6.22 mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction
mixture was refluxed at 110°C for 20 hrs. The reaction mixture was filtered through a celite
bed, washed with toluene, concentrated, ethyl acetate added and then extracted with 1.5 (N)
aqueous HC1 solution three times. The combined aqueous layers were washed with diethyl
ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and
then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed
with water and saturated brine solution, dried over anhydrous sodium sulfate and
concentrated to afford the product.
Synthesis of l-(4-Mcthanesulfony!-phcnyI)-piperazine

[0126] Piperazine (0.98 g, 11.5 mmol), Pd(II)acetate (0.017 g), sodium t-butoxide(0.37 g,
4.2 mmol) and BINAP (0.049 g) were stirred at room temperature in 10 mL dry toluene for
15 min. l-Bromo-4-methanesulfonyl-benzene (0.9 g, 3.8 mmol) in 10 mL dry toluene was
added into the reaction mixture. Then the reaction mixture was refluxed at 110°C for 20 hrs.
The reaction mixture was filtered through a celite bed and washed with toluene. The toluene
was concentrated and the reaction mixture was taken in ethyl acetate and extracted with 1.5
(N) HC1 solution three times. The combined aqueous layers were washed with diethyl ether.
The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then
extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with
water and saturated brine solution, dried over anhydrous sodium sulfate, concentrated and
chromatographed (9/l-CHCl3/MeOH) to afford the product.

Synthesis of l-(4-Chloro-3-methoxy-phenyl)-piperazine

[0127J An oven dried glass vial was charged with 5-Bromo-2-chloroanisole (1.0 mmol), N-
Bocpiperazine (1.2 mmol), NaOtBu (1.4 mmol), tris(dibenzylideneacetone)-dipalladium(O)
{Pd2dba3} (0.0O25 mmol, 0.5 mol %) and BINAP (0.0075 mmol), and the vial was then
flushed with nitrogen and capped tightly. The mixture was heated to 80°C overnight and then
cooled to room temperature, taken up in ether, filtered and concentrated. The crude product
was purified by flash column chromatography on silica gel with ethyl acetate to yield 4-(4-
CMoro-3-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
[01281 This product (ca. 1 mmol) was dissolved in a methylene chloride (10 mL) and the
reaction mixture was cooled to 0°C. To the reaction mixture was added TFAiCflbCb. (
2:1)(50% overall) slowly and the reaction was allowed to warm to room temperature. When
TLC (1:1 Ethyl acetate: hexane ) suggested total consumption of starting material, solvent
was removed and the oil residue was taken in ethyl acetate (2 x 25 mL) and washed with
saturated aqueous NaHCC>3. The organic layer was dried by MgSCU and solvent was
removed to yield the title compound as a yellow oil, which solidified on standing. 'H NMR.
(400 MHz, CDC13) 6 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 4.8 (s, 2H),
6.62-3.8 (m, 4H), 3.46-3.6 (m, 4H). I3C NMR (400 MHz, CDC13) 8 164,158.2,156.4,148,
119.2,117, 52.8, 52.2,48.5, 46.2,42,40.4.
[0129] Similar approaches, using a key Buchwald coupling, were taken for the preparation
of related phenylpiperazines, some examples of which are listed below.

Synthesis of l-(4-Chloro-3-isopropoxy-phenyl)-piperazine

[0130] l-Bromo-3-isopropoxy-4-chlorobenzene (preparation described elsewhere) was
combined with 1.11 g (6 mmol) of 1 -Bocpiperazine, 672 mg (7.0 mmol) of sodium tert-
butoxide, 93 mg (0.15 mmol) of rac-2,2'-Bis(diphenylphosphine)-l,r-binaphfliyl, and 45 mg
(0.05 mmol) Tris(dibenzylideneacetone)dipalladium (O) in a flask under an N2 atmosphere,
and the mixture was heated at 85°C for 3.5 hours. The resulting residue was partitioned
between a 1/1 mixture of ether and ethyl acetate and water, and the phases were separated.
The ether/ethyl acetate phase was diluted with one volume of hexanes, washed twice with
0.5M pH = 7 phosphate buffer, and once each with 1M NaOH and brine. The final organic
phase was dried over Na2SO4, filtered, and concentrated in vacuo to an oil. The oil was
dissolved in ethyl acetate, 10 mL each of 2M HC1 in ether and methanol were added, and the
product was isolated by filtration after crystallization. *H NMR (D20, 400MHZ) 8 7.23 (d,
1H), 6.69 (s, 1H), 6.59 (d, 1H), 4.53 (m, 1H), 3.28 (m, 8H), 1.20 (d, 6H) ppm.
Synthesis of l-(4-Chloro-3-ethoxy-phenyl)-piperazine

[0131] Title compound was obtained following the same procedure as that used to obtain 1-
(4-Chloro-3-isopropoxy-phenyl)-piperazine hydrochloride, with the single modification of
adding ethanol in place of isopropanol during the ether-forming reaction. 'H NMR (D2O,
400MHz) 7.22 (d, 1H), 6.64 (s, IE), 6.54 (d, 1H), 4.03 (q, 2H), 3.29 (m, 8H), 1.25 (t, 3H)
ppm.

Synthesis of 4-Piperazin-1-yl-benzoic acid methyl ester

[0132] BINAP (230 mg, 0.37 mmol), Pd(II)acetate (417 mg, 0.186 mmol), tBuONa
(1.25 g, 13 mmol), N-boc piperazine (1.9 g, 10.2 mmol) andTHF (40 mL) were mixed
together and stirred at room temperature for 30 min under a nitrogen atmosphere. 4-
bromomethyl benzoate (2 g, 9.3 mmol) in THF (10 mL) was added to the mixture drop wise
and heated at 70°C for 14h. Excess THF was then evaporated and extracted with ethyl
acetate. The crude product was obtained on concentration of the ethyl acetate layer after
washing with brine and drying. Flash chromatography on silica gel done eluting with 8%
ethyl acetate in petroleum ether yielded pure N-BOC protected product. This intermediate
(650 mg, 2.01 mmol) was dissolved in methanol (20 mL) and then HC1 saturated ether
(7 mL) was added. The mixture was stirred at room temperature for 14 hours and
concentrated. The concentrate was washed with petroleum ether to obtain white solid
compound, 4-Piperazin-1-yl-benzoic acid methyl ester.
Synthesis of l-(2,4-DicliIoro-phenyl)-piperazine

10133] BINAP (219 mg), Pd(II)acetate (397 mg, 0.176 mmol), tBuONa (1.19 g,
12.3 mmol), piperazine (837 mg, 9.73 mmol) and THF (40 mL) were mixed together and
stirred at room temperature for 30 min under nitrogen atmosphere. 2,4-
dichlorobromobenzene (2 g, 8.84mmol) in THF (10 mL) was added to the mixture drop wise
and heated at 70°C for 14h. Excess THF was then evaporated and extracted with ethyl
acetate. The crude product was obtained on concentration of the ethyl acetate layer after
washing with brine and drying. Flash chromatography on silica gel eluting with 2% MeOH in
CHCI3 gave l-(2,4-Dichloro-phenyl)-piperazine.

Synthesis of l-(4-Chloro-phenyl>3-(R)-methyl-piperazine

[0134] A single neck round bottom flask was charged with 1 -chloro-4-iodo benzene (1.0 g,
0.0041 mol) and R(-)-2-methylpiperazine (0.5 g, 0.005 mol), potassium t-butoxide (0.705 g,
0.0062 mol), tris(benzylideneacetone)dipalladium(O) (0.095 g, 0.0002 mol) and 1,3 bis(2,6-
diisopropylphenyl)imidazole-2-ylidene) (0.073 g, 0.0001 mol). The flask was evacuated and
filled with nitrogen. Dry dioxane (20 mL) was added and stirred at 70 °C overnight. The
reaction mixture was diluted with dichloromethane and filtered. Crude compound was
purified by column chromatography. The compound was dissolved in ether and purged with
HC1 gas to yield l-(4-Chloro-phenyl)-3-methyl-piperazine.
Synthesis of l-(4-ChIoro-2-Fluorophenyl)-piperazine

[0135] Piperazine (1.5 g, 17.8 mmol), Pd(II)acetate (0.032 g, 0.143 mmol), sodium t-
butoxide (0.688 g, 10.06 mmol) and BINAP (0.18 g, 0.286 mmol) were stirred at room
temperature in 10 mL dry toluene for 15 min. l-bromo-4-chloro-2-fluorobenzene (1.5 g,
7.15 mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction
mixture was refluxed at 110°C for 20 hrs. The reaction mixture was filtered through a celite
bed and washed with toluene, then concentrated and the reaction mixture was taken into ethyl
acetate and extracted with 1.5 (N) HC1 solution three times. The combined aqueous layer was
washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium
hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl
acetate layers were washed with water and saturated brine solution, dried over anhydrous
sodium sulfate, and concentrated to afford the product as a white solid.

Synthesis of l-(3-methoxy-phenyl)-3-(S)-methyl-piperazine:

[0136] Combined 467 mg (2.5 mmol, 1.0 eq) of 3- bromoanisole, 300 mg (2.99 mmol, 1.2
eq) S-(+)- 2-methylpiperazine, 336 mgNaOtBu (3.5 mmol, 1.4 eq), 50 mg BINAP (0.08
mmol, 0.03 eq), 27 mg Pd2Dba3 (0.03 mmol, 0.01 eq), and 500 uL toluene in a 4 mL vial.
The mixture was briefly agitated then placed in a 90C oil bath. LC/ MS showed complete
conversion in one hour. An excess of 2M HCl/Et20 was added to the reaction mixture, and
the solid collected by vacuum filtration and dried down to get 700 mg of the
dihydrochloride.
Synthesis of l-(3-trifluoromethoxy-phenyl)-piperazine:

[0137] Following protocol A, l-Bromo-3-(trifluoromethoxy)-benzene (1.0 g, 0.0042 mol),
piperazine (5.4 g, 0.0632 mol), potassium tert-butoxide (0.72 g, 0.0076 mol), palladium
acetate (0.94 g, 0.0O02 mol) and Diisopropylimidazolium chloride (0.08 g, 0.0002 mol) in 5
mL of dry dioxane were heated at 100°C for 24 hours under argon. The reaction mixture was
cooled to ambient temperature, quenched with water, and extracted with ethyl acetate. The
ethyl acetate phase was washed once each with water and brine, and was concentrated. The
residue was purified by column chromatography to give the title compound.
l-(4-Chloro-3-methoxvphenyl)-3-(S)-methyl-piperazine:

[0138] Following protocol A, 5-Bomo-2-chloroaniline (0.5 g, 0.0023 mol), (S)-(+)-2-
methyl piperazine (0.35 g, 0.0035 mol), palladium acetate (0.026 g, 0.0001 mol), BINAP

(0.14 g, 0.00023 tnol) and sodium tert-butoxide (0.35 g, 0.0037 mol) in 5 mL of dry toluene
were heated at 110 °C under argon atmosphere for 18 h. The reaction mixture was quenched
with water and extracted with ethyl acetate. The extract was washed with water, brine, and
concentrated in vacuo. The product was purified by column chromatography to give an oil.
l-(4-Chloro-3-methoxyphenyl)-3-(R)-methyl-piperazine:

[0139] The title compound was prepared following protocol A, using (R)-(+)-2-methyl
piperazine as the starting material. The product was isolated as a low-melting solid.
l-(4-Fluoro-2-methoxy-phenyl)-piperazine:

[0140] 4-Chloro-3-methoxy-aniline (25 g, 158 mmol) was dissolved in cone. HC1 (160 mL)
at 80°C, and the solution was cooled to -10°C. An aqueous solution of NaNC>2 (12.04 g,
174.6 mmol) was added drop wise with stirring. After an additional 20 minutes, HPF6
(80 mL) was added with stirring, keeping the temperature at or below 0°C. After an
additional 30 minutes, the solid was filtered and washed with cold water and an ether-
methanol mixture (4:1), and dried overnight in vacuo. The solid was added in portions to
mineral oil at 170°C with stirring. After complete addition the mixture was cooled to ambient
temperature, and 175 mL of 10% Na2CO3 was added slowly to it. The mixture was steam
distilled, and the distillate was extracted with dichloromethane. The dichloromethane phase
was washed with brine, dried with Na2SO4, filtered, and concentrated to give 2-Chloro-5-
fluoroanisole.
[0141] Following protocol A, Mono Boc-piperazine (7.64 g, 41.12 mmol), Pd (II) acetate
(153 mg, 0.65 mmol), sodium tert. butoxide (4.61 g, 47 mmol) and BINAP (0.853 g,
1.37 mmol) were mixed together and stirred at rt in 100 mL dry toluene for 15 min under
nitrogen atmosphere. 2-chloro-5-fluoroanisole (5.5 g, 34.2 mmol) in dry toluene (10 mL)
was then added, and the mixture was refluxed for 20 hours. After cooling, the reaction
mixture was filtered through a celite bed, followed by extensive washing with toluene. The

toluene was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate
was decanted, and was concentrated to obtain crude material that was taken directly to the
next step.
[0142] The crude compound from the previous step was dissolved in 20 mL of
dichloromethane, and 2M HC1 in dry ether (20 mL) was added to it. The reaction mixture
was stirred overnight, and the solvent was evaporated. The residue was dissolved in water,
and was washed once with ethyl acetate. The aqueous layer was basified with 10% sodium
hydroxide solution to pH 12, and was extracted with ethyl acetate three times. The combined
ethyl acetate layers were washed with water and saturated brine solution, dried over
anhydrous sodium sulfate, filtered, and concentrated to afford l-(4-Fluoro-2-methoxy-
phenyl)-piperazine as a white solid.
Synthesis of 1-[4-Chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazine:

[0143] Following protocol Fl (below), to 1.11 g (4.24 mmol) of triphenylphosphine in
25 mL of CH2C12 at 0°C was added 0.67 mL (4.24 mmol) of diethylazodicarboxylate. After
10 minutes, 0.80g (3.86 mmol) of 5-Bromo-2-chlorophenol was added, followed rapidly by
0.38 g (4.24 mmol) of 2-Ethoxyethanol. The reaction was complete within three hours, and
was partitioned between ether and water. The phases were separated, and the ether phase was
diluted with hexanes and washed twice with 10% aqueous methanol and once with brine.
The ether/hexanes phase was dried over Na2SO4, filtered, and concentrated in vacuo to yield
(5-Bromo-2-chloro-eth.oxy-ethoxy-benzene as a clear oil.
[0144] 418 mg (1.5 mmol) of (5-Bromo-2~chloro-ethoxy-ethoxy-benzene, 335 mg (1.8
mmol) of 1-Boc-piperazine, 202 mg (2.1 mmol) sodium tert-butoxide, 30 mg (0.045 mmol)
of rac-binap, and 14 mg (0.015 mmol) of Pd2DBA3 were slurried in 0.5 mL of dry toluene,

and the mixture was heated at 90°C for 12 hours. The reaction was partitioned between water
and ethyl acetate, and the phases were separated. The ethyl acetate phase was washed with
brine, dried over Na2SO4, filtered, and concentrated to an oil. The oil via chromatography to
give 1 -[4-Chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazine.
Further examples of arylpiperazines synthesized by metal catalysed arylation methods
(PROTOCOL A)
[0145] Many other arylpiperazine derivatives were prepared in addition to the specific
experimental examples listed above using similar Palladium mediated coupling
methodologies. Examples are listed below.

PROTOCOL B: Piperazine ring formation via cvclization reactions

Synthesis 0f i-(3,4-DifluorophenyI)piperazine

[0146] 3,4-Difluoro-aniline (1 g, 7.7 mmol) was dissolved in dry n-butanol (10 mL) and
dry sodium carbonate (3.2 g, 30 mmol) was added to it and the reaction mixture stirred for 1
hour under nitrogen. Bis(2-chloroethyl) amine hydrochloride (1.3 8 g, 7.7 mmol) in nBuOH
(10 mL) were then added to the mixture via a syringe. The reaction was then heated at 120°C
for 48h. The nBuOH was evaporated in vacuo and the residue was extracted with ethyl
acetate. Drying of the organic layer with Na^SC^ followed by concentration afforded the
crude product. Purification using flash column chromatography (chloroform/methanol)
afforded l-(3,4-Difluorophenyl)-piperazine as an off white solid.
Synthesis of l-(4-bromo-phenyl)-piperazine

[0147] 4-Bromo-aniline (2 g, 1.162 mmol) was taken in dry nBuOH (25 mL) and dry
potassium carbonate (4.8 g, 34,8 mmol) was added to it and stirred at rt for lh under nitrogen.
5is-(2-chloroethyl) amine hydrochloride 2 (2.49 g, 13.9 mmol) in nBuOH (10 mL) was then
added to the mixture through a syringe. The reaction mass was then heated at 100°C for 12h.
nBuOH was evaporated in vacuo and the residue was extracted with etfryl acetate. Drying of
the organic layer with Na2SO4 followed by concentration afforded the crude product that on
purification silica gel column (chloroform/methanol) afforded the title compound.
PROTOCOL Ct Piperazine ring formation via a ring opening / ring cvclization strategy

Synthesis of 3-[2-(5-Methoxy-2-methyl-phenylamiiio)-ethyl]-oxazolidiii-2-one:

[0148] To a flask was added 2.95 g (10.3 mmol) of Toluene-4-sulfonic acid, 2-(2-oxo-
oxazolidin-3-yl)-ethyl ester, 1.56 g (11.4 mmol) of 2-methyl-5-methoxyaniline, 2.58 g
(18.7 mmol) of potassium carbonate, and 22 mL of anhydrous dimethylformamide, and the
mixture was heated at 100 °C for seven hours. The reaction was allowed to cool to room
temperature, and was partitioned between ethyl acetate and water. The phases were separated,
and the ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and
concentrated to an oil. The oil was purified by chromatography (120 mL silica, 60 ethyl
acetate / 40 hexanes) to give the corresponding product as a clear oil that solidified upon
drying: *H NMR (DMSO-d6,400MHz) 6.81 (d, 1H), 6.11 (s, 1H), 6.04 (d, 1H), 4.92 (t, 1H),
4.21 (t, 2H), 3.65 (s, 3H), 3.59 (m, 2H), 3.31 (m, 2H), 3.23 (m, 2H), 1.95 (s, 3H) ppm.
Synthesis of:'l-(5-Methoxy-2-methyl-phenyl)-piperazine

[0149] To 505 mg (2.0 mmol) of 3-[2-(5-Methoxy-2-methyl-phenylamino)-ethyl]-
oxazolidin-2-one in a flask was added 2 mL of 48% HBr in acetic acid, 1 mL of acetic acid,
and 1 mL of anisole, and the mixture was heated at 90°C for six hours. The solution was
allowed to cool to room tempterature, and 5 mL of CH2CI2 was added. The product
crystallized and was isolated by filtration. The solids were dissolved in 55 mL of ethanol, 201
mg (2 mmol) of triefhylamine were added, and the solution was heated at reflux for 3 hours.
The solution was then concentrated in vacuo to give a residue that was partitioned between
ether and water. The phases were separated, and the aqueous phase as basified with 1M
"NaOH. The aqueous phase was then extracted twice with ethyl acetate. The combined ethyl
acetate phases were washed once with brine, dried over Na2SO4, filtered, and acidified with
2M HC1 in ether. The product was isolated via filtration.

Addition of various piperazines to aryl halides and heteroaryl halides via aryl-halogen
displacement methodologies
[0150] A direct halogen displacement strategy, with thermal assistance if necessary, can be
complimentary to the metal mediated approaches, discussed above, for the construction of the
ring systems provided herein.
Synthesis of 4-Piperazin-1-yl-benzoic acid ethyl ester

[0151J To 4-bromobenzoic acid (25 g) and ethanol (1000 mL) was added conc.sulfuric acid
(20g) drop wise. The reaction mixture was heated at 85 °C overnight. The reaction was
cooled and ethanol was removed by distillation and the reaction mixture quenched with water
and extracted with ethyl acetate. The extract was washed with 10% sodium bicarbonate,
water, brine and then concentrated to yield the crude ester. 4-bromoethyl benzoate (10.0 g,
0.0437 mol) was taken into 250 mL of dry DMF, piperazine (37 g, 0.437 mol) was added,
followed by 30g (0.2185 mol) of dry potassium carbonate, 1.0 g of TBAI and 1.5 g of
potassium iodide. The reaction mixture was heated at 135 °C for over night. The reaction
mixture was quenched with water and extracted with ethyl acetate. The extracts were washed
with water, then brine and then concentrated to yield 4-Piperazin-1-yl-benzoic acid ethyl
ester as an off-white solid.
Synthesis of l-(4-Methoxy-pyridin-2-yl)-piperazine:

[0152] To 756 mg (5.29 mmol) of 2-Chloro-4-methoxypyridine and 2.27 g (26 mmol) of
piperazine in a pressure flask was added 2.7 mL dimethylformamide, and the mixture was
heated at 115°C for 5 hours. The solution was allowed to cool before opening the flask, and
the resulting slurry was partitioned between ethyl acetate and water. The phases were
separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined
ethyl acetate phases were washed once with brine, dried over NazSO/j, filtered, and the filtrate

was acidified with 2M HC1 in ether. The product crystallized over night, and the solids were
isolated by filtration to yield product as a white solid: 'H NMR (D20, 400MHZ) 7.72 (d, 1H),
6.61 (d, 1H), 6.48 (s, 1H), 3.88 (s, 3H), 3.79 (m, 4H), 3.36 (m, 4H) ppm.
Synthesis of l-(3-Methoxy-pyridin-2-yl)-piperazine:

[0153] To 966 mg (6.7 mmol) of 2-Chloro-6-methoxypyridine and 2.90 g (34 mmol) of
piperazine in a pressure flask was added 3.3 mL dimethylformamide, and the mixture was
heated at 115°C for 5 hours. The solution was allowed to cool before opening the flask, and
the resulting slurry was partitioned between ethyl acetate and water. The phases were
separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined
ethyl acetate phases were washed once with brine, dried over Na2SC>4, filtered, and the filtrate
was acidified with 2M HO in ether. The product crystallized overnight, and was isolated by
filtration to give a white solid: 'H NMR (D20,400MHz) 7.73 (t, 1H), 6.52 (d, 1H), 6.31 (d,
1H), 3.81 (s, 3H), 3.68 (m, 4H), 3.26 (m, 4H) ppm.
PROTOCOL D: Synthesis and addition of elaborated piperazines to aryl and heteroaryl
halides via aryl-halogen displacement methodologies
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazoH-yl)-1-piperazin-1-yl-
ethanone

[0154] To a solution of 1.69 g (9.1 mmol) Boc-piperazine, 2.0g (8.3 mmol) of (4-Chloro-
5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid, and 1.12 g (8.3 mmol) of 1-
Hydroxybenzotriazole in 20 mL of dimethylformamide at 0°C was added 1.73 g (9.1 mmol)
of l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was allowed
to stir and warm to room temperature over night, then was partitioned between ether and
water. The phases were separated, and the ether phase was washed once each with 1M HC1,

w|ter, 1M NaOH, and brine. The ether phase was then dried over Na2SO4, filtered, and
concentrated to a residue.
[0155] This crude residue was dissolved in 20 mL ether and 8 mL ethyl acetate, and 20 mL
of 5M HCl in isopropanol was added. After 1 hour the mixture was placed in the freezer over
night. The product was isolated by filtration to give a white solid. 'H NMR (DMSO-d6,
400MHz) 9.21 (br s, 2H), 5.3 8 (s, 2H), 3.69 (m, 4H), 3.32 (m, 4H), 2.20 (s, 3H) ppm.
Alternative synthesis of 2-(4-Chloro-5-methyl-3-trifiuoromethyl-pyrazoI-1-yl)-1-
piperazin-1-yl-ethanone

[0156] (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.5 g, 6.18 mmol)
was taken in dry DCM (20 mL) and cooled to 0°C. To this cold mixture was added N-boc
piperazine (1.15 g, 6.18 mmol) followed by addition of T3P (8 g, 12.4 mmol, 50% solution in
EtOAc). The reaction was left overnight at it. The mixture was diluted with CH2CI2, washed
with NaHCO3 soln, brine, dried (Na2SO4) and concentrated to afford the crude product that
was washed thoroughly with ether-pet ether to afford 4-[2-(4-Chloro-5 methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (1.2 g,
2.9 mmol). This was dissolved in methanol (25 mL) cooled to 0°C and HCl saturated ether
(3 mL) was added to it. The mixture was stirred at room temperature for 4h and concentrated.
Crystallization from MeOH / Petroleum ether yielded product.
Synthesis of 1-[4-(5-Bromo-pvrimidin-2-yI)-piperazin-1-yl]-2-(4-chIoro-5-methyl-3-
trifluoromethyI-pyrazol-1-yl)-ethanone (PROTOCOL D)

[0157] To 86 mg (0.25 mmol) of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-
piperazin-1-yl-ethanone hydrochloride, 76 mg (0.6 mmol) potassium carbonate, and 48 mg

(0,3 mmol) of 5-Bromo-2-chloropyrimidine in a vial was added 0.7 mL anhydrous
dimethylformamide, and the mixture was heated at 120°C for 12 hours. The reaction was
allowed to cool to room temperature, and was partitioned between ethyl acetate and water.
The phases were separated, and the aqueous phase was back-extracted once with ethyl
acetate. The combined ethyl acetate phases were washed once each with water, 0.5M pH = 7
phosphate buffer, water, 1M NaOH, and brine. The ethyl acetate phase was dried over'
Na2SO4, filtered, and acidified with 2M HC1 in ether to precipitate the product as a powder:
!H NMR (DMSO-d6,400MHz) 8.48 (s, 2H), 5.37 (s, 2H), 3.81 (m, 2H), 3.72 (m, 2H), 3.57
(m, 4H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 467.0, found 466.9.
Additional compounds of the invention prepared by the aryl-halogen displacement
method
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(7H-purin-6-
yl)piperazinl-yl]-ethanone:

[0158] Title compound was prepared following protocol D, wherein 6-Chloropurine was
used as the heteroaryl halide component: !H NMR (DMSO-d6, 400MHz) 8.23 (s, 1H), 8.14
(s, 1H), 5.39 (s, 2H), 4.32 (br, 2H), 4.22 (or, 2H), 3.60 (m, 4H), 2.19 (s, 3H) ppm; MS (ES)
expect M+H = 429.1, found 429.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-quinolin-2-yl-
piperazin-1-yl)ethanone:


10159] Title Compound was prepared following protocol D, wherein 2-Chloroquinoline
was used as the heteroaryl halide component: 'H NMR (DMSO-d63 400MHz) 8.44 (d,1H),
8.29 (br, 1H), 7.91 (d, 1H), 7.77 (t, 1H), 7.57 (d, 1H), 7.48 (t, 1H), 5.44 (s, 2H), 4.14 (br, 2H),
4.01 (br, 2H), 3.78 (br, 2H), 3.70 (br, 2H), 2.20 (s, 3H) ppm; MS (ES) expect M+H = 438.1,
found 438.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-1-[4-(5-chloro-
pyridin-2-yI)-piperazin-1-yI]-ethanone:

[0160] Title compound was prepared following protocol D, wherein 2,5-Dichloropyridine
was used as the heteroaryl halide component: MS (ES) expect M+H = 422.1, found = 422.0;
HPLC retention time = 4.75 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazoI-1-yl)-1-(2,3,5,6-tetrahydro-
[l,2']bipyrazinyl-4-yl)-ethanone:

[0161] Title compound was prepared following protocol D, wherein 2-Chloropyrazine was
used as die heteroaryl halide component: 'H NMR (DMSO-d6, 400MHz) 8.34 (s, 1H), 8.09
(d, 1H), 7.85 (d, 1H), 5.38 (s, 2H), 3.68 (m, 2H), 3.58 (m, 4H), 3.44 (m, 2H), 2.19 (s, 3H)
ppm; MS (ES) expect M+H = 389.1, found 389.0.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-I4-(6-methyl-
pyridazin-3-yl)-piperazin-1-yl]-ethanone:

[0162] Title compound was prepared foil owing protocol D, wherein 3-Chloro-6-
methylpyridazine was used as the heteroaryl halide component:MS (ES) expect M+H =
403.1, found = 403.0; HPLC retention time = 1.68 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u., 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
Synthesis of 2-(4-ChIoro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-1-[4-(4,6-dimethoxy-
[l,3,5]triazin-2-yl)-piperazin-1-yl]-ethanone:

[0163] Title compound was prepared following protocol D, wherein 2-Chloro-4,6-
dimethoxytriazine was used as the heteroaryl halide component: MS (ES) expect M+H =
450.1, found = 450.0; HPLC retention time = 4.24 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-
methylsulfanyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanone:

[0164] Title compound was prepared following protocol D, wherein 4-Chloro-2-
methylthiopyrrimidine was used as the heteroaryl halide component: *H NMR (DMSO-d6,
400MHz) 8.16 (d, 1H), 6.87 (d, 1H), 5.41 (s, 2H), 3.90 (br m, 4H), 3.62 (m, 4H), 2.57 (s,
3H), 2.19 (s, 3H) ppm; MS (ES) expect M+Na = 435.1, found 435.0.
Synthesis of 2-(4-Chloro-5-methyI-3-trifluoramethyI-pyrazol-1-yl)-1-[4-(4,6-dimethoxy-
pyrimidin-2-yl)-piperazin-1-ylj-ethanone:

[0165] Title compound was prepared following protocol D, wherein 2-Chloro-4,6-
dimemoxypyrrimidine was used as the heteroaryl halide component: MS (ES) expect M+H =
449.1, found = 449.0; HPLC retention time = 4.92 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
Synthesis of 1-[4-(6-Chloro-5-methyl-pyridazin-3-yl)-piperazin-1-yI]-2-(4-chIoro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:


[0166] Title compound was prepared following protocol D, wherein 3,6-Dichloro-4-
methylpyridazine was used as the heteroaryl halide component: MS (ES) expect M+H =
437.1, found = 437.0; HPLC retention time = 4.17 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-1- [4-(5-methoxy-1-H-
benzoimidazol-2-yl)-piperazin-1-yl]-ethanone:

[0167] Title compound was prepared following protocol D, wherein 2-Chloro-5-
methoxybenzimidazole was used as the heteroaryl halide component: MS (ES) expect M+H =
457.1, found = 457.0; HPLC retention time = 2.85 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
Further functionalization of arylpiperazine ring system after its formal construction
[0168] Key compounds of the current invention have, in addition to other selected
substituents, a halogen atom at the 2- or 4-position. Approaches to install this are described
in the following section.
[0169] Functionalization of the aryl ring within the arylpiperazine ring system can, in
general, take place either before or after introduction of the piperazine ring, as illustrated in
the examples below.

PROTOCOL E: Selected examples of halogenation of aromatic systems after
attachment of the piperazine ring system
Synthesis of l-(4-Bromo-3-methoxy-phenyl)-piperazine hydrochloride:

[0170] To a solution of 2.33 g (8.8mmol)of l-(3-Methoxyphenyl)piperazine
dihydrochloride and 756 mg (9.7 mmol) sodium acetate in 70 mL of acetic acid and 15 mL of
water at 0°C was added 1.55 g (9.7 mmol) bromine. After 1 hour, the reaction was
concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M
NaOH. The phases were separated, and the ethyl acetate phase was washed once each with
water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in
vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was
acidified with 2M HC1 in ether. The product was isolated by filtration. !H NMR (D2O,
400MHz) 7.36 (d, 1H), 6.73 (s, 1H), 6.50 (d, 1H), 3.75 (s, 3H), 3.32 (m, 8H) ppm.
Synthesis of l-(4-Bromo-3-methyl-phenyl)-piperazine hydrochloride:

[0171] To a solution of 966 mg (4.0 mmol) of 1 -(3-Methylphenyl)piperazine
dihydrochloride in 9 mL of acetic acid and 1 mL of water at 0°C was added 640 mg
(4.0 mmol) of bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the
oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the
ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered,
and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum
volume of methanol, and the solution was acidified with 2M HC1 in ether. The product was
isolated by filtration. !H NMR (D20,400MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 3.37
(m,8H), 2.17 (s,3H) ppm.

Synthesis of l-(2-Chloro-5-methoxy-phenyl)-piperazine hydrochloride:

[0172] To a solution of 5.3 g (20 mmol)of l-(3-Methoxyphenyl)piperazine
dihydrochloride in 120 mL of acetic acid and 30 mL of water at 0°C was added 3.3 g (20
mmol) of N-chlorosuccinimide. After 5 hours, the reaction was concentrated to an oil in
vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were
separated, and the ethyl acetate phase was washed once each with water and brine, dried over
Na2SC>4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in
a minimum volume of methanol, and the solution was acidified with 2M HC1 in ether. The
product was isolated by filtration. 'H NMR (D20, 400MHZ) 7.28 (d, 1H), 6.66 (m, 3H), 3.70
(s, 3H), 3.32 (m, 4H), 3.20 (m, 4H) ppm.
Synthesis of l-(2,4-Dichloro-5-methoxy-phenyI)-piperazine hydrochloride:

[0173] To a solution of 530 mg (2.0 mmol) of l-(3-Methoxyphenyl)piperazine
dihydrochloride in 7 mL of acetic acid and 4 mL of water at 0°C was added 700 mg (4.4
mmol) of N-chlorosuccinimide. The reaction was taken out of the ice/water bath after 2
hours, and allowed to stir overnight. After 12 hours, the reaction was concentrated to an oil in
vacuo, and the oil was partitioned between ether and water. The phases were separated, the
aqueous was basificd with 1M NaOH, and was extracted with ethyl acetate. The ethyl acetate
phase was washed once each with water and brine, dried over Na2SCU, filtered, and the
filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of
methanol, the solution was acidified with 5M HC1 in isopropanol and was diluted with ethyl
acetate to effect crystallization. The product was isolated by filtration. 'H NMR (D2O,
400MHz) 7.38 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 3.19 (m, 4H) ppm.
Synthesis of l-(4-Chloro-5-Methoxy-2-methyl-phenyl)-piperazine


[0174] Following protocol E, to 90 mg (0.32 mmol) of l-(5-Methoxy-2-methyl-phenyl)-
piperazine hydrochloride in 1.3 mL of acetic acid and 1 mL of water at 0° C was added 58 mg
(0.36 mmol) of N-chlorosuctinimide. The reaction was allowed to warm to ambient
temperature over two hours, and after 14 hours it was concnentrated to a dark residue in
vacuo. The residue was partitioned between ether and water, and the phases were separated.
The aqueous phase was basified to pH > 10 with 1M NaOH, and was extracted twice with
ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over
Na2SO4 , filtered, and concentrated to an oil. The oil was dissolved in methanol, acidified
with 2 M HC1 in ether, and diluted with ether to give the product as a solid.
Synthesis of l-(4-Bromo-3-Methoxy-phenyl)-3-(S)-methyl-piperazine:

[0175] To 500 mg of S-(+)-3-methyl- Nl- (4-chloro -3- methoxy)phenylpiperazine (1.79
mmol, 1.0 eq) in 5 mL of 1:1 AcOH/DCM was added 91 uL Br2 (1.79 mmol, 1.0 eq) to the
stirring slurry. LC/ MS shows mixture of polyhalogenated species. Crude mixture purified
by preparative HPLC to get the titled intermediate.
Synthesis of l-(2,4-Dichloro-5-Methoxy-phenyl)-3-(S)-methyI-piperazine:

[0176] To 500 mg of S-(+)-3-methyl- Nl- (4-chloro -3- methoxy)phenylpiperazine (1.44
mmol, 1.0 eq) in 2 mL of 1:1 AcOH/DCM was added 85 mg NCS (0.64 mmol, 0.44 eq) to
the stirring slurry. LC/ MS shows mixture of polyhalogenated species. Crude mixture
purified by preparative HPLC to get the desired intermediate.

PROTOCOL Fl; Selected examples of demethvlation / etherification of aromatic
precursors for attachment of the piperazine ring system to access key arvlpiperazine
moieties
Synthesis of 3-Bromo-6-chlorophenol:

[0177] To 50 mL of a 1M solution of boron tribromide in CH2C12 at 0°C was added 5.71 g
(25.8 mmol) of 5-Bromo-2-chloroanisole. After 2 hours, the reaction was allowed to warm to
room temperature. After 5 hours, the solution was cooled to 0°C, and quenched with
methanol. The resulting solution was partitioned between water and ethyl acetate, and the
phases were separated. The aqueous phase was back-extracted once with ethyl acetate. The
combined ethyl acetate phases were diluted with one volume of ether, and were extracted
twice with 1 }A NaOH. The combined basic aqueous phases were acidified with 12M HC1,
and were extracted once with ethyl acetate. The final ethyl acetate phase was washed once
with brine, dried over MgSO4, filtered, and concentrated to give the phenol as a tan solid. !H
NMR(DMSO-rf5,400MHz) 10.66 (s, 1H), 7.27 (d, 1H), 7.08 (s, 1H), 6.95 (d, lH)ppm.
Synthesis of l-Bromo-3-isopropoxy-4-chlorobenzene:

[0178] To 1.70g (6.5 mmol) of triphenylphosphine in 25 mL of CH2C12 at 0°C was added
1.14 g (6.5 mmol) of diethylazodicarboxylate. After 10 minutes, 390 mg (6.5 mmol) of
isopropanol was added, followed rapidly by 1.03 g (5.0 mmol) of 3-Bromo-6-chlorophenol.
The reaction was complete within three hours, and was partitioned between ether and water.
The phases were separated, and the ether phase was diluted with hexanes and washed twice
with 10% aqueous methanol and once with brine. The ether/hexanes phase was dried over
Na2SO4, filtered, and concentrated in vacuo to yield product as a clear oil.

PROTOCOL F2: Additional examples of analogous ring systems constructed using
similar demethvlation / etherification strategies.

Synthesis of 2-chloro-5-bromo-O-(4-methylbenzenesulfonyl)benzyl alcohol:

[0179] To 1.0 g of 2-chloro-5-bromobenzyl alcohol (4.5 mmol, 1.0 eq) in 5 mL dry THF,
was added 200 mg 60% NaH/mineral oil dispersion (5.0 mmol, 1.1 eq), and the resulting
slurry was stirred under nitrogen for 0.5 hours. 900 mg portion of 4-methylbenzenesulfonyl
chloride (4.8 mmol, 1.05 eq) was added, and the mixture allowed to stir overnight for 12
hours. The reaction was poured into 25 mL aqueous K2CO3, and this was extracted with 2 X
10 mL of 20% Hexane/EtOAc. The aqueous phase was discarded, and the combined organic
phases were dried under vacuum to obtain a white crystalline solid.
Preparation of (2-ChIoro-5-piperazin-1-yl-benzyl)-methyI-carbamic acid benzyl ester:

[0180] To 200 mg of 2-chloro-5-bromo-O-(4-methylbenzenesulfonyl)benzyl alcohol (0.53
mmol, 1.0 eq) in 500 uL dry THF was added 230 mg of 60% NaH dispersion in mineral oil
(0.58 mmol, 1.1 eq), followed by 1.5 eq of the N-Cbz-methylamine. The mixture was heated
at 60°C overnight, and the crude products were purified by preperative HPLC to give (5-
Bromo-2-chloro-benzyl)-methyl-carbamic acid benzyl ester.
[0181] 500 mg of (5-Bromo-2-chloro-ben2yl)-methyl-carbamic acid benzyl ester (1.36
mmol), 303 mg (1.63 mmol) of N-Boc-piperazine, 182 mg (1.90 mmol) of NaOtBu, 27 mg

(0.1)4 mmol) of BINAP, and 12 mg (0.01 mmol) of Pd2Dba3 in 0.5 mL of toluene were heated
at 90°C overnight. The crude material was purified by prep HPLC to give 4-{3-
[(Benzyloxycarbonyl-methyl-amino)-niethyl]-4-chloro-phenyl}-piperazine-1-carboxylicacid
tert-butyl ester.
[0182] 220 mg of 4-{3-[(Benzyloxycarbonyl-methyl-amino)-methyl]-4-chloro-phenyl}-
piperazine-1-carboxylic acid tert-butyl ester was dissolved in 2 mL of a 1:2
TFA:dichloromethane solution. After 0.5 hour, the solvent and TFA are removed under
vacuum to give (2-Chloro-5-piperazin-1-yl-benzyl)-methyl-carbamic acid benzyl ester as an
oil.
Other Substituted arylpiperazines prepared using this procedure:

(2-Chloro-5-piperazin-1-yl-phenyI)-carbamic acid tert-butyl ester:

[0183] To 25 g (0.106 mol) of 4-bromo-1-chloro-2-nitrobenzene in 400 mL of methanol
was added 30g (0.528 mol) of iron powder. The mixture was heated to 50°C, and 45 g
(0.8456 mol) of ammonium chloride in 200 mL of water was slowly added. The reaction was
heated to 70°C over night, cooled to ambient temperature, and filtered through paper. The
filtrate was concentrated in vacuo, the residue was dissolved in water, and this was extracted
with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried
with Na2SO4, filtered, and concentrated to give 5-Bromo-2-chloroaniline.
[0184] To lOg (0.048 mol) of 5-bromo-2-chloroaniline in 300 mL of dry dichloromethane
was added 15 g (0.1452 mol) of triethylamine. The reaction was cooled to 0°C, and 13 g
(0.0581 mol) of Boc-anhydride was added. The reaction was warmed to ambient temperature,
and 6 g (0.048 mol) of DMAP was added. After 14 hours the solvent was removed in vacuo,

anfi the residue was purified by chromatography to give tert-butyl-5-bromo-2-chlorophenyl
carbamate as a pale orange solid.
(0185] Following protocol A, 5 g (0.02 mol) of tert-butyl-5-bromo-2-chlorophenyl
carbamate, 14 g (0.1628 mol) ofpiperazine, 8.6 g (0.025 mol) of cesium carbonate, 0.1 g
(0.0025 mol) of palladium acetate, and 0.1 g (0.002 mo-1) of BINAP in 5 mL of dry toluene
were heated at 110CC for 12 hours. After cooling to ambient temperature, the reaction was
quenched with water, and the mixture was extracted with ethyl acetate. The ethyl acetate
phase was washed with brine, dried with Na2SC>4, filtered, and concentrated. The residue was
purified by 60-120 silica gel using 0.5 % of methanol in chloroform, to give (2-Chloro-5-
pipera2in-1-yl-phenyl)-carbamic acid tert-butyl ester as a low melting solid.
l-(4-Chloro-3-methoxymethyl-phenyl)-piperazme:

[0186] 1 g (0.0045 mol) of 5-bromo-2-chlorobenzyl alcohol in dry THF was added to 0.4 g
(0.00032 mol) of sodium hydride in dry THF at 0°C, and the mixture was stirred at 0°C for 1
hour. 1.28 g (0.009 mol) of methyl iodide was added, and the reaction was allowed to warm
to ambient temperature. After stirring for 12 hours, the reaction was quenched with water,
and was extracted with ethyl acetate. The ethyl acetate phase was washed once each with
water and brine, dried with Na2SC>4, filtered, and concentrated to give 4-Bromo-1-chloro-2-
methoxymethyl-benzene.
[0187] Following protocol A, 0.98 g (0.0041 mol) of 4-bromo-1-chloro-2-methoxymethyl-
benzene, 0.35 g (0.0041 mol) ofpiperazine, 0.0466 g (O.0002 mol) of palladium acetate,
0.25 g (0.00041 mol) of BINAP, and 0.63 g (0.0066 mol, 1.6 eq) of sodium tert-butoxide in
10 mL of dry toluene were heated at 110°C under argon atmosphere for 24 hours. The
reaction mixture was quenched with water and extracted with ethyl acetate. The extract was
washed once each with water and brine, dried with Na2SO4, filtered, and concentrated. The
residue was purified by chromatography to give l-(4-Cliloro-3-methoxymethyl-phenyl)-
piperazine as a low melting solid.

l-C4-chloro-3-methoxy-pbenyl)-2-(R)-methyl-piperazine:

[0188] 2 g (0.02 mol) of R-(-)-2-methylpiperazine, 2.5 g (0.0197 mol) of benzylchloride,
and 5 g (0.0599 mol) of sodium bicarbonate in 25 mL of ethanol were heated to 85°C for 12
hours. After cooling, the reaction was filtered through paper, and the ethanol was removed
under vacuum. The residue was purified by chromatography to give l-Benzyl-3-(R)-methyl-
piperazine as a yellow liquid.
[0189] 1.2 g (0.0054 mol) of 5-bromo-2-chloroanisole, 1 g (0.0054 mol) of l-Benzyl-3-(R)-
methyl-piperazine, 0.06 g (0.00027 mol) of palladium acetate, 0.34 g (0.00054 mol) of
BINAP, and 0.83 g (0.0086 mol) of sodium tert-butoxide in dry toluene (5 mL) were heated
at 110°C for 48 hours. After cooling, the reaction mixture was quenched with water and
extracted with ethyl acetate. The ethyl acetate phase was washed with water, brine, dried with
Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give 4-
Benzyl-1-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine as a yellow semi solid.
[0190] 0.3 g (0.00091 mol, leq) of 4-Benzyl-1-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-
piperazine in 20 mL of dry 1,2-Dichloroethane was cooled to 0°C, 0.16 g (0.0011 mol) of 1-
chloroethylchloroformate was added drop wise, and the resulting mixture was stirred at 0°C
for 15 min. The mixture was then heated at 70°C for lhr, followed by removal of the 1,2-
Dichloroethane under vacuum. The residue was dissolved in 30 mL of methanol, and heated
at 65°C for 1 hr. The methanol was removed under vacuum, the residue was dissolved in 10
mL of water, and this was washed with ether twice. The aqueous phase was basified to pH> 9
using solid sodium bicarbonate, and was extracted with dichloromethane. The
dichloromethane phase was washed with brine, dried with Na2SC>4, filtered, and concentrated
to give l-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine as a low melting solid.

l-{4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazine:

[0191] This compound was prepared following the same procedure as that used to
synthesize l-(4-chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine, using 2-(S)-(+)-Methyl-
piperazine as the starting material, to give the title compound as a pale yellow semi solid.
Synthesis of 2-(R)-BenzyIoxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazlne:

[0192J Following protocol A, 818 mg (3.70 mmol) of 5-Bromo-2-chloroanisole, 1.15 g
(3.88 mmol) of l-Benzyl-3-(R)-benzyloxymethyl-piperazine, 0.50g (5.18 mmol) of sodium
tert-butoxide, 33 mg (0.037 mmol) of tris-dibenzylideneacetone-dipalladium(O), and 66 mg
(0.11 mmol) of rac-Binap in 2 mL of dry toluene were heated at 85°C for 6 hours. The
mixture was cooled to ambient temperature, and was partitioned between ethyl acetate and
water. The phases were separated, and the ethyl acetate phase was washed with brine, dried
over Na2SO4, filtered, and concentrated. The residue was chromatographed to give 4-Benzyl-
2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-piperazine.
[0193] 1.05 g (2.40 mmol) of 4-Benzyl-2-(R)-benzyloxymethyl-1-(4-chloro-3-methoxy-
phenyl)-piperazine in 50 mL of dichloromethane was cooled to 0°C, and 406 mg (2.88 mmol)
of 1-Chloroethyl chloroformate was added. The mixture was allowed to warm to ambient
temperature after 30 minutes, then was heated at 75°C in a sealed vessel for 3 hours. The
solution was then concentrated in vacuo, the residue was dissolved in 30 mL of methanol,
and the solution was heated at 60°C for 2 hours. The solution was concentrated in vacuo, and
the residue was partitioned between ethyl acetate and 1M NaOH. The phases were separated,
and the ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and
concentrated to give 2-(R)-Benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-pipera2dne.

Synthesis of [4-(4-Chloro-3-methoxy-phenyl)-piperazin-2-(S>yl]-methanol:

[0194] Following protocol A, 1.41 g (6.34 mmol) of 5-Bromo-2-chloroanisole, 2.04 g
(6.66 mmol) of N1-Boc-2-(R)-Benzyloxyraethyl-piperazineJ 0.85 g (8.86 mmol) of sodium
tert-butoxide, 28 mg (0.032 mmol) of tris-dibenzylideneacetone-dipalladium(O), and 58 mg
(0.095 mmol) of rac-Binap in 3 mL of dry toluene were heated at 90°C for 6 hours. The
mixture was cooled to ambient temperature, and was partitioned between ethyl acetate and
water. The phases were separated, and the ethyl acetate phase was washed with brine, dried
over Na2SC>4, filtered, and concentrated. The residue was chromatographed to give a white
foam.
[0195] The purified material from above was heated in 25 mL of 48% HBr in acetic acid at
75°C for 1 hour. The reaction was allowed to cool to room temperature, and was partitioned
between ether and water. The phases were separated, the aqueous phase was basified to pH >
10 with solid K2CO3, and was extracted twice with ethyl acetate. The combined ethyl acetate
phases were washed with brine, dried over Na2SC>4, fdtered, and was concentrated to give [4-
(4-Chloro-3-methoxy-phenyl)-piperazin-2-(S)-yl]-methanol as a tan solid.
Synthesis of l-(4-Chloro-2-fluoro-S-methoxy-phenyI)-piperazine:

[0196] 5.0 g (34.1 mmol) of 2-chloro-4-fluorophenol in 75 mL of 10% sodium hydroxide
was cooled to 0°C, and 4.0g (42.6 mmol) of methylchloroformate was added. After 45
minutes, the solids were isolated by filtration to give 2-chloro-4-fluoro-phenyl-methyl
carbonate.
[0197] To 6.0g (29.3 mmol) of 2-chloro-4-fluoro-phenyl-methyl carbonate in 3 mL of
concentrated sulfuric acid at 0°C was added 6 mL of nitrating mixture. After 45 minutes, the
reaction was quenched with ice-water, and the solids were isolated by filtration to give 2-
chloro-4-fluoro-5-nitrophenyl methyl carbonate.

[0198] To 7.0g (28.0 tnmol) of 2-cMoro-4-fluoro-5-nitrophenyl methyl carbonate in
100 mL of methanol at 0°C was added 75 mL of 0.5M NaOH. After 1 hour, the methanol was
removed in vacuo, the solution was acidified with 1.5M HC1, and was extracted with ethyl
acetate. The ethyl acetate phase was washed with water and brine, and concentrated to give 2-
chloro-4-fluoro-5-nitrophenol.
[0199] To 5.6 g (29.2 mmol) of 2-chloro-4-fluoro-5-nitrophenol in 250 mL of dry acetone
were added 21 g (146 mmol) of methyl iodide and 20g (146 mmol) of potassium carbonate,
and the mixture was heated at 55°C for three hours. The acetone was removed in vacuo, and
the residue was partitioned between ethyl acetate and water. The phases were separated, and
the ethyl acetate phase was washed with brine, and concentrated to give 2-chloro-4-fiuoro-5-
nitro-anisole.
[0200] To 4.5 g (22.2 mmol) of 2-chloro-4-fluoro-5-nitro-anisole in 75 mL of methanol
was added 6 g (11 mmol) of iron powder, the mixture was heated to 50°C, and 1 Og
(175 mmol) of ammonium chloride in 150 mL of water was added. The reaction was warmed
further to 70°C, and was stirred for 12 hours. The mixture was cooled to ambient
temperature, filtered through celite, and the filtrate was concentrated in vacuo. The residue
was partitioned between ethyl acetate and water, and the phases were separated. The ethyl
acetate phase was washed with brine, and was concentrated to give 4-Chloro-2-fluoro-5-
methoxy-aniline.
[0201] 3.0g (17.1 mmol) of 4-Chloro-2-fluoro-5-methoxy-aniline in 23 mL of hydrobromic
acid and 23 mL of water, and the solution was cooled to 0°C. To this was added 1.5 g
(21.4 mmol) of sodium nitrite in 2 mL of water. 9 g (36 mmol) of copper bromide was added
in 30 mL of 50% hydrobromic acid. After the addition, the mixture was heated to 55°C for
one hour. The mixture was cooled, and was extracted with ethyl acetate. The ethyl acetate
phase was washed once each with water and brine, and was concentrated to give 5-Bromo-2-
chloro-4-fluoroanisole.
[0202] 1.0g (4.2 mmol) of 5-Bromo-2-cWoro-4-fluoroanisole, 47 mg (0.21 mmol) of
palladium acetate, 180 mg (0.29 mmol) of binap, 0.65 g (6.7 mmol) of sodium tert-butoxide,
and 3.6 g (42 mmol) of piperazine in 3 mL of dry toluene werw heated at 110°C for 24 hours.
The reaction was partitioned between ethyl acetate and water, and the phases were separated.
The ethyl acetate phase was washed once each with water and brine, and was concnentrated.

The residue was purified by chromatography to give l-(4-Chloro-2-flxioro-5-methoxy-
phenyl)-piperazine.
Synthesis of l-(4-Chloro-3-methoxy-phenyl)-3-methoxymethyl-piperazine:

[0203] To 1.26 g (4.90 mmol) of [4-(4-Chloro-3-methoxy-phenyl)-piperazin-2-(S)-yl]-
methanol and 779 mg (6.37 mmol) of 2,4,6-collidine in 15 mL of dry N,N-
dimethylformamide at 0°C was added 1.18 g (5.40 mmol) of Di-tert-butyldicarbonate. The
reaction was allowed to warm to ambient temperature after two hours, and was stirred for 14
additional hours. The reaction was partitioned between water and ethyl acetate, and the
phases were separated. The ethyl acetate phase was washed once each with 1M NaHSO4,
water, brine, dried over Na2SO4, filtered, and concentrated to give 4-(4-Chloro-3-methoxy-
phenyl)-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester as an oil that
solidified on standing.
[0204] To 122 mg (0.34 mmol) of 4-(4-Chloro-3 -methoxy-phenyl)-2-(R)-hydroxymethyl-
piperazine-1-carboxylic acid tert-butyl ester and 57 mg (0.41 mmol) of methyl iodide in dry
N,N-dimethylformamide at 0°C was added 20 mg (0.48 mmol) of 60% sodium hydride in oil.
The reaction was allowed to warm to ambient temperature in ten minutes, and the reaction
was quenched with water after one hour. The mixture was extracted with ethyl acetate, and
the phases were separated. The ethyl acetate phase was washed with trine, dried over
Na2SO4, filtered, and concentrated to give 4-(4-Chloro-3-methoxy-phenyl)-2-
methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester as an oil.
[0205] The oil from above was dissolved in 1 mL of ethyl acetate and 1 mL of 5M HC1 in
isopropanol. After 10 hours, the solution was concentrated, and the residue was partitioned
between 1M NaOH and ethyl acetate. The phases were separated, and the ethyl acetate phase
was washed with brine, dried overNa2SO4, filtered, and concentrated to give l-(4-Chloro-3-
methoxy-phenyl)-3-methoxymethyl-piperazine.

Synthesis of 4-(4-Chloro-3-methoxy-phenyl)-piperazine-2-carboxylic acid (-)-menthol
est&r:

[0206] 8.75 g (43.4 mmol) of 2-piperazine carboxylic acid and 16.4 g (195 mmol) of
sodium hydrogencarbonate were dissolved in 140 mL of water, 140 mL of acetonitrile was
added, and the mixture was cooled to 0°C. To this was added 20.9 g (95.4 mmol) of Di-tert-
butyldicarbonate, and the mixture was allowed to warm to ambient temperature after 2 hours.
After stirring for twelve hours, the mixture was concentrated in vacuo to remove the
acetonitrile, and the mixture was washed with ether. The aqueous solution was acidified with
1M NaHSO4, and was extracted with ethyl acetate. The ethyl acetate phase was washed with
brine, dried over Na2SC>4, filtered, and concentrated to give Piperazine-1,2,4-tricarboxylic
acid 1,4-di-tert-butyl ester.
[0207] A solution of 13 g (39 mmol) of piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl
ester, 13.4 g (86 mmol) of (-)-menthol, and 940 mg (7.8 mmol) of 4-Tvf,N-Dimethylamino-
pyridine in 200 mL of dichloromethane was cooled to 0°C, and 8.90g (47 mmol) of 1-[3-
(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added. The solution was
allowed to warm to ambient temperature after two hours, and was stirred for an additional 12
hours. The reaction was concentrated in vacuo, and the residue was partitioned between ether
and water, and the phases were separated. The organic phase was washed once each with 1M
NaHSO4 and brine, dried over Na2SO4, filtered, and concentrated to give a semi-solid.
[0208] The semi-solid from above was dissolved in 300 mL of ethyl acetate, 100 mL of
dichloromethane, and 100 mL of 5M HC1 in isopropanol. After 20 hours, the solids were
isolated by filtration to give piperazine-2-carboxylic acid 2-(-)-menthol ester dihydrochloride.
[0209] 1.36 g (4.0 mmol) of piperazine-2-carboxylic acid 2-(-)-menthol ester
dihydrochloride, 803 mg (3.63 mmol) of 5-Bromo-2-chloroanisole, 1.09 g (11.4 mmol) of
sodium tert-butoxide, 62 mg (0.10 mmol) of rac-Binap, and 30-mg (0.034 mmol) of Tris-
dibenzylideneacetone dipalladium (O) were slurried in 5 mL of toluene, and the mixture was

heated at 80°C for 12 hours. The reaction was partitioned between ethyl acetate and water,
and the phases were separated. The ethyl acetate phase was washed once each with water,
brine, dried over Na2SC>4, filtered, and concentrated. The residue was chromatographed to
give 4-(4-Chloro-3-methoxy-phenyl)-piperazine-2-carboxylic acid (-)-menthol ester.
Synthesis of l-(4-Chloro-3-methoxy-phenyl)-3-(S)-(2-methanesulfonyl-ethyl)-piperazine:

[0210] l.OOg (3.99 mmol) of l-Benzyl-3-(S)-(2-methylsulfanyl-ethyl)-piperazine, and
81 mg (0.8 mmol) of triethylamine in 5 mL of dichloromethane were cooled to 0°C, and
1.05 g (4.79 mmol) of Di-tert-butyldicarbonate was added. After stirring for two hours, the
solution was allowed to warm to ambient temperature, and was stirred for an additional 12
hours. The reaction was partitioned between ether and water, and the phases were separated.
The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to
give l-Benzyl-3-(S)-(2-methylsulfanyl-ethyl)-4-tert-butoxycarbonylpiperazine as an oil.
[0211] 608 mg (1.74 mmol) of l-Benzyl-3-(S)-(2-methylsulfanyl-ethyl)-4-tert-
butoxycarbonylpiperazine was dissolved in 8 mL of dichloromethane, and the solution was
cooled to 0°C. To this was added 899 mg (5.21 mmol) of meta-Chloroperbenzoic acid, and
the mixture was allowed to warm to ambient temperature over one hour. The reaction was
partitioned between ethyl acetate and water, and the phases were separated. The organic
phase was washed with 1M NaOH, brine, dried over Na2SO4, filtered, and concentrated to
give l-Benzyl-3-(S)-(2-methylsulfonyl-ethyl)-4-tert-butoxycarbonylpiperazine as an oil.
[0212] 180 mg (0.47 mmol) of 1 -Benzyl-3-(S)-(2-methylsulfonyl-ethyl)-4-tert-
butoxycarbonylpiperazine in 2.5 mL of methanol was purged with nitrogen, 20 tug of 20%
Pd(OH)2 on carbon was added, and the mixture was stirred under a hydrogen atmosphere for
30 hours. The mixture wasflushed with nitrogen, filtered through celite, and concentrated to
give 3-(S)-(2-methylsulfonyl-ethyl)-4-tert-butoxycarbonylpiperazine as an oil.
[0213] 96 mg (0.33 mmol) of 3-(S)-(2-methylsulfonyl-ethyl)-4-tert-
butoxycarbonylpiperazine, 73 mg (0.33 mmol) of 5-Bromo-2-chloroanisole, 6 mg

(0.01 mmol) of rac-Binap, 3 mg(0.003 mmol) of Tris-benzylidineacetone dipalladium (O),
and 44 mg (0.46 mmol) of sodium tert-butoxide were slurried in 0.6 mL of toluene, and the
mixture was heated at 85°C for 8 hours. The reaction was partitioned between ethyl acetate
and water, and the phases were separated. The ethyl acetate phase was washed once each
with water, brine, dried over Na2SC>4, filtered, and concentrated. The residue was
chromatographed to give 4-(4-Chloro-3-methoxy-phenyl)-2-(S)-(2-methanesulfonyl-ethyl)-
piperazine-1-carboxylic acid tert-butyl ester.
[0214] 30 mg (0,07 mmol) of 4-(4-Chloro-3-methoxy-phenyl)-2-(S)-(2-methanesulfonyl-
ethyl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL of ethyl acetate,
and 0.5 mL of 5M HC1 in isopropanol was added. After 20 hours, the solids were isolated by
filtration to give l-(4-Chloro-3-methoxy-phenyl)-3-(S)-(2-methanesulfonyl-ethyl)-piperazine
as the hydrochloride salt.
Synthesis of l-(4-Chloro-3-methylsulfanyl-phenyl)-piperazine:

[0215] To 5-Bromo-2-chlorophenol (1.7 g, 0.0087 mol) in 9 mL of water was audded
potassium carbonate (0.5 g, 0.0087 mol), and the mixture was stirred for 15 min, then cooled
to 10° C. N,N-dimethylthiocarbamylchloride (1.4 g, 0.0117 mol) in 3 mL of THF was added,
the reaction was allowed to warm to ambient temperature, and was stirred for 2 hours. The
mixture was extracted with ethyl acetate, washed once each with water and brine, and
concentrated to give 0-(5-bromo-2-chlorophenyl) dimethylthiocarbamate as a yellow solid.
[0216] 0-(5-bromo-2-chlorophenyl) dimethylthiocarbamate (1.8 g, 0.0061 mol) in 60 mL
of diphenyl ether was heated to 260 °C over sand bath for 15 hours. The reaction was allowed
to cool to ambient temperature, and was directly loaded onto a bed of silica. The column was

eluted with petroleum ether to give S-(5-bromo-2-chlorophenyl)dimethylthiocarbaxnate as a
soli3.
[0217] To S-(5-bromo-2-chlorophenyl)dimethylthiocarbamate (0.5 g, 0.0022 mol) in 10
mL of ethylene glycol was added potassium hydroxide (0.19 g, 0.0033 mol) dissolved in 3
mL of water. The reaction was heated to 150 °C for 4 hours. The reaction was cooled to
ambient temperature, was quenched with water, and was extracted with ethyl acetate. The
ethyl acetate phase was washed once each with water and brine, and was concentrated to give
5-Bromo-2-chlorobenzenethiol as an off-white solid.
[0218] 5-B'romo-2-chlorobenzenethiol (0.34 g, 0.0015 mol), methyl iodide (1.1 g, 0.5 mL,
0.0075 mol), and dry potassium carbonate (0.64 g, 0.0045 mol) in 15 mL of dry acetone were
heated to 50° C for 9 hours. The solvent was removed in vacuo, and the residue was
dissolved in ethyl acetate, washed once each with water and brine, and concentrated to give
5-Bromo-2-chlorotiiioanisole as a yellow liquid.
[0219] 5-Bromo-2-chlorothioanisole (0.3 g, 0.0012 mol), piperazine (1.0 g, 0.012 mol),
palladium acetate (0.015 g, 0.00006 mol), BINAP (0.075 g, 0.00012 mol), and sodium tert-
butoxide (0.17 g, 0.0018 mol) in 5 mL of dry toluene were heated to 110° C under an argon
atmosphere for 18 hours. The reaction mixture was cooled to ambient temperature, quenched
with water, and extracted with ethyl acetate. The ethyl acetate phase was washed once each
with water and brine, and was concentrated to a residue. The residue was purified by column
chromatography, using 2 % methanol in chloroform, to give the l-(4-Chloro-3-
methylsulfanyl-phenyl)-piperazine as a low melting solid.
5-Chloro-4-methoxy-2-piperazin-1-yl-phenyIamine:

[0220] 17.5 g (0.09943 mol) of 2,5-dichloroanisole was dissolved in 4 mL of conc.sulfuric
acid, the solution was cooled to 0°C, and 18 mL of nitrating mixture (prepared by adding 9
mL of cone, sulfuric acid to 9 mL of nitric acid at 0°C) was added. The reaction was allowed
to warm to ambient temperature, and was stirred for 2 hours. The solids were isolated by
filtration, and were washed with pet ether to give 2,5-Dichloro-4-nitroanisole.

[0221] 5 g (0.0225 mol) of 2,5-Dichloro-4-nitroajoisole, 8.3 g (0.0450 mol) of mono-boc
piperazine, 7.7 g (0.056 mol) of dry potassium carbonate, and 0.2 g of TBAI in 100 mL of
dry DMSO was heated at 120°C for 10 hours. After cooling, the reaction mixture was
quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed
with water and brine, and concentrated. The residue was purified by chromatography to give
4-(4-Qiloro-5-methoxy-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
[0222] 5.3 g (0.0142 mol) of 4-(4-Chloro-5-meth.oxy-2-nitro-phenyl)-piperazine-1-
carboxylic acid tert-butyl ester and 5.4 mL (0.07 nxol) of trifluoroacetic acid in 100 mL of
dichloromethane were stirred over night. The reaction mixture was basified using 1M NaOlH,
and was extracted with dichloromethane. The dichloromethane phase was washed with water
and brine, dried over Na2SO4 and concentrated to give 4-(4-Chloro-5-methoxy-2-nitro-
phenyl)-piperazine.
[0223] To 3.5 g (0.012 mol) of 4-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperazine in
25 mL of methanol was added 0.4 g of 10 % palladium acetate, and the mixture was stirred
under 1 Atm. hydrogen for 15 minutes. The reaction mixture was filtered through Celite, and
concentrated. The residue was purified by column chromatography to give 5-Chloro-4-
methoxy-2-piperazin-1 -yl-phenylamine.
Synthesis of l-(4-oxazol-5-yl-phenyl)-piperazine:

[0224] To 4-Bromobenzaldehyde (1.0 g, 0.0054 mol) in 20 mL of dry methanol was added
the TOSMIC reagent (1.2 g, 0.0059 mol), followed by dry potassium carbonate (0.8 g, 0.0O58
mol). The reaction mixture was heated to 65 °C for 2 hours. The reaction mixture was
dissolved in ethyl acetate, washed once each with water and brine, and concentrated. The
residue was purified by column chromatography, vising 10% ethyl acetate in pet ether, to give
4-Bromo-oxazol-5-yl-benzene.
[0225] 4-Bromo-oxazol-5-yl-benzene (0.5 g, O.0>O23 mol), piperazine (1.9 g, 0.022 mol),
palladium acetate (0.026 g, 0.00011 mol), BESTAP (0.14 g, 0.00023 mol) and sodium tert-

butoxide (0.35 g, 0.0037 mol) in 5 mL of dry toluene were heated to 110 °C under an argon
atmosphere for 18 hours. The reaction mixture was cooled to ambient temperature, quenched
with water, and was extracted with ethyl acetate. The ethyl acetate phase was washed once
each with water and brine, and concentrated. The residue was purified by column
chromatography, using 2% of methanol in chloroform, to give l-(4-oxazol-5-yl-phenyl)-
piperazine as a yellow solid.
PROTOCOL Gl: General procedure for the synthesis of elaborated aryl bromides from
anilines
Synthesis of 4-Chloro-2-fluoro-1-bromobenzene

[0226] Sodium nitrite (2.35 g, 34.13 mmol) solution (40 mL) was added dropwise to 4-
Chloro-2-fluoro aniline (4.5 g, 31 mmol) in 170 mL HBr at -10°C bath temperature, then the
mixture was stirred for 30 min at -10°C bath temperature. In parallel, copper sulfate (10.22 g,
24.29 mmol) and sodium bromide (3.79 g, 36.8 mmol) were mixed and the reaction mixture
was heated at 60°C for 30 min. Then sodium sulfite (2.66 g, 21.2 mmol) was added into this
copper sulfate reaction mixture and heated for 95°C for 30 min. The reaction mixture was
cooled to room temperature and solid formed was washed with water to afford white solid
cuprous bromide. The diazonium salt was portion wise added into the freshly prepared
cuprous bromide in 40 mL HBr at -10°C bath temperature and the reaction mixture was then
warmed to room temperature. The reaction mixture was heated at 55°C for 20 min, cooled
and then extracted with ethyl acetate three times. The combined organic layer was washed
with water and saturated brine solution, dried over sodium sulfate and concentrated. The
crude material was purified by column chromatography (5:95 ethyl acetate: pet ether) to
afford solid product.

Synthesis of (2-Bromo-5-chloro-phenyl)-phenyl-methanone

[0227] Sodium nitrite (2.5 g, 36.28 mmol) solution (40 mL) was dropwise added to the
aniline (7 g, 30.2 mmol) in 100 mL HBr at -10°C bath temperature, then the mixture was
stirred for 30 min at -10°C bath temperature to make diazonium salt.
[0228] Copper sulfate (10.22 g, 24.29 mmol) and sodium bromide (3.79 g, 36.8 mmol) was
heated at 60°C for 30 min. Then sodium sulfite (2.66 g, 21.2 mmol) was added into copper
sulfate reaction mixture and heated for 95°C for 30 min. Then the reaction mixture was
cooled to rt and solid formed was washed with water to afford white solid cuprous bromide.
[0229] Diazonium salt was portion wise added into the freshly prepared cuprous bromide in
40 mL HBr at -10°C bath temperature and the reaction mixture warmed to room temperature.
Then the reaction mixture was heated at 55°C for 20 min, cooled to room temperature and
extracted with ethyl acetate three times. The combined organic layer was washed with water
and saturated brine solution, dried over sodium sulfate and concentrated. The product was
purified by crystallization from DCM/Pet ether.
PROTOCOL G2: Additional examples of analogous ring systems constructed using
similar Sandmeyer type strategies

[0230] These preceding aryl bromides and similar substrates were used in a variety of
chemistries, already described, to access arylpiperazines such as those listed below.



Synthesis of hcteroaromatic ring systems: core ring structure formation
[0231] The types of chemistries which can be applied to synthesize the key heteroaryl ring
structures are listed below. They are separated into examples of ring formation and ring
functionalization reactions.
PROTOCOL H: Pvrazole synthesis via addition of hydrazines to a,B-acetyIenic ketones
Synthesis of 5-Butyl-3-trifluoromethyl-1H-pyrazole

[0232] To a solution of 1-Hexyne (3.37 mL, 29.4 mmol) in THF (30 mL) was added n-
BuLi (2.78 M, 10.2 mL, 29.4 mmol). The solution was stirred at -78°C for 30 minutes then
CF3CC>2Et (3.5 mL, 29.35 mL) and BF3-OEt2 were added successively. The reaction was
further stirred at -78°C for 2h and was quenched with satd. NH4CI. It was then warmed up to
the room temperature. The THF was removed, the residue taken into ether, washed with
saturated brine solution, dried over Na2SO4 and reduced. The crude product was then
dissolved in benzene (25 mL) and hydrazine (29.4 mmol) was added. The reaction mixture
was refluxed overnight, then cooled, the solvent evaporated, and the residue taken into
CH2CI2 (30 mL), washed with brine, dried over Na2SO4 and concentrated to give the title
compound as colorless oil.

Synthesis of 5-isopropyl-3-trifluoromethyl-1H-pyrazole.
r
[0233] Following protocol H, 3 -methylbutyne was treated with n-BuLi, CF3CO2Et and
BF3-OEt2 in THF. Reaction with hydrazine in benzene under similar reaction conditions
yielded title compound.
Synthesis of 5-propyl-3-trifhioromethyl-1H-pyrazole.

[0234] Following protocol H, 1 -pentyne was treated with n-BuLi, CF3CO2Et and BF3-OEt2
in THF. Reaction with hydrazine in benzene under similar reaction conditions yielded title
compound.
Synthesis of 5-(3-Fluorophenyl)-3-trifluoromethyl-1H-pyrazole.

[0235] Following protocol H, 1 -Ethynyl-3-fluoro-benzene was treated with n-BuLi,
CF3CO2Et and BF3-OEt2 in THF. Reaction with hydrazine in benzene under similar reaction
conditions yielded title compound.
Other pyrazoles synthesized via this method:


PROTOCOL I: General procedure for the synthesis of pyrazoles via condensation of
hydrazines with B-diketones:
Synthesis of 5-ethyl-3-trifluoromethyl-1H-pyrazole

[0236] To a solution of 1,1,1 -Trifluoro-hexane-2,4-dione (1 g, 5.95 mmol) in absolute
ethanol (10 mL) was added NH2NH2.XH2O drop-wise at 0°C. The reaction mixture warmed
to the room temperature during 1 hour and refluxed overnight. Ethanol was then evaporated,
residue dissolved in ethyl acetate (20 mL), washed consecutively with saturated brine
solution and water, dried with Na2SO4 and concentrated to give the title compound as
colorless oil.
Synthesis of 4-Chloro-3-methyl-5-thiophen-2-yl-pyrazole:

[0237] To a solution of 2-acetyl-thiophene (5 g, 0.04 mol) in 200 mL of THF at -78°C was
added 24.5 mL of a solution of NaHMDS (0.05 mol) in hexane. After the addition was
complete, the reaction was kept at this temperature for lh. Acetyl chloride (3.4 g, 0.04 mol)
was then added dropwise, and the reaction mixture was then allowed to wa.rm to ambient
temperature, and stirring was continued for 2 hours. The reaction was quenched with
saturated NH4CI solution, and the THF was removed in vacuo. The aqueous mixture was
extracted with ethyl acetate, and the phases were separated. The ethyl acetate layer was
washed once each with water and brine, dried with Na2SO4, filtered, and concentrated. The
residue was purified by column chromatography to give the diketone.
[0238] The diketone (1.6 g, 9.5 mmol) was dissolved in ethanol (60 mL) and cooled to 0°C.
To this solution was added hydrazine hydrate (0.6 g, 11.4 mmol) dropwise with stirring.
After the addition was complete, the mixture was refluxed overnight. The ethanol was
evaporated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed
once each with water and brine, and dried over Na2SO4, filtered, and concentrated to give 3-
Methyl-5-thiophen-2-yl-pyrazole.

[0239] 3-Methyl-5-thiophen-2-yl-pyrazole (1.4 g, 8.5 mmol) was dissolved in 50 mL of
chloroform, and N-Chlorosuccinimide (1.6 g, 11.9 mmol) was added. The mixture was
stirred overnight at ambient temperature. The solution was washed with brine, dried over
Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by chromatography to
give4-Chloro-3-methyl-5-thiophen-2-yl-pyrazole.
PROTOCOL J: Pyrazole synthesis via condensation of hydrazines with B-Cvanoketones
Synthesis of 5-Phenyl-1-pyrazol-3-amine

[0240] 2.0 g (0.0138 mol, 1 eq) of benzoylacetonitrile in 40 mL of absolute ethanol was
added 2.0 g (0.0399 mol, 3eq) of anhydrous hydrazine and the reaction mixture stirred at
85°C for 2 h. Ethanol was removed at 50 °C under vacuum. 5-Phenyl-1-pyrazol-3-amine,
obtained as a yellow solid, was washed with pet ether (100 mL) and dried under vacuum.
Synthesis of functionalized heteroaryl ring systems
Chlorination or bromination of Pyrazoles


PROTOCOL K: chlorination of pyrazoles with NaOCl in glacial Acetic acid
Synthesis of 4-Chloro-1H-pyrazole.

[0241] To a solution of pyrazole (0.5 g, 7.34 mmol) in glacial acetic acid (4 mL) was
added NaOCl (0.55 g, 7.34 mmol). The reaction mixture was left at room temperature for
18h, then neutralized with saturated Na2CO3 solution, extracted with CH2CI2 (2 x 25 mL), the
combined organic layers evaporated, then diluted with NaOH, and further extracted with
CH2CI2 (3 X 20 mL). The organic extracts were combined, dried over Na2SC>4 and
evaporated to give the title compound as a white solid.
Synthesis of 4-Chloro-3-trifluoromethyl-1H-pyrazole

[0242] Following protocol K, 3-trifluoromethylpyrazole was treated with glacial acetic acid
and NaOCl, yielding title compound.
Synthesis of 4-Chloro-3-methyl-1H-pyrazole.

[0243] Following protocol K, 3-methylpyrazole was treated with glacial acetic acid and
NaOCl, yielding title compound.
Synthesis of 4-Chloro-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester.

[0244] Following protocol K, 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester was
treated with glacial acetic acid and NaOCl under similar reaction conditions, yieliding the

title compound.
PROTOCOL L: chlorination or bromination of pyrazoles with N-chlorosuccinimide
fNCS) or N-bromosuccinimide fiVBS):
Synthesis of 4-Chloro-3-methyI-5-trifiuoromethyl-1H-pyrazole

[0245] 3-methyl-5-trifluoromethylpyrazole or 3,5-bistrifluoromethylpyrazole was taken
into dry DMF (20 mL) and N-chloro succinimide (1.78 g) was added in portions. The
mixture was then heated at 70°C for 22 h, cooled to room temperature, and then water
(100 mL) was added and the mixture extracted with ethyl acetate (4X25 mL). The organic
layer was washed with water and brine and dried witii Na2SC>4. Evaporation of the solvent
afforded the title compounds.
Other halogenated pyrazoles prepared using protocol L
Synthesis of 4-Chloro-5-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole:

[0246] Following protocol L, 5-(4-Fluorophenyl)-3-trifluoromethyl-1-H-pyrazole was
treated with NCS in acetonitrile to yield the title compound.

Synthesis of 4-Chloro-5-(4-methoxy-phenyl)-3-trifluoromethyl-1H-pyrazole:

[0247] Following protocol L, 5-(4-methoxyphenyl)-3-trifluoromethyl-l -H-pyrazole was
treated with NCS in acetonitrile to yield the title compound.
Synthesis of 4-Chloro-5-(4-trifluoromethyl-phenyl)-3-trifluoromethyl-1H-pyrazole:

[0248] Following protocol L, 5-(4-trifluoromethyl-phenyl)-3-trifluoromethyl-1 -H-pyrazole
was treated with NCS in acetonitrile to yield the title compound.
Synthesis of 4-Chloro-5-(2-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole:

[0249] Following protocol L, 5-(2-fluoro-phenyl)-3-trifluoromethyl-l -H-pyrazole was
treated with NCS in acetonitrile to yield the title compound.
Synthesis of (4-Chloro-S-trifluoromethyl-2H-pyrazol-3-yl)-methanol:

[0250] Following protocol L, (5-trifluoromethyl-2H-pyrazol-3-yl)-methanol was treated
with NCS in acetonitrile to yield the title compound.

Synthesis of 4-Chloro-5-methoxymethyl-3-trifluoromethyMH-pyrazole:
>-
[0251] Following protocol L, 5-methoxymethyl-3-trifluoromethyl-1H-pyrazole was treated
with NCS in acetonitrile to yield the title compound.
Synthesis of 4-Chloro-5-cyclopropyI-3-trifluoromethyl-1H-pyrazoIe:

[0252] Following protocol L, 5-cyclopropyl-3-trifluoromethyl-1H-pyrazole was treated
with NCS in acetonitrile to yield the title compound.
Syntheses of 4-Chloro-5-thiophen-2-yI-2H-pyrazole-3-carboxylic acid ethyl est&r

[0253] Pyrazole(leq) in DMF (0.14M Solution) was treated with NCS (1.5 eq.) in portions,
and when all the NCS was dissolved in the reaction mixture, it was then heated at 70°C
overnight. The reaction mixture was then cooled to rt and quenched with water, extracted
with ethyl acetate and dried in MgSC>4. Two products were isolated, including the title
compound
Synthesis of 4-Chloro-3,5-diisopropyl-pyrazoIe


[0254] Following protocol L, a the solution of 3, 5-diisopropyl-pyrazole (0.5 g, 3.57
mmol) in DMF (10 mL) was added NCS (0.72 g, 5.3 mmol) in portions under vigorous
stirring. The reaction mixture was then heated at 80°C for 14h and then the reaction was
quenched with water. It was then extracted with ethyl acetate (2 x 30 mL). The combined
organics were washed with brine. The organic extracts were combined and dried with
Na2SO4 and finally evaporated to give the title compound as colorless oil.
Synthesis of 4-Chloro-3-thiophen-2-yl-1H-pyrazoIe.

[0255] Following protocol L, 3-thiophen-2-yl-1 H-pyrazole was treated with NCS in DMF.,
to yield title compound.
Synthesis of 5-tert-Butyl-4-chloro-3-trifIuoromethyl-1H-pyrazole.
+
[0256] Following protocol L, 5-tert-butyl-3-trifluoromethyl-1H-pyrazole was treated with
NCS in DMF to yield title compound.
Synthesis of 4-Chloro-3-methyMH-pyrazole-5-carboxylic acid ethyl ester.

[0257] Following protocol L, 3-methyl-2H-pyrazole-5-carboxylic acid ethyl ester was
treated with NCS in DMF to yield the title compound.
Synthesis of 4-Chloro-3-thiophen-2-yl-1H-pyrazoIe-5-carboxylic acid ethyl ester.

[0258] Following protocol L, 3-Thiophen-2-yl-1H-pyrazole-5-carboxylic acid ethyl ester
was treated with NCS in DMF to yield the title compound.

Synthesis of 4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylic acid ethyl
>-
ester.

[0259] Following protocol L, 3-Thiophen-2-yl-1 H-pyrazole-5-carboxylic acid ethyl ester
was treated with NCS in DMF under to yield the title compound.
Synthesis of 4-Chloro-3-(4-fluoro-phenyl)-5-methylsulfanyl-1H-pyrazoIe.

[0260] Following protocol L, 3-(4-fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole was
treated with NCS in to yield the title compound.
Synthesis of 5-Butyl-4-chloro-3-trifluoromethyl-1H-pyrazole.

[0261] Following protocol L, 5-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS
in DMF to yield the title compound.
Synthesis of 4-Chloro-5-phenyI-1-pyrazol-3-amine

[0262] Following protocol L, to 0.5 g (0.0031 mol, leq) of 5-phenyl-1-pyrazol-3-amine in
25 mL of dry acetonitrile was added 0.4 g (0.0031 mol, leq) of N-chlorosuccinimide portion
wise and the reaction mixture stirred at room temperature for 30 min. The reaction mixture
was quenched with water and extracted with ethyl acetate. The organic layer was washed
with water, brine and concentrated. The product was purified by 60-120 silica gel column
(1% of methanol in chloroform).

Synthesis of 4-Bromo-5-phenyl-1-pyrazol-3-amine
y

[0263] Following protocol L, to 0.5 g (0.0031 mol, leq) of 5-phenyl-1-pyrazol-3-amine in
25 mL of dry acetonitrile was added 0.55 g (0.0031 mol, leq) of N-bromosuccinimide
portion wise and the reaction mixture stirred at room temperature for 30 min. The reaction
mixture was quenched with water and extracted with ethyl acetate. The organic layer was
washed with water, brine and concentrated. The product was purified by 60-120 silica gel
column (1% of methanol in chloroform).
Synthesis of 4-Chloro-5-isopropyl-3-trifluoromethyIpyrazole.

[0264] Following protocol L, to the solution of 3-trifluoromethyl- 5-isopropyl-pyrazole
(0.22 g, 1.23 mmol) in CH3CN (10 mL) was added NCS (0.19 g, 1.43 mmol) in portions
with vigorous stirring. The reaction mixture was then heated under reflux for 14h, cooled
and the reaction quenched with saturated NaHCO3, extracted with methylene chloride (2x30
mL) and the combined organic extracts was washed with brine, dried with NaiSC^ and
evaporated to give the title compound as a white solid.
Synthesis of 4-chIoro-5-Ethyl-3-trifluoromethyl-1H-pyrazoIe.

[0265] Following protocol L, 5-ethyl-3-trifluoromethyl-1H-pyrazole was treated with NCS
in CH3CN to yield title compound
Synthesis of 4-chloro-5-propyl-3-trifluoromethyl-1H-pyrazoIe.


10266] Following protocol L, 5-propyl-3-hifluoromethyl-1H-pyrazole was treated with
NCS in CH3CN to yield the title compound.
Synthesis of4-chloro-5-(3-fluorophenyl)-3-trifluoromethyI-1H-pyrazole.

[0267] Following protocol L, 5-(3-fluorophenyl )-3-trifluoromethyl-1H-pyrazole was
treated with NCS in CH3CN to yield the title compound.
Synthesis of 4-chIoro-3,5-bistrifIuoromethyI-1H-pyrazoIe.

[0268] Following protocol L, 3,5-bistrifluoromethyl-1H-pyrazole was treated with NCS in
CH3CN to yield the title compound.
Synthesis of N-(4-Chloro-5-methyl-1 H-pyrazoI-3-yI)-2,2,2-trifluoro-acetamide.

[0269] Following protocol L, 2,2,2-Trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide was
treated with NCS in CH3CN to yield the title compound.
PROTOCOL M: General procedure for reduction of Nitropyrazoles
Synthesis of 3-Heptafluoropropyl-5-methyl-1H-pyrazoI-4-ylamine.

[0270] To a suspension of zinc dust (1.5 g) in glacial acetic acid (10 mL) was added drop-
wise, a solution of 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole (0.295 g, 1.0 mmol)
in glacial acetic acid (5 mL). The reaction mixture was then allowed to stir at room
temperature for 14h. The zinc salts were then removed by filtration and the residue washed
with ethyl acetate. The combined organic extract was concentrated in vaccum, re-dissolved

in CHCI3, washed with NaHCO3, water and brine. Finally the organic layer was dried with
Na2SO4 and solvent evaporated to give the title compound as white solid.
Synthesis of Bromo-pyrazoles for aryl-aryl cross coupling reactions and for metal
mediated animations

General procedure for trifluoroacetvlation of aminopyrazoles:
Synthesis of 2,2,2-Trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide.

[0271] To a solution of 3-amino-5-methylpyrazole (0.97 g, 10 mmol) and Et3N (1.39 mL,
10 mmol) in dioxane (25 mL) was added Trifluoroacetic anhydride (TFAA) (1.39 mL, 10
mmol) drop-wise at 10°C. The reaction mixture was stirred at that temperature for lh then
slowly warmed to room temperature through next lh. Once the reaction is over dioxane was
evaporated, residue resolved in water (20 mL), washed with methylene chloride (30 mL).
Organic layer was then dried with Na2SO4 and concentrated to give the title compound as
white solid.

PROTOCOL N: Functionalization of allcvl substituted heteroaryl ring systems:
aminomethylation
Synthesis of (5-Bromomethyl-4-chloro-3-methyI-pyrazol-1-yl)-acetic acid ethyl ester

Reagents and Conditions: i) BrCffeCOzEt/KaCOj/CHjCN; ii) NBS/AIBN/CCU
[0272] 4-CHoro-3-methyl-5-trifluoromethyl-1H-pyrazole, (lOg, 54 mmol) was dissolved in
acetonitrile (100 mL) and potassium carbonate (30g, 0.215 mol) added. After stirring at room
temperature for 1 hour, ethyl bromoacetate (11 g, 65 mmol) was added. After 14h at 70°C,
the mixture was filtered and the filtrate was concentrated to obtain the crude product, which
was re-crystallized from petroleum ether.
[0273] This intermediate ester (5 g, 0.019 mol) was taken in CCL, (100 mL) and AIBN
(0.053 g, 0.33 mmol) was added to it under nitrogen. The mixture was irradiated with a
regular light bulb. The mixture was brought to reflux and then NBS (3.42 g, 0.019 mol), in
four portions in 15 min intervals, was added to the mixture. After complete addition the
mixture was left refluxing under the influence of light for 3h. The reaction mixture was then
filtered and the filtrate was washed with water and brine. Drying the organic layer (Na2SC>4)
followed by evaporation of the solvent afforded (5-Bromomethyl-4-chloro-3-trifluoromethyl-
pyrazol-1 -yl)-acetic acid ethyl ester.
PROTOCOL O: Synthesis of (5-Azidomethyl-4-chloro-3-trifluoromethvl-pyrazol-1-yn-
acetic acid;

[0274] To 4.6 g (13.2 mmol) of(5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid ethyl ester dissolved in 40 mL of anhydrous dimethylformamide was added
1.03 g (15.8 mmol) of sodium azide. After stirring for 12 hours, the solution was partitioned
between ethyl acetate and water. The phases were separated, the aqueous phase was back-

extracted with ethyl acetate and the combined ethyl acetate phases were washed with water
and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield an orange oil.
[0275] The oil was dissolved in 25 mL of tetrahydrofuran, 25 mL of 1M NaOH was added,
and the mixture was stirred vigorously for three hours. The tetrahydrofuran was then removed
in vacuo, and the aqueous solution was washed once with ether. The aquous phase was then
acidified with 1M HC1, and extracted twice with ethyl acetate. The combined ethyl acetate
phases were washed with brine, dried over Na2SO4, filtered, and concentrated to yield the
title compounds as an orange solid.
t
Coupling of pvrazolyl systems with carboxylic acid equivalents
[0276] The following synthesis is an example of this type of chemistry: additional
examples (procedure N) have been described above.
Synthesis off4-Chloro-3-methyI-5-trifhuoromethylpyrazoI-1-yl)-acetic acid

Reagents and conditions: BrCH2CO2Et/K2CO3/CH3CN, then LiOH/THF
[0277] 4-Chloro-3-methyl-5-trifiuoromethylpyrazole (lOg, 0.0539 mol) was taken up in
acetonitrile (100 mL) and K2CO3 (30g, 0.213 mol) was added to it. The mixture was stirred
at rt for lh and ethyl bromoacetate (11 g, 0.065 mol) was added slowly to it. The mixture
was then stirred for 12h at 70°C. The mixture was filtered and the filtrate was concentrated to
get a crude mixture. This crude product was re-crystallized from pet ether to obtain the
corresponding ester
[0278] The ester (14.8 g, 0.0565 mol) was dissolved in THF (100 mL) and a solution of
LiOH (6.9 g) in water (50 mL) was added to it. The mixture was stirred for lOh at room
temperature. Excess THF was evaporated under reduced pressure and the aqueous layer was
washed with ethyl acetate to remove any unhydrolysed material. The aqueous layer was then
acidified with 1.5N HCl and extracted with ethyl acetate. The ethyl acetate layer was dried
and concentrated to obtain the crude acid. On re-crystallization from ether/petroleum ether,

the product was obtained as white crystals.
PROTOCOL P; Couplings of arvlpiperazincs with pyrazolyl-acetic acid derivatives -
compounds prepared by HATU mediated coupling;
Synthesis of 2-(5-Azidomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yI)-1-[4-(4-
chlorophenyl)-piperazin-1-yl]-ethanone:

[0279] To 2.71 g (13.7 mmol) of l-(4-Chlorophenyl)piperazine and 3.58 g (12.5 mmol) of
(5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid in 40 mL of anhydrous
dimethylformamide was added 4.36 mL (31.2 mmol) of triethylamine. The solution was
cooled to 0°C, and 5.21 g (13.7 mmol) of OK7-AzabenzotriazoM-yl)-N,N,N\N'-
tetramethyluronium hexafluorophosphate (HATU) was added. After 2 hours the reaction was
diluted with two volumes of water, and the solvent was decanted away from the resulting oil.
The oil was crystallized by dissolving in methanol and adding water in small portions. The
product was isolated as a white solid by filtration: 'H NMR (DMSO-d6,400MHz) 7.23 (d,
2H)5 6.97 (d, 2H), 5.48 (s, 2H), 4.62 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H) ppm;
MS (ES) M+H expected = 462.1, found = 462.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,5-dimethyl-
phenyl)-piperazin-1-yl]-ethanone

[0280] To 38 mg (0.20 mmol) of 1 -(2,5-Dimethylphenyl)piperazine and 53 mg
(0.22 mmol) of (4-Chloro-5-methyl-3-trifiuoromethyl-pyrazol-1-yl)-acetic acid in 1.6 mL of
anhydrous dimethylformamide was added 62 mg (0.6 mmol) of triethylamine, followed by
84 mg (0.22 mmol) of 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium

hexafluorophosphate (HATU). After 6 hours, the reaction was partitioned between ethyl
Y
acetate and water, and the phases were separated. The aqueous phase was back-extracted
once with ethyl acetate, and the combined ethyl acetate phases were washed once each with
0.5M pH = 7 phosphate buffer, water, 1M NaOH, water, brine. The ethyl acetate phase was
then dried over Na2SC>4, filtered, and concentrated to a residue in vacuo. The residue was
dissolved in a minimum volume of 5M HC1 in isopropanol, and was precipitated by diluting
the solution with ethyl acetate. The product was isolated by filtration to give a white solid: LH
NMR (DMSO-d6,400MHz) 7.07 (d 1H), 6.90 (s, 1H), 6.82 (d, 1H), 5.39 (s, 2H), 3.66 (m,
4H), 2.98 (m, 2H), 2.89 (m, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H
expected = 415.1, found 415.1.
Examples of additional compounds prepared by HATU mediated coupling:
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-methoxy-
phenyl)-piperazin-1-ylJ-ethanone:

[0281] Title compound was prepared following protocol P, wherein l-(3-
methoxyphenyl)piperazineand(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic
acid were used as the coupling components, to give the product as a white solid: 'H NMR
(DMSO-d6, 400MHz) 7.15 (t, 1H), 6.65 (d, 1H), 6.60 (s, 1H), 6.47 (d, 1H), 5.38 (s, 2H), 3.72
(s, 3H), 3.65 (m, 4H), 3.28 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect =
417.1, found = 417.1.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-I4-(4-chloro-
phenyl)-2-(R)-methyI-piperazin-1-yl]-ethanone:

[0282] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chlorophenyl)-3-(R)-methylpiperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a white solid: 'H NMR (CDC13, 300MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H),
4.28 (m, 1H), 3.80-3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm;
MS (ES) expect M+H = 435.1, found 435.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazoI-1-yl)-1-(4-o-toIyl-
piperazin-1-yl)-ethanone:

[0283] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: *H NMR
(DMSO-rfo; 400MHz) 7.14 (m, 2H), 6.98 (m, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 2.89 (m, 2H),
2.81 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expect = 401.1, found = 401.1.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-
phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone:

[0284] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chlorophenyl)-3-(5)-methylpiperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: *H NMR (CDC13, 300MHZ) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28
(m, 1H), 3.80-3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm; MS
(ES) M+H expected = 435.1, found = 435.0.
Synthesis of 2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(5-fluoro-2-
methoxy-phenyl)-piperazin-1-yi]-ethanone

[0285] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Methoxy-5-fiuorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: *H NMR (DMSO-eW, 400MHz) 6.93 (m, 1H), 6.77 (m, 3H), 5.36 (s, 2H), 3.77 (s, 3H),
3.59 (m, 4H), 3.07 (m, 2H), 2.98 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect 435.1,
found 435.0.

Synthesis of 2-{4-chloro-3-methyl-5-trifluoromethyl-pyra2oH-yl}-1-[4-(3-
Methylsulfanyl-phenyl)-piperazin-1-yl]-ethanone

[0286] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Methylthiophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DIVISOR, 400MHz) 7.21 (t, 1H), 6.98 (s, 1H), 6.91 (d, 1H), 6.81 (d, 1H),
5.39 (s, 2H), 3.68 (m, 4H), 3.34 (m, 2H), 3.24 (m, 2H), 2.44 (s, 3H), 2.19 (s, 3H) ppm; MS
(ES) M+H expect 433.1, found 433.0.
Synthesis of 1-[4-(4-Bromo-phenyl)-piperazin-1-yl]-2-(4-chIoro-S-methyl-3-
trifluoromethyl-pyrazol-lyl)-ethanone:

[0287] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Bromophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: 'H NMR
(DMSO-rftf, 400MHz) 7.36 (d, 2H), 6.92 (d, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H),
3.14 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect = 465.0, found = 465.0.

Synthesis of 2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(23-dimethyl-
phenyl)piperazin-1-yl]-ethanone

[0288] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2t3-Dimethylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSO-rfo", 400MHz) 7.04 (t, 1H), 6.99 (m, 2H), 5.38 (s, 2H), 3.64 (m, 4H),
2.89 (m, 2H), 2.81 (m, 2H), 2.21 (m, 9H) ppm; MS (ES) M+H expect 415.1, found 415.1.
Synthesis of 2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazoI-1-yI)-1-[4-(2-chIoro-5-
methoxy-phenyl)-piperazin-1-yl]-ethanone
(.■
[0289] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Chloro-5-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)~acetic acid were used as the coupling components, to give the product as a
solid: !H NMR (DMSO-d6,400MHz) 7.31 (d, 1H), 6.65 (m, 2H), 5.37 (s, 2H), 3.73 (s, 3H),
3.62 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect = 451.1,
found = 451.0.

Synthesis of 1-[4-(4-Bromo-3-raethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0290] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Bromo-3-methoxyphenyl)piperazine and (4-CMoro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSO-d6,400MHz) 7.34 (d, 1H), 6.71 (s,lH), 6.52 (d, 1H), 5.39 (s, 2H),
3.82 (s, 3H), 3.62 (m, 4H), 3.30 (m, 2H), 3.20 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 495.0, found = 495.0.
Synthesis of 2-(4-Chloro-5-methyl-3-triiluoromethyl-pyrazoH-yl)-1-[4-(2,4-dichloro-
phenyl)-piperazin-1-yl]-ethanone:

[0291] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2,4-Dichlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: lH NMR (DMSO-^, 400MHz) 7.56 (s, 1H), 7.36 (d, 1H), 7.15 (d, 1H), 5.37 (s, 2H),
3.61 (m, 4H), 3.01 (m, 2H), 2.94 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect 455.0,
found = 454.9.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-raethoxy-
pyridin-2-yl)-piperazin-1-yl]-ethanone:

10292] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'HNMRCDMSO-^, 400MHZ) 7.92 (d, 1H), 6.67 (s 1H), 6.63 (d, 1H), 5.42 (s, 2H),
3.96 (s, 3H), 3.88 (m, 2H), 3.73 (m, 4H), 3.62 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 418.1, found = 418.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-dimethyl-
phenyI)-piperazinl-yl]-ethanone:

[0293] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3,4-Dimethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'HNMR CDMSO-ctf, 400MHz) 7.03 (d, 1H), 6.94 (br s, 1H), 6.84 (br s, 1H), 5.38 (s,
2H), 3.68 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 6H), 2.14 (s, 3H) ppm; MS (ES) M+H
expected = 415.1, found = 415.1.

Synthesis of 2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(4-
trifluoromethoxy-phenyl)-piperazin-1-yl]-ethanone

[0294] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Trifluoromethoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: !H NMR (DMSO-d6,400MHz) 7.20 (d, 2H), 7.04 (d, 2H), 5.38 (s, 2H),
3.60 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected =
471.1, found = 471.0.
Synthesis of 2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-5-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0295] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2,4-Dichloro-5-methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluorornethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: *H NMR (DMSO-rftf, 400MHz) 7.50 (s, 1H), 6.84 (s, 1H), 5.37 (s, 2H),
3.85 (s, 3H), 3.62 (m, 4H), 3.07 (m, 2H), 3.00 (tn, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 485.1, found = 485.0.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-nitro-phenyl)-
piperazin-1-yl]ethanone:

[0296] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Nitrophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyra2ol-1-
yl)-acetic acid were used as the coupling components, to give the product as a yellow solid:
'H NMR (DMSO-d6, 400MHz) 8.05 (d, 2H), 7.01 (d, 2H), 5.38 (s, 2H), 3.62 (m, 6H), 3.52
(m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H = 432.1, found = 432.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-2-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0297] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-2-methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: !H NMR (DMSO-J5, 400MHz) 7.02 (s, 1H), 6.93 (m, 2H), 5.36 (s, 2H),
3.82 (s, 3H), 3.60 (m, 4H), 3.03 (m, 2H), 2.95 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 451.1, found = 451.0.
Synthesis of 1-[4-(4-Bromo-3-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:


[0298] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Bromo-3-rnethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifmoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: !HNMR (DMSO-d 3.60 (m, 4H), 3.26 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 479.0, found = 478.9.
Synthesis of 1-[4-(4-Acetyl-phenyl)-piperazin-1-yI]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanoiie:

10299] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Acetyl-phenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: !H NMR
(DMSO-d6, 400MHz) 7.80 (d, 1H), 6.98 (d,2H), 5.38 (s, 2H), 3.61 (m, 4H), 3.48 (m, 2H),
3.39 (m, 2H), 2.46 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 429.1, found =
429.0.
Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-dichloro-
phenyl)-piperazin-1-yl]-ethanone:

[0300] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3,4-Dichlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSO-d6,400MHz) 7.40 (d, 1H), 7.16 (s, 1H), 6.95 (d, 1H), 5.37 (s, 2H),

3.59 (m, 4H), 3.31 (m, 2H), 3.21 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected =
'455.0, found = 455.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-chloro-
phenyl)-piperazin-lyl]-ethanone:

[0301] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 1 -(3-Chlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: 'H NMR
(DMSO-dd, 400MHz) 7.23 (t, 1H), 7.19 (s, 1H), 6.90 (d, 1H), 6.79 (d, 1H), 5.37 (s, 2H), 3.58
(m, 4H), 3.29 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 421.1,
found = 421.p.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-m-tolyl-
piperazin-1-yl)-ethanone

[0302] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Methylphenyl)piperazine and (4-Chloro-5-methy]-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: 'H NMR
(DMSO-d6, 400MHz) 7.17 (t, 1H), 6.97 (br, 2H), 6.77 (d, 1H), 5.39 (s, 2H), 3.68 (m, 4H),
3.31 (m, 2H), 3.22 (m, 2H), 2.27 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 401.1,
found = 401.1.

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-etirianone:

[0303] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chlorc-3-methoxyph.enyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSO-d6,400MHz) 7.21 (d, 1H), 6.74 (s,lH), 6.56 (d, 1H), 5.39 (s, 2H),
3.82 (s, 3H), 3.63 (m, 4H), 3.30 (m, 2H), 3.19 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 451.1, found 451.0.
Synthesis of 4-{4- [2-(4-Chloro-5- methyI-3-trifluoromethyl-pyrazol-1 -yl)-acetyl] -
piperazin-1-yl}-benzoic acid methyl ester:

[0304] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 4-Piperazin-1-yl-benzoic acid methyl ester and (4-Chloro-5-methyl-3-
trifIuoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: *H NMR (DUSO-d6,400MHz) 7.78 (d, 2H), 6.98 (d, 2H), 5.38 (s, 2H),
3.71 (s, 3H), 3.60 (m, 4H), 3.46 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect
M+H = 445.1, found 445.0.

Synthesis of 2-(4-Chloro-3,5-dimethyl-pyrazol-1-yl)-1-(4-pyridin-4-yl-piperazin-1-yl)-
ethanone

[0305] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetic acid were used as the coupling components, to give the product as a solid: lH NMR
(DMSO-d6, 400MHz) 8.28 (d, 2H), 7.18 (d,2H), 5.41 (s, 2H), 3.83 (m, 2H), 3.72 (m, 4H),
3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 388.1, found = 388.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-t4-(5-methoxy-2-
methyl-phenyl)-piperazin-1-yl]-ethanone

[0306] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Methoxy-5-methylphenyl)piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: !H NMR (DMSO-rfo", 400MHz) 7.06 (d, 1H), 6.56 (m,2H), 5.38 (s, 2H),
3.69 (s, 3H), 3.62 (m, 4H), 2.92 (m, 2H), 2.84 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H
expected = 431.1, found = 431.1.

Synthesis of 2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-(4-phenyl-
piperazin-1-yl)-ethanone:

[0307] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 1-Phenylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic
acid were used as the coupling components, to give the product as a solid: *H NMR (DMSO-
d6,400MHz) 7.32 (m 4H), 7.02 (m, 1H), 5.40 (s, 2H), 3.74 (m, 4H), 3.39 (m, 2H), 3.29 (m,
2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H = 387.1, found 387.1.
Synthesis of 1-[4-(4-ChIoro-3-ethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0308] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-ethoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: *H NMR (DMSO-, 400MHz) 7.20 (d, 1H), 6.66 (s,lH), 6.48 (d, 1H), 5.38 (s, 2H),
4.08 (q, 2H), 3.61 (m, 4H), 3.25 (m, 2H), 3.16 (m, 2H), 2.18 (s, 3H), 1.33 (t, 3H) ppm; MS
(ES) M+H expected - 465.1, found 465.0.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-pyridm-2-yl-
piperazin-1-yl)-ethanone:

[03091 Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetic acid were used as the coupling components, to give the product as a solid: *H NMR
(DMSO-J5,400MHz) 8.11 (d, 1H), 7.53 (t, 1H), 6.85 (d,lH), 6.65 (t, 1H), 5.37 (s, 2H), 3.59-
3.50 (m, 8H), 2.18 (s, 3H) ppm; MS (ES) MH-H expected = 388.1, found = 388.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-1-(4-p-tolyl-
piperazin-1-yl)-ethanone:

[0310] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: lH NMR
(DUSO-d6,400MHz) 7.20 (m, 4H), 5.40 (s, 2H), 3.79 (m, 4H), 3.37 (m, 2H), 3.28 (m, 2H),
2.49 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 401.1, found 401.0.

Synthesis of 1-[(4-Methanesulfonyl-phenyl)-piperazine-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0311] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Methanesulfonyl-phenyl)-piperazine and (4-Chloro-5-methyl-3-trinuoromethyl-
pyrazoI-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: XH NMR (DMSO-cW, 400MHz) 7.69 (d, 2H), 7.08 (d,2H), 5.38 (s, 2H), 3.59 (m, 4H),
3.49 (m, 2H), 3.38 (m, 2H), 3.09 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 465.1,
found = 465.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-1-[4-(4-chloro-
phenyl)-piperazin-1-yl]-ethanone.

[0312] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chlorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid:'H NMR
(CDC13) 400 MHz) 7.22 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.77 (m, 2H), 3.72 (m, 2H), 3.19
(m, 2H), 3.16 (m, 2H), 2.28 (s, 3H) ppm; MS (ES) M+Na expected - 443.0, found 443.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1- [4-(4-methoxy-
phenyl)-piperazin-1-yl]-ethanone.

[0313] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-

l-yl)-acetic acid were used as the coupling components, to give the product as a solid: *H
NMR (CDC13> 400 MHz) 6.88 (m, 4H), 5.00 (s, 2H), 3.78 (m, 3H), 3.76 (m, 2H), 3.70 (m,
2H), 3.08 (m, 4H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected = 439.0, found 439.0.
Synthesis of 4-{4-[2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-acetyl]-
piperazin-1-yl}-benzonitrile

[0314] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Cyanophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: 'H NMR
(CDC13, 400MHz) 7.44 (d, 2H), 6.77 (d, 2H), 4.90 (s, 2H), 3.67 (m, 4H), 3.29 (m, 4H), 2.22
(s, 3H) ppm; MS (ES) M+Na expected = 434.0, found 434.0.
Synthesis of 2-(4-Chloro-5-methyI-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-fluoro-
I:
phenyl)-piperazin-1-yl]-ethanone

[0315] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Fluorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: 'H NMR
(CDCI3,400 MHz) 7.02 (m, 4H), 5.00 (s, 2H), 3.80 (m, 2H), 3.70 (m, 2H), 3.53 (m, 2H),
3.25 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected = 427.0, found 427.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1- [4-(2-methoxy-
phenyl)-piperazin-1-yl]-ethanone


[0316] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-
l-yl)-acetic acid were used as the coupling components, to give the product as a solid: *H
NMR (CDCI3,400 MH2) 6.62 (m, 1H), 6.48 (m, 3H), 5.01 (s, 2H), 3.73 (s, 3H), 3.61 (m,
4H), 3.43 (m, 2H), 2.31 (s, 3H) ppm; MS (ES) M+H expected = 439.0, found 439.1.
Synthesis of 2-(4-ChIoro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-
trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone.

[0317] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Trifluoromethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluorornethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (CDC13,400 MHz) 7.38 (m, 1H), 7.11 (m, 3H), 5.00 (s, 2H), 3.79 (m, 2H),
3.73 (m, 2H), 3.27 (m, 2H), 3.23 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+H expected =
455.0, found 455.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazoI-1-yl)-1-(4-pyrimidin-2-yI-
piperazin-1-yl)-ethanone:

[0318] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Pyrimidinyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yl)-acetic acid were used as the coupling components, to give the product as a solid: MS (ES)
M+H expected = 389.1, found = 389.0; HPLC retention time = 3.99 minutes (Agilent Zorbax
SB-C18,2.1X50 mm, 5|i, 35°C) using a4.5 minute gradient of 20% to 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-
3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0319] Title compound was prepared following the HATU mediated coupling protocol P5
wherein l-(4-Chloro-3-isopropoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: *H NMR (DMSO-d 5.38 (s, 2H), 4.66 (m, 1H), 3.58 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 3H), 1.26 (d,
6H) ppm; MS (ES) M+H expected = 479.1, found = 479.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1- [4-(3,4-difluoro-
phenyl)piperazin-1-yl]-ethanone

[0320] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3,4-Difluorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: JH NMR (DMSO-rftf, 400MHz, not F-decoupled) 7.25 (q, 1H), 7.04 (m,lH), 6.74 (d,
1H), 5.37 (s, 2H), 3.57 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H
expected = 423.1, found 423.0.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yi)-1-l4-(6-methoxy-
pyridin-2-yl)-piperazin-1-ylJ-ethanone

[0321] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(6-Methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-rnethyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSCK/5, 400MHZ) 7.45 (t, 1H), 6.34 (d,lH), 6.05 (d, 1H), 5.37 (s, 2H),
3.77 (s, 3H), 3.50 (m, 6H), 3.34 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected = 418.1,
found = 418.0.
Synthesis of 4-{4-[2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-
piperazin-1-yl}-N,N-dimethyl-benzenesulfonamide:

[0322] Title compound was prepared following the HATU mediated coupling protocol P,
wherein N,N-Dimethyl-4-piperazin-1-yl-benzenesulfonamide and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-J5,400MHz) 7.54 (d, 2H), 7.08 (d, 2H), 5.38 (s, 2H),
3.62 (m, 4H), 3.48 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected =
494.1, found = 494.0.

Synthesis of 1-[4-(4-Chloro-3-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifiuoromethyl-pyrazol-1-yl)-ethanone

[0323] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSO-i6,400MHz) 7.25 (d, 1H), 7.05 (s,lH), 6.90 (d, 1H), 5.38 (s, 2H),
3.64 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H
expected = 435.1, found = 435.0.
Synthesis of 2-(4-ChIoro-5-methyl-3-trifluoromethyI-pyrazol-1-yI)-1-[4-(3-hydroxy-
phenyl)-piperazin-1-yI]-ethanone

[0324] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Hydroxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-
l-yl)-acetic acid were used as the coupling components, to give the product as a solid: *H
NMR (DMSO-d6,400MHz) 7.10 (t, 1H), 6.66 (m,2H), 6.45 (d, 1H), 5.39 (s, 2H), 3.74 (m,
4H), 3.33 (br, 2H), 3.24 (br, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 403.1, found
403.0.

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-
' trifluoromethyl-phenyl)-piperazin-1-yI]-ethanone

[0325] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Trifluromethylphenyl)-piperazine and (4-ChIoro-5-methyl-3-trifluoromethyl-
pyrazol-1 -yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'HNMR (DMSO-d 3.41 (m, 2H), 3.31 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected = 455.1, found =
455.0.
Synthesis of 2-(4-Chloro-S-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(3-meth.yl-4-m-
tolyl-piperazin-1-yl)-ethanone:

[0326] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Methylphenyl)-2-methyl-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: !H NMR (DMSO-J6,400MHz) 7.68 (br, 1H), 7.17 (br, 1H), 6.71 (br, 2H), 5.41 (m,
2H), 4.08 (m, 4H), 3.70 (m, 2H), 3.50 (br m, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 1.01 (m, 3H)
ppm; MS (ES) M+H expected = 415.1, found = 415.1.

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperaziu-1-yl]-2-(4-chloro-
5-methyL-3-trifluoromethyl-pyrazoH-yl)-ethanone:

[0327] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxyphenyl)-3-(S)-methyl-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-d6, 400MHz, 95°C) 5 7.16 (d, 1H), 6.62 (s, 1H), 6.48 (d,
1H), 5.26 (br, 2H), 3.65 (m, 1H), 3.53 (m, 1H), 3.01 (m, 4H), 2.84 (m, 1H), 2.21 (s, 3H), 1.29
(d, 3H) ppm; MS (ES) M+H expect = 465.1, found = 465.0.
Synthesis of 1-[4-(4-Chloro-3-methylsulfanyl-phenyl)-piperazin-1-ylJ-2-(4-chIoro-5-
methyI-3-trifluoromethyl-pyrazol-1-yI)-ethanone:
I:
[0328] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methylsulfanyl-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifiuoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-d6,400MHz) 5 7.27 (m, 1H), 6.81 (m, 2H), 5.40 (s,
2H), 3.64 (m, 4H), 3.31 (m, 2H), 3.21 (m, 2H), 2.50 (s, 3H), 2.92 (s, 3H) ppm; MS (ES) M+H
expect = 467.0, found = 467.0.

Synthesis of 1-[4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifiuoromethyl-pyrazol-1-yl)-ethanone:

[0329] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(3-Trifluoromethoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give tlie
product as a solid: !H NMR (DMSO-J6,400MHz) 5 7.33 (t, 1H), 6.99 (m, 1H), 6.90 (s, 1H),
6.76 (m, 1H), 5.39 (s, 2H), 3.62 (m, 4H), 3.33 (m, 2H), 3.23 (m, 2H), 2.19 (s, 3H) ppm; MS
(ES) M+H expect = 471.0, found = 471.0.
Synthesis of 2-(4-ChIoro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-oxazol-5-yI-
phenyl)-piperazin-1-yl]-ethanone:

[0330] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-oxazol-5-yl-phenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: 'H NMR (DMSO-d6, 400MHz) 8 8.34 (s, 1H), 7.59 (d, 2H), 7.48 (s, 1H), 7.07 (d, 2H),
5.40 (s, 2H), 3.63 (m, 4H), 3.35 (m, 2H), 3.25 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H
expect = 454.0, found = 454.0.

Synthesis of l-{4-(3-Chloro-4-methoxy-naphthalen-1-yl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0331] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 1-[4-(3-Chloro-4-methoxy-naphthalen-]-yl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-d6,400MHz) 6 8.22 (m, 1H), 8.07 (m, 1H), 7.64 (m,
2H), 7.13 (s, 1H), 5.43 (s, 2H), 3.91 (s, 3H), 3.73 (m, 4H), 3.10 (m, 2H), 3.01 (m, 2H), 2.21
(s, 3H) ppm; MS (ES) M+H expect = 501.0, found = 501.0.
Synthesis of 2-(5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazoI-1-yl)-1-[4-(4-chloro-
3-methoxy-phenyl)-piperazin-1-yl]-ethanone:

10332] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 1-[4-(4-chloro-3-methoxy-phenyl)-piperazine and (5-Azidomethyl-4-Chloro-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: *H NMR (DMSO-d6, 400MHz) S 7.21 (d, 1H), 6.71 (d, 1H), 6.53 (dd,
1H), 5.50 (s, 2H), 4.64 (s, 2H), 3.80 (s, 3H), 3.62 (m, 4H), 3.29 (m, 2H), 3.18 (m, 2H) ppm;
MS (ES) M+H expect = 492.0, found = 492.0.

Synthesis of 1-[4-(5-Bromo-6-methoxy-pyridin-2-yl)-piperazin-1-yl]-2-(4-chloro-5-
■ methyl-3-trifluoromethyI-pyrazol-1-yl)-ethanone:

[0333] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(5-Bromo-6-methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-d6, 400MHZ) 7.69 (d, 1H), 6.37 (d, 1H), 5.39 (s, 2H),
3.87 (s, 3H), 3.62 (m, 4H), 3.55 (m, 4H), 2.20 (s, 3H) pm; MS (ES) M+H expect = 496.0,
found = 496.0.
Synthesis of 1-[4-(4-Chloro-5-methoxy-2-methyl-phenyl)-piperazin-1-yI]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0334] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-5-methoxy-2-methyl-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: MS (ES) M+H expect = 465.0, found = 465.0; HPLC retention time = 5.27
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5p, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(5-Chloro-4-methoxy-pyridin-2-yl)-piperazin-1-yl]-2-(4-chloro-5-
'metihyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0335] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(5-Chloro-4-methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-
trifiuoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-ctf, 400MHz) 6 8.13 (m, 113), 6.92 (m, 1H), 5.38 (s,
2H), 3.91 (s, 3H), 3.62 (m, 4H), 3.29 (m, 2H), 3.21 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H
expect = 452.0, found = 452.0.
Synthesis of 1-[4-(3-tert-Butoxycarbonylamino-4-chloro-phenyl)-piperazin-1-yI]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0336] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(34ert-Butoxycarbonylamino-4-chloro-phenyl)-pipera_zine and (4-Chloro-5-
methyl-3-trifiuoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to
give the product as a solid: 'H NMR (DMSO-d6,400MHz) S 8.43 (s, 1H), 7.25 (s, 1H), 7.21
(m, 1H), 6.78 (m, 1H), 5.39 (s, 1H), 3.62 (m, 4H), 3.22 (m, 2H), 3.13 (m, 2H), 2.19 (s, 3H),
1.45 (s, 9H) ppm; MS (ES) M+H expect = 536.0, found = 536.0.

Synthesis of l-{4-[4-Chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazin-1-yl}-2-(4-chloro-5-
' meiiiyl-3-trifluoromethyl-pyrazol-1-yI)-ethanoiie:

[0337] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 1-[4-Chloro-3-(2-ethoxy-ethoxy)-phenyl]-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (CDC13,400MHz) 5 7.22 (d, 1H), 6.57 (s, 1H), 6.45 (d, 1H), 4.99
(s, 2H), 4.17 (t, 2H), 3.84 (t, 2H) 3.77 (t, 2H), 3.71 (t, 2H), 3.64 (q, 2H), 3.16 (m, 4H), 2.30
(s, 3H), 1.25 (t, 3H) ppm; MS (ES) M+H expect = 449.0, found = 449.0.
Synthesis of 1-[4-(2-Amino-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazoI-1-yI)-ethanone:

[0338] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2-Amino-4-chloro-5-methoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (CDC13, 400MHz) 5 6.79 (s, 1H), 6.59 (s, 1H), 5.00 (s, 2H), 3.82
(s, 3H), 3.70 (m, 4H), 2.92 (m, 4H), 2.31 (s, 3H) ppm; MS (ES) M+H expect = 449.0, found
= 449.0.

Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyi-pyrazol-1-yl)-ethanone:

[0339] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluorometKyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: !H NMR (400 MHz, CDC13) 5 7.11 (d, 1H), 6.50 (d, 1H), 5.02 (s, 2H),
3.87 (s, 3H), 3.83-3.74 (m, 4H), 3.14-3.08 (m, 4H), 2.31 (s, 3H) MS (ES) (M+H) expected =
469.1, found = 469.0
Synthesis of 1-[4-(4-Bromo-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-
bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:
1.
[0340] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Bromo-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (4-Bromo-5-methyl-3-
trifluoromethyl-pvrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: [H NMR (400 MHz, CDCI3) 5 7.37 (d, 1H), 6.42 (s, 1H), 6.37 (d, 1H),
5.00 (s, 2H), 3.89 (s, 3H), 3.60-2.90 (m, 7H), 2.32 (s, 3H), 1.41 (d, 3H); HPLC retention time
= 7.25 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5p, 35°C) using a 2.0 starting isocratic
period, followed by a 5.0 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B
(A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile), and a final 2.5 minute isocratic period at 95%B.

Synthesis of 1-[4-(2,4-Dichloro-5-methoxy-phenyl)- piperazin-1-yl]-2-(4-bromo-5-
m^thyl-3-trifluoromethyl-pyrazoI-1-yI)-ethanone:

[0341] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2,4-dichloro-5-methoxy-phenyl)-piperazine and (4-Bromo-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (400 MHz, CDC13) 5 7.38 (s, 1H), 6.55 (s, 1H), 5.02 (s, 2H), 3.89
(s, 3H), 3.82- 3.73 (m, 4H), 3.08- 3.02 (m, 4H), 2.33 (s, 3H); HPLC retention time = 7.72
minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 starting isocratic
period, followed by a 5.0 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B
(A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile), and a final 2.5 minute isocratic period at 95%B.
Synthesis of 1-[4-(2,4-Dichloro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-
bromo-5-methyl-3-trifluoromethyI-pyrazoI-1-yl)-ethanone:

[0342] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2,4-dichloro-5-methoxy-phenyl)-3-(S)-methyl-piperazine and (4-Bromo-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to
give the product as a solid: ^ NMR (400 MHz, CDC13) 5 7.40 (s, 1H), 6.55 (s, 1H), 4.99 (d,
2H), 3.90 (s, 3H), 3.54- 2.73 (m, 7H), 2.32 (s, 3H), 1.52 (d, 3H); HPLC retention time - 7.92
minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 starting isocratic
period, followed by a 5.0 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B

(A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
' ace%nitrile), and a final 2.5 minute isocratic period at 95%B.
Synthesis of 1-[4-(4-Chloro-3-ethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0343] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-ethyl-phenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a
solid: lH NMR (DMSO-do",400MHz) 8 7.26 (m, 1H), 7.03 (, 1H), 6.90 (m, 1H), 5.40 (d, 2H),
3.64 (m, 4H), 3.29 (m, 2H), 3.20 (m, 2H), 2.64 (q, 2H), 2.20 (s, 3H), 1.16 (t, 3H) ppm; MS
(ES) M+H expect = 449.0, found = 449.0.
Synthesis of 2-(4-Chloro-5-meth.yl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fIuoro-2-
methoxy-phenyl)-piperazin-1-yl]-ethanone:

r
[0344] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Fluoro-3-methoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: JH NMR (DMSO-d6,400MHz) 6 7.01 (m, 1H), 6.93 (m, 1H), 6.73 (m,
1H), 5.38 (s, 2H), 3.83 (s, 3H), 3.63 (m, 4H), 3.06 (m, 2H), 2.97 (m, 2H), 2.19 (s, 3H) ppm;
MS (ES) M+H expect = 435.0, found = 435.0.

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazin-1-yl]-2-(4-
ch|oro-5-methyl-3-trifluoromethyl-pyrazoI-1-yI)-ethanone:

[0345] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-2-(R)-methyl-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (DMSO-d6,400MHz) 5 7.21 (m, 1H), 6.65 (m, 1H), 6.52 (m,
1H), 5.53 (m, 1H), 5.27 (m, 1H), 4.22 (m, 1H), 3.85 (s, 3H), 3.80-3.49 (m, 4H), 3.10-2.83 (m,
2H), 2.19 (s, 3H), 1.38-1.10 (m, 3H) ppm (mixture of rotomers); MS (ES) M+H expect =
465.0, found = 465.0.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(S)-(2-methanesulfonyl-ethyl)-
piperazin-1-yl]-2-(4-chIoro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0346] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-3-(S)-(2-methanesulfonyl-ethyl)-piperazine and (4-
Chloro-5-methyl-3-trifiuoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling
components, to give the product as a solid: ]H NMR (DMSO-d6,400MHz) 8 7.20 (m, 1H),
6.67 (m, 1H), 6.52 (m, 1H), 5.49 (m, 1H), 5.37 (m, 1H), 4.75 (m, 1H), 4.21 (par.obsc.m, 1H),
3.83 (s, 3H), 3.81-3.65 (m, 4H), 3.41 (m, 1H), 3.06 (m, 1H), 2.95 (s, 3H), 2.81 (m, 1H), 2.26
(m, 1H), 2.19 (s, 3H), 2.05 (m, 1H) ppm (rotamers); MS (ES) M+H expect = 557.0, found =
557.0.

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazin-1-yl]-2-
(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0347] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazine and (4-Chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to
give the product as a solid: 'H NMR (DMSO-d6, 400MHz) 8 7.21 (d, 1H), 6.66 (m, III), 6.52
(m, 1H), 5.50 (m, 1H), 5.32 (m, 1H), 5.24 (t, 1H), 4.22 (m, 1H), 4.06 (m, 1H), 3.84 (s, 3H),
3.83-3.63 (m, 4 H), 3.04-2.62 (m, 3H), 2.17 (s, 3H) ppm (rotamers); MS (ES) M+H expect =
481.0, found = 481.0.
Synthesis of 1-[4-(4-Chloro-3-dimethylaminomethyl-phenyl)-piperazin-1-yl]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazoI-1-yI)-ethanone:

[0348] Title compound was prepared following the HATU mediated coupling protocol P,
wherein (2-Chloro-5-piperazin-1-yl-benzyl)-dimethyl-amine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: *H NMR (CDC13,400MHz) 8 7.32 (d, 1H), 7.25 (s,' 1H), 6.88 (dd, 1H),
5.01 (s, 3H), 4.88 (s, 2H), 4.35 (s, 2H), 3.75 (t, 2H), 3.65 (t, 2H), 3.25 (t, 2H), 3.20 (t, 2H),
2.86 (s, 6H) ppm; MS (ES) M+H expect = 481.0, found = 481.0.

Synthesis of (2-ChIoro-5-{4- [2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-
acetyl]-piperazin-1-yl}-benzyl)-methyl-carbamic acid benzyl ester:

[0349] Title compound was prepared following the HATU mediated coupling protocol P,
wherein (2-Chloro-5-piperazin-1-yl-benzyl)-methyl-carbamic acid benzyl ester and (4-
Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling
components, to give the product as a solid: MS (ES) M+H expect = 481.0, found = 481.0.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yi)-1-{4-[4-chloro-3-(2-
morpholin-4-yl-ethoxy)-phenyl]-piperazin-1-yl}-ethanone:

[0350] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 1-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-piperazine and (4-Chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to
give the product as a solid: 'H NMR (DMSO-etf, 400MHz) 5 7.27 (d, 1H), 6.79 (m, 1H), 6.60
(m, 1H), 5.41 (s, 2H), 4.48 (m, 2H), 4.01 (m, 2H), 3.75 (m, 2H), 3.62 (m, 8H), 3.30 (par obsc
m, 6H), 3.20 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H expect = 550.0, found = 551.1.

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-3-(R)-methyl-piperazin-1-yl]-2-(4-
chloro-5-methyl-3-trifiuoromethyl-pyrazol-1-yl)-ethanone:

[0351] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-3-(R)-methyl-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (CDC13,400MHz) 5 7.25 (s, 1H), 6.55 (d, 1H), 6.47 (d, 1H),
5.07- 4.91 (m, 2H), 3.88 (s, 3H), 3.76- 3.13 (m, 5H), 2.30 (s, 3H), 1.01 (q, 3H) ppm (mixture
of rotomers); MS (ES) M+H expect = 465.0, found = 465.0.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazin-1-yl]-2-(4-chloro-
5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0352] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (CDC13,400MHz) 8 7.25 (s, 1H), 6.55 (d, 1H), 6.47 (d, 1H),
5.07- 4.91 (m, 2H), 3.88 (s, 3H), 3.76- 3.13 (m, 5H), 2.30 (s, 3H), 1.01 (q, 3H) ppm (mixture
of rotomers); MS (ES) M+H expect = 465.0, found = 465.0.

Synthesis of 1-[4-(4-Chloro-3-methoxymethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0353] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-niethoxymethyl-phenyl)-piperazine and (4-Chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the
product as a solid: 'H NMR (CDC13,400MHz) 5 7.25 (s, 1H), 7.05 (d, 1H), 6.78 (dd, 1H),
4.99 (s, 2H), 4.52 (s, 2H), 3.75 (dt, 4H), 3.48 (s, 3H), 3.21 (dt, 4H), 2.30 (s, 3H) ppm; MS
(ES) M+H expect = 465.1, found = 465.0.
Synthesis of2-(5-Aminomethyl-4-chIoro-3-trifluoromethyl-pyrazoi-1-yl)-1-[4-(2,4-
dich!oro-5-methoxy-phenyl)-piperazin-1-yl]-ethanone:

[0354] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(2,4-dichloro-5-methoxy-phenyl)-piperazine and (5-Azidomethyl-4-chloro-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components. Following
completion of the coupling reaction, a 10-fold excess of Tin (II) chloride was added directly
to the reaction, and stirring was continued for an additional 4 hours. The reaction was
purified by reverse-phase HPLC to give the product: 'H NMR (400 MHz, CDCI3) 8 7.38 (s,
1H), 6.73 (d, 2H), 6.56 (s, 1H), 5.32 (d, 2H), 4.41 (d, 2H) 3.89 (s, 3H), 3.80- 3.73 (m, 4H),
3.37- 3.02 (m, 4H); HPLC retention time = 5.83 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 2.0 starting isocratic period, followed by a 5.0 minute gradient
of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile), and a final 2.5 min isocratic period
at 95%B.

Synthesis of 2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-Bromo-
3-methoxy-phenyi)-piperazin-1-yl]-ethanone:

[0355] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Bromo-3-methoxy-phenyl)-piperazine and (5-Azidomethyl-4-chloro-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components. Following
completion of the coupling reaction, a 10-fold excess of Tin (II) chloride was added directly
to the reaction, and stirring was continued for an additional 4 hours. The reaction was
purified by reverse-phase HPLC to give the product: !H NMR (400 MHz, CDC13) 5 7.53 (d,
1H), 6.82 (s, 1H), 6.68 (d, 1H), 5.35 (s, 2H), 4.41 (s, 2H), 3.93 (s, 4H), 3.90 (s, 3H), 3.52-
3.39 (m, 4H); HPLC retention time = 5.44 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5|i,
35°C) using a 2.0 starting isocratic period, followed by a 5.0 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile), and a final 2.5 min isocratic period at 95%B.
Synthesis of 2-(5-AminomethyI-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-Chloro-
2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-ethanone:

[0356] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazine and (5-Azidomethyl-4-chloro-
3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components.
Following completion of the coupling reaction, a 10-fold excess of Tin (II) chloride was
added directly to the reaction, and stirring was continued for an additional 4 hours. The
reaction was purified by reverse-phase HPLC to give the product: rH NMR (400 MHz,

CDC13) 8 7.10 (d, 1H), 6.48 (d, 1H), 5.33 (s, 2H), 4.39 (s, 2H)5 3.85 (s, 3H), 3.78 (m, 4H),
3t05 (m, 4H) MS (ES) (M+H) expected = 484.1, found = 484.0
Synthesis of 2-(5-Aminomethyl-4-chloro-3-trifluoromethyI-pyrazol-1-yl)-1-[4-(4-Chloro-
3-inethoxy-phenyI>2-(S)-methyl-piperazin-1-yl]-ethanone:

[0357] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (5-Azidomethyl-4-
chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components.
Following completion of the coupling reaction, a 10-fold excess of Tin (II) chloride was
added directly to the reaction, and stirring was continued for an additional 4 hours. The
reaction was purified by reverse-phase HPLC to give the product: 'H NMR (400 MHz,
CDC13) 8 7.22 (d, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 5.27 (m, 2H), 4.35 (s, 2H), 3.81 (s, 3H),
3.76- 3.42 (m, 4H), 3.35- 2.96 (m, 4H), 1.45 (d, 3H) MS (ES) (M+H) expected = 480.1,
found = 480.1
Synthesis of2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-Bromo-
3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone:

[0358] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Bromo-3-methoxy-phenyl)-3-(S)-methyl-piperazine and (5-Azidomethyl-4-
chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components.
Following completion of the coupling reaction, a 10-fold excess of Tin (II) chloride was
added directly to the reaction, and stirring was continued for an additional 4 hours. The

reaction was purified by reverse-phase HPLC to give the product: 'H NMR (400 MHz,
GDC13) 8 7.51 (d, 1H), 6.98 (s, 1H), 6.59 (d, 1H), 5.35 (m, 2H), 4.45 (s, 2H), 3.90 (s, 3H),
3.83- 3.60 (m, 5H), 3.32- 3.19 (m, 4H), 1.45 (d, 3H); HPLC retention time = 5.72 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u,, 35°C) using a 2.0 starting isocratic period,
followed by a 5.0 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1 % formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile), and a final 2.5 min isocratic period at 95%B.
PROTOCOL O: Synthesis of 2-f5-Aminomethvl-4-chloro-3-trifluromethvl-pvrazol-1-
yl>-1-[4-(4-chlorophenvl)-piperazin-1-vn-ethanone

[0359] 2.85 g (6.2 mmol) of 2-(5-Azidomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-
[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone was dissolved in 80 mL methanol, and 3.61 g
(16.0 mmol) of SnCk hydrate was added. After two hours, the reaction was concentrated in
vacuo to remove the methanol. The residue was partitioned between 0.5M NaOH and ethyl
acetate, and the phases were separated. The aqueous phase was back-extracted once with
ethyl acetate. The combined ethyl acetate phases were extracted twice with 1M HC1. The
acidic aqueous phase was basified with 1M NaOH, and was extracted once with ethyl acetate.
The final ethyl acetate phase was washed once with brine, dried over Na2SO4, filtered, and
concentrated to an oil. The oil was dissolved in methanol, acidified with 2M HC1 in ether,
and the product was isolated by filtration after precipitation: 'H NMR (DMSO-i/6,400MHz)
8.58 (s, 3H), 7.27 (d, 2H), 7.03 (d, 2H), 5.71 (s, 2H), 4.10 (d, 2H), 3.64 (m, 4H), 3.32 (m,
2H), 3.19 (m, 2H) ppm; MS (ES) M+H expected = 436.1, found = 436.0.
Synthesis of 2-(5-N,N-DimethyIaminomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-
[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone:


10360] To a solution of 50 mg (0.1 mmol) of 2-(5-Aminomethyl-4-chloro-3-trifluromethyl-
r^azol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone hydrochloride and 13 mg
(0.20 mmol) sodium cyanoborohydride in 0.7 mL methanol was added 0.025 mL (0.3 mmol)
of 37% aqueous formaldehyde. After stirring for four hours, the reaction was quenched with
0.1 mL 12M HCl. One hour later, the solution was concentrated in vacuo. The residue was
partitioned between water and ether, and the phases were separated. The ether phase was
back-extracted once with water. The combined aqueous phases were basified with 1M
NaOH, and was extracted once with ethyl acetate. The ethyl acetate phase was washed once
with brine, dried over Na2SO4, filtered, and concentrated to an oil. The oil was dissolved in
methanol, acidified with 2M HCl in ether, and the product was isolated as a white solid by
filtatration: 'H NMR (DM50-d6,400MHz) 11.07 (br, 1H), 7.26 (d, 2H), 7.02 (d, 2H), 5.76
(s, 2H), 4.43 (s, 2H), 3.62 (m, 4H), 3.31 (m, 2H), 3.18 (m, 2H), 2.81 (s, 6H) ppm; MS (ES)
M+H expected = 464.1, found = 464.0.
Synthesis of 2-(5-AminomethyI-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-
3-methoxy-phenyl)-piperazin-1-yl]-ethanone:

[0361] Following protocol Q, 224mg (0.46 mmol) of 2-(5-Azidomethyl-4-chloro-3-
trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone
was dissolved in 5 mL of methanol, and 256 mg (1.14 mmol) of Tin (II) chloride was added.
After 4 hours, the solution was concentrated in vacuo to an oil. The oil was partitioned
between ether and water, and the phases were separated. The aqueous phase was basified to
pH > 9 with 1 M NaOH, and was extracted twice with ethyl acetate. The combined ethyl
acetate phases were washed twice with water, once with brine, dried over Na2SO4, filtered,
and concentrated to an oil. The oil was dissolved in methanol, acidified with 2 M HCl in
ether, and diluted with ether to give the product as a solid: 'H NMR (DMSO-d6,400MHz) 8
8.50 (br, 3H), 7.23 (m, 1H), 6.74 (m, 1H), 6.56 (m, 1H), 5.70 (s, 2H), 4.13 (m, 2H), 3.84 (s,
3H), 3.64 (m, 4H), 3.35 (m, 2H), 3.23 (m, 2H) ppm; MS (ES) M+H expect = 466.0, found =
466.0.

PROTOCOL R; Urea derivatization of aminomethyl functionality on pyrazole ring
system
Synthesis of l-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yI]-2-oxo-ethyI}-5-
trifluoromethyI-2H-pyrazol-3-yImethyI)-urea:

[0362] To a slurry of 12 mg (0.07 mmol) carbonyldiimidazole and 25 mg (0.05 mmol) of 2-
(5-Aminomethyl-4-chloro-3-trifluromethyl-pyrazol-1 -yl)-1 -[4-(4-chlorophenyl)-piperazin-1 -
yl]-ethanone hydrochloride in 1.0 mL CH2C12 at 0°C was added 23 mg (0.22 mmol) of
triethylamine dissolved in 0.2 mL CH2CI2 over five minutes. The mixture was allowed to
warm to room temperature after one hour, and was stirred for an additional hour.
[0363] 1.0 mL (0.5 mmol) of 0.5M ammonia in dioxane was added, and the resulting
solution was stirred for 12 hours. The solution was concentrated in vacuo, and the resulting
residue was partitioned between ethyl acetate and water. The phases were separated, and the
aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate
phases were washed once each with water, 1M NaOH, brine, dried over Na2SO4, filtered, and
concentrated to a residue. The residue was triturated with ethyl acetate, and the product was
isolated as a white solid by filtration: 'H NMR (DMSCWd, 400MHz) 7.23 (d, 2H), 6.96 (d,
2H), 6.48 (t, 1H), 5.62 (s, 2H), 5.48 (s, 2H), 4.16 (d, 2H), 3.57 (m, 4H), 3.25 (m, 2H), 3.14
(m, 2H) ppm; MS (ES) M+H expected = 479.1, found = 479.0.
Synthesis of 3-(4-Chloro-2-{2-[4-(4-chloro-phenyl>piperazin-1-yI]-2-oxo-ethyl}-5-
trifluoromethyl-2H-pyrazol-3-ylmethyl)-l,l-dimethyl-urea:


[0364] Title compound was prepared following protocol R, using 2M dimethylamine in
tetrahydrofuran as the amine component in the second step, to give the desired product as a
solid: lK NMR (DMSCWo",400MHz) 8 7.23 (d, 2H), 6.96 (d, 2H), 6.81 (t, 1H), 5.43 (s, 2H),
4.21 (d, 2H), 3.56 (m, 4H), 3.22 (m, 2H), 3.13 (m, 2H), 2.73 (s, 3H) ppm; MS (ES) M+H
expected = 507.1, found = 507.1.
Synthesis of l-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-
trifluoromethyl-2H-pyrazol-3-ylmethyl)-3-methyl-urea:

[0365] Title compound was prepared following the protocol R, using 2M methylamine in
tetrahydrofuran as the amine component in the second step, to give the desired product as a
solid: 'H NMR (DMSO-c? 5.48 (s, 2H)/4.18 (d, 2H), 3.58 (m, 4H), 3.31 (s, 3H), 3.25 (m, 2H), 3.13 (m, 2H) ppm; MS
r.-
(ES) M+H expected = 493.1, found = 493.0.
Synthesis of 3-(4-Chloro-2-{2- [4-(4-chIoro-phenyI)-piperazin-1-yl]-2-oxo-ethyl}-5-
trifluoromethyl-2H-pyrazol-3-yImethyI)-1-methoxy-1-methyl-urea:

[0366] Title compound was prepared following protocol R, using 1M N,0-
dimethylhydroxylamine in tetrahydrofuran as the amine component in the second step, to
give the desired product as a solid: 'H NMR (DMSO-d6,400MHz) 7.63 (t, 1H), 7.23 (d,
2H), 6.96 (d, 2H), 5.42 (s, 2H), 4.25 (d, 2H), 3.57 (m, 4H), 3.52 (s, 3H), 3.25 (m, 2H), 3.13
(m, 2H), 2.89 (s, 3H) ppm; MS (ES) M+H expected = 523.1, found 523.0.

Synthesis of l-(4-Chloro-2-{2-l4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-
trifluoromethyl-2H-pyrazol-3-yImethyl)-3-ethyl-urea:

[0367] Title compound was prepared following protocol R, using 2M ethylamine in
tetrahydrofuran as the amine component in the second step, to give the desired product as a
solid: lH NMR (JDUSO-d6, 400MHz) 7.26 (d, 2H), 7.03 (d, 2H), 6.95 (br, 1H), 6.47 (br,
1H), 5.49 (s, 2H), 4.17 (s, 1H), 3.61 (m, 4H), 3.28 (m, 2H), 3.17 (m, 2H), 2.95 (q, 2H), 0.93
(t, 3H) ppm; MS (ES) M+H expected = 507.1, found = 507.0
PROTOCOL S: preparation of chloroacetyl arylpiperazines
Synthesis of 2-Chloro-1-[4-(4-fluoro-phenyI)-piperazin-1-ylJ-ethanone

[0368] l-(4-Fluorophenyl) piperazine (2.8 mmol) was dissolved in 10 mL of CH2CI2.
Triethylamine (5.5 mmol) was added to it and the reaction was cooled to 0°C.
Chloroacetylchloride (4.2 mmol) was added to it slowly, and the reaction was warmed to
room temperature overnight. After completion, the reaction was quenched with brine
solution and reaction mixture was extracted with methylene chloride. The combined organic
phases were washed with brine and water and dried over magnesium sulfate. The solvent
was evaporated and the compound purified by column chromatography (hexane/ ethyl acetate
= 1.5/1) to afford the title compound as a white solid. 'H NMR (400 MHz, CDCI3) 5 6.9-7.2
(m, 2H), 6.82-6.92 (m, 2H), 4.1 (s, 2H), 6.62-3.8 (m, 4H), 3.46-3.6 (m, 4H). 13C NMR (400
MHz, CDC13) 5 164,158, 156.2,148.5,118.2,116.8, 52.6, 52.2, 48, 46, 42.1,40.6.

Synthesis of 2-Chloro-1-l4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone
>
[0369] Protocol S was followed using l-(4-chloro-phenyl) piperazine, Et3N, chloroacetyl
chloride and methylene chloride. Column chromatography using a solvent mixture (hexane/
ethyl acetate = 1.5/1) afforded the title compound as a white solid.
Synthesis of 2-ChIoro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

[0370] Protocol S was followed using l-(4-chloro-3-methoxyphenyl) piperazine, EtsN,
chloroacetyl chloride and methylene chloride. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1.5/1) afforded the title compounds as a white solid
Synthesis of 2- Chloro-1-[4-(4-bromo-3-methoxy-phenyI)-piperazin-1-yI]-ethanone

[0371] Protocol S was followed using l-(4-bromo-3-methoxyphenyl) piperazine, EtaN,
chloroacetyl chloride and methylene chloride. Column chromatography using a solvent
mixture (hexane/ ethyl acetate =1.5/1) afforded the title compounds as a white solid.
Synthesis of 2-Chloro-1-[4-(4-chloro-phenyl)-2-methyI-(R)-piperazin-1-yI]-ethanbne

[0372] Protocol S was followed using 1 -(4-Chloro-phenyl)-3-(R)-methyl-piperazine, Et3N,
chloroacetyl chloride and methylene chloride. Column chromatography afforded the title
compound.
Synthesis of 2-Chloro-1-[4-(4-chloro-phenyl)-2-methyl-(S)-piperazin-1-yl]-ethanone


[0373] Protocol S was followed using 1 -(4-Chloro-phenyl)-3-(S)-methyl-piperazine, Et3N,
ehloroacetyl chloride and methylene chloride. Column chromatography afforded the title
compound.
PROTOCOL T: RaCO* mediated coupling reaction of ehloroacetyl arylpiperazines
with pyrazoles
Synthesis of 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-pyrazol-1-yl-ethanone

[0374] Pyrazole (112.33 mg, 1.65 mmol) was dissolved in DMF (10 mL). K2CO3 (228.05
mg, 1.65 mmol) and 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (300 mg, 1.67
mmol) were added to it. The reaction was heated to 80°C for 14h. After completion, the
reaction was cooled to room temperature, quenched with brine and then extracted with ethyl
acetate. The organic layer was further washed with water (2X 25 mL) and brine (2X 25 mL)
and dried over magnesium sulfate. The solvent was removed by rotary evaporation to give
the crude product which was purified by column chromatography on silica gel using a solvent
mixture (hexane/ ethyl acetate = 1/1) to afford the title compound as white solid. !H NMR
(400 MHz, CDC13) 6 7.2-7.58 (d, 2H), 6.94-7.2 (t, 2H), 6.84-6.9 (dd, 2H), 6.32-6.36 (t, 1H),
5.6 (s, 2H), 3.76-3.82 (m, 2H), 3.68-3.74 (m, 2H), 3.04-3.1 (m, 2H), 3.0-3.04 (m, 2H). I3C
NMR (400 MHz, CDClj) 8 165, 158, 146.5, 140, 130, 118.4, 118.2, 116, 115.8, 107,54,51,
50.8 45.8,42.8.
Synthesis of2-(4-Chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-
phenyl)-piperazin-1-yl]-ethanone and2-(4-ChIoro-3-phenyl-5-trifluoromethyl-pyrazoI-
l-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

[0375] Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column

chromatography using a solvent mixture (hexane/ ethyl acetate = 1.5/1) afforded a mixture of
the title compounds, both as white solids

*H NMR (400 MHz, CDC13) 5 7.44-7.54 (m, 5H), 6.94-7.2 (t, 2H), 6.84-6.9 (dd, 2H), 4.94 (s,
1H), 3.72-3.8 (m, 2H), 3.5-3.6 (m, 2H), 3.0-3.1 (m, 4H). 13C NMR (400 MHz, CDC13) 8
163.8, 158,146.5,130,128.6, 128.2,118.2, 114.5, 52,50,44.5, 42.

'HNMR (400 MHz, CDCI3) 8 7.82-7.88 (m, 2H), 7.38-7.48 (m, 3H), 6.96-7.04 (m, 2H),
6.86-6.94 (m, 2H), 5.2 (s, 1H), 3.76-3.86 (m, 2H), 3.62-3.68 (m, 2H), 3.06-3.22 (m, 4H). nC
NMR (400 MHz, CDCI3) 8 164, 130, 128.4, 126, 118, 116.4, 52, 50, 43.8,41.6.
Synthesis of 2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-thiophen-2-yl-2H-
pyrazoIe-3-carboxylic acid ethyl ester

[0376] Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid
ethyl ester, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1.5/1) afforded the
title compound. *H NMR (400 MHz, CDC13) 5 7.32-7.36 (m, 1H), 7.22-7.26 (m, 1H), 7.08
(s, 1H), 7.02-7.08 (dd, 1H), 6.96-7.2 (m, 2H), 6.86-6.92 (m, 2H), 4.3-4.4 (q, 2H), 3.52-3.58
(m, 4H), 3.05-3.25 (m, 4H), 1.3-1.42 (m, 3H). 13C NMR (400MHz, CDC13) 8 164,130,
126.8, 126.4, 120,118.2, 115.4, 62.3, 54, 50.5, 42, 44.5,14.6.

Synthesis of 2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yI)-1- [4-(4-fluoro-phenyl)-
piperazin-1-yl]-ethanone

[0377] Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1 -[4-(4-fluoro-phenyl)-piperazin-1 -yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 3/7) afforded the title
compound as yellow solid. *H NMR (400 MHz, CDC13) 5 7.74-7.78 (m, 2H), 7.24-7.36 (m,
3H), 6.86-6.92 (m, 2H), 6.74-6.78 (m, 2H), 4.9 (s, 2H), 4.22 (s, 2H), 3.64-3.74 (m, 4H), 2.86-
3.04 (m, 4H). 13C NMR (400 MHz, CDC13) 5 164, 146.2, 144.8, 128, 126.8, 118, 114.8, 60,
50.2, 50, 48.8, 46, 42, 20.
Synthesis of 2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yI)-1-(4-(4-chIoro-phenyI)-
piperazin-1-yl]-ethanone

[0378] Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title
compound as white solid. *H NMR (400 MHz, CDC13) 5 7.7-7.8 (m, 2H), 7.24-7.3 (m, 3H),
6.8-6.92 (m, 2H), 6.74-6.78 (m, 2H), 4.9 (s, 2H), 4.2 (s, 2H), 3.6-3.7 (m, 4H), 2.86-3.04 (m,
4H). I3C NMR (400 MHz, CDC13) 8 164, 146,145, 128, 127, 118,114.8, 60.2, 50.4, 50,
48.8,46,42, 22.
Synthesis of 1- [4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(3-heptafluoropropyl-5-methyl-4-
nitro-pyrazol-1-yl)-ethanone


[0379] Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-l H-pyrazole,
K^CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 3/7) afforded the title
compound as oil. !H NMR (400 MHz, CDCl3) 8 6.9-7.0 (m, 2H), 6.8-6.9 (m, 2H), 5.06-5.14
(d, 2H), 3.6-3.8 (m, 4H), 3.06-3.18 (m, 4H), 2.56-2.66 (d, 3H). 13C NMR (400 MHz, CDCI3)
5 160,146.2, 144, 119.2,118,52.2, 50.8, 50.4,46,42.2,12.
Synthesis of 1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-pbenyl-3-
trifluorometliyl-pyrazol-1-yl)-ethanone

[0380] Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the title
compound as' white solid. *HNMR (400 MHz, CDC13) 8 7.82-7.84 (m, 2H), 7.4-7.48 (m,
3H), 6.9-7.04 (m, 2H), 6.88-6.94 (m, 2H), 5.22 (s, 1H), 3.76-3.88(m, 2H), 3.6-3.68 (m, 2H),
3.1-3.22 (m,4H). ,3CNMR(400 MHz, CDC13)8 164.2,130.4, 128, 126, 118.2, 116.4,52.2,
50,44,41.8.
Synthesis of 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(4-bromo-5-methyl-3-
trifluorometliyl-pyrazol-1-yl)-ethanone

[0381] Protocol T was followed using 4-Bromo-5-methyl-3 -trifluoromethyl-1 H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the title
compound as white solid. *H NMR (400 MHz, CDC13) 8 6.96-7 (m, 2H), 6.84-6.9 (m, 2H), 5
(s, 2H), 3.6-3.8 (m, 4H), 3.02-3.16 (m, 4H), 2.3 (s, 3H). 13C NMR (400 MHz, CDC13) 8
162.6, 146.5, 142, 118.5,116, 52.2, 50.4, 46, 42.2, 15.

Synthesis of 1- [4-(4-Chloro-phenyl)-piperazin-1-yl] -2-(4-bromo-5-methyl-3-
trifluoromethyl-pyrazoI-1-yl)-ethanone

[0382] Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the title
compound as white solid. lH NMR (400 MHz, CDC13) 5 6.96-7.1 (m, 2H), 6.84-6.89 (m,
2H), 5.2(s, 2H), 3.6.2-3.8 (m, 4H), 3.0-3.16 (m, 4H), 2.32 (s, 3H). 13C NMR (400 MHz,
CDCI3) S 162,146.4,142.2, 118.5, 116.2, 52, 50.4, 46.2, 42.2, 15.2.
Synthesis of 1-[4-(4-Chloro-phenyl)-piperazin-1-yI]-2-(3-heptafluoropropyl-5-methyl-4-
nitro-pyrazol-1-yl)-ethanone

10383] Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4, Rf = 0.81) afforded the
title compound as colorless oil. 'H NMR (400 MHz, CDC13) 5 6.92-7.02 (m, 2H), 6.82-6.9
(m, 2H), 5.04-5.14 (m, 2H), 3.64-3.82 (m, 4H), 3.06-3.18 (m, 4H), 2.6-2.66 (d, 3H). 13C
NMR (400 MHz, CDC13) 5 160.4,146,144.2,119.2,118.2, 52,50.8, 50.6,46,42,12.2.
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyI)-piperazin-1-yl]-2-(4-chloro-S-phenyl-3-
trifluoromethyl-pyrazol-1-yI)-ethanone

[0384] Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the
title compound as a white solid. ]H NMR (400 MHz, CDCI3) 8 7.4-7.52 (m, 5H), 7.18-7.22

(d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 4.72 (s, 2H), 3.86 (s, 3H), 3.5-3.78 (m, 4H),
3.1 (s, 4H). 13C NMR (400 MHz, CDC13) 164,156.2,150.4, 130.5,130,128.5, 110,102.2,
56,52, 50,44.8,42.
Synthesis of 1-[4-(4-Bromo-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-phenyl-5-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0385] Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the
title compound as a white solid. lH NMR (400 MHz, CDC13) 5 7.42-7.52 (m, 4H), 7.36-7.38
(d, 1H), 6.42-6.46 (d, 1H), 6.34-6.38 (dd, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 3.74-3.78 (m, 2H),
3.54-3.58 (m, 2H), 3.12-3.18 (m, 4H). 13CNMR(400MHz, CDC13)5 164, 156.2, 152,
132.6, 130.2, 130,128.8, 110, 102.2, 56, 52, 50, 44.8, 42.
Synthesis of 1-[4-(4-Chloro-3-methoxy-piperazin-1-yl]-2-(4-bromo-5-methyI-3-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0386] Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the
title compound as white solid. *H NMR (400 MHz, CDC13) 8 7.18-7.22 (d, 1H), 6.44-6.48 (d,
1H), 6.36-6.42 (dd, 1H), 5.0 (s, 2H), 3.6.2-3.8 (m, 4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H). l3C
NMR(400MHz,CDCl3)S 162, 146.6, 142.2, 118.8,116,52.2,50.4,46.2,42.2, 15.2.

Synthesis of 2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxyphenyI)-piperazin-1-yI]-ethanone

[0387] Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title
compound as white solid. lH NMR (400 MHz, CDCI3) 8 7.78-7.84 (d, 2H), 7.32-7.42 (m,
3H), 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.88
(s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18 (m, 4H). I3C NMR (400 MHz, CDC13) 5 164.6, 154.8,
150.2, 144.6, 130,128.2, 128,126.4, 109.2,102, 56, 51, 50, 49.6, 45.6,42.
Synthesis of 2-(3-Amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxyphenyl)-piperazin-1-yl]-ethanone

[0388] Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title
compound as colorless oil. lU NMR (400 MHz, CDCI3) 5 7.18-7.22 (d, 1H), 6.44-6.48 (d,
1H), 6.36-6.42 (dd, 1H), 5.0 (s, 2H), 4.24 (s, 2H), 2.4 (s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18
(m, 4H). 13C NMR (400 MHz, CDCI3) 8 164.6,154.8,144.6,130.2,130, 128.8,109.2,102,
56,51,49.6,45.6,42.
Synthesis of 1-[4-(4-Bromo-3-methoxy-plperazin-1-yl]-2-(4-bromo-5-methyI-3-
trifluoromethyl-pyrazol-1-yl)-ethanone


[0389] Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole,
>-
K2CO3,2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the
title compound as white solid. !H NMR (400 MHz, CDCI3) 5 7.38-7.4 (d, 1H), 6.44-6.46 (d,
1H), 6.26-6.4 (dd, 2H), 5.0 (s, 2H), 3.88 (s, 3H), 3.68-3.8 (m, 4H), 3.14-3.22 (m, 4H), 2.3 (s,
3H). 13CNMR (400 MHz, CDCI3) 8 164.4, 158, 152.2, 144,134, 110, 102.2, 56.6, 54.2, 50,
48.8,46,42.2,12.
Synthesis of 1- [4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(3-thiophen-2-yl-pyrazol-1-yl)-
ethanone

[0390] Protocol T was followed using 3-(2-thienyl)pyrazole, K2CO3, 2-Chloro-1-[4-(4-
fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. 'H NMR
(400 MHz, CDCI3) 5 7.48-7.52 (d, 1H), 7.24-7.28 (dd, 1H), 7.14-7.2 (dd, 1H), 6.98-7.2 (m,
1H), 6.88-6.96 (m, 2H), 6.78-6.84 (m, 2H), 6.46-6.52 (d, 1H), 5.0 (s, 2H), 3.64-3.8 (m, 4H),
2.94-3.1 (m,4H). 13C NMR (400 MHz, CDC13) 8 164.4, 158, 152.2,144, 134,132,126, 124,
123.8, 118,116, 115.8,102.2, 54, 51.2, 50.8, 45.8, 42.2.
Synthesis of 2-(4-Chloro-3-trifiuoromethyI-pyrazol-1-yI)-1-[4-(4-fiuoro-phenyI)-
piperazin-1-yl]-ethanone

[0391] Protocol T was followed using 4-Chloro-3-trifluoromethyl-1H-pyrazole, K2CO3,2-
Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography
using a solvent mixture (hexane/ ethyl acetate =1/1) afforded the title compound as colorless
oil. lH NMR (400 MHz, CDCI3) 5 7.64-7.68 (d, 1H), 6.98-7.4 (m, 2H), 6.86-6.92 (m, 2H),
6.98-7.2 (m, 1H), 5.4 (s, 2H), 3.78-3.84 (m, 2H), 3.68-3.92 (m, 2H), 3-3.1 (m, 4H). 13C
NMR (400 MHz, CDCI3) 5 164.4,158,152.2, 144, 132,118.2,116, 54, 50.2, 50.0,46.0,
42.2.

Synthesis of 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(3,4,5-tribromo-pyrazol-1-yl)-
ethanone

[0392] Protocol T was followed using 3,4,5-Tribromo-l H-pyrazole, K2CO3,2-Chloro-1-[4-
(4-fmoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title compound as white solid. *H
NMR (400 MHz, CDC13) S 6.96-7.2 (m, 2H), 6.84-6.9 (m, 2H), 5.4 (s, 2H), 3.74-3.8 (m, 2H),
3.6-3.68 (m, 2H), 3.04-3.14 (m, 4H). 13C NMR (400 MHz, CDC13) 5 164.4, 158,156,144.2,
128, 118.4,118.2,116, 100,52.8, 50.2, 50.0,46.0,42.2.
Synthesis of 2-(3-tert-Bufyl-4-cliloro-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-
phenyl)-piperazin-1-yl]-ethanone

[0393] Protocol T was followed using 5-tert-Butyl-4-chloro-3 -trifluoromethyl-1 H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-fiuoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title
compound as white solid. 'H NMR (400 MHz, CDCI3) 5 6.94-7.22 (m, 2H), 6.84-6.92 (m,
2H), 5.3 (s, 2H), 3.68-3.8 (m, 2H), 3.6-3.68 (m, 2H), 3.04-3.2 (m, 4H), 1.4 (s, 9H). 13C NMR
(400 MHz, CDCI3) 5 164.8,119, 118.4, 118.2,116.2, 116, 54, 51, 50.8, 45.4, 42.2, 30,29,27.
Synthesis of 2-I3-(4-Fluoro-phenyI)-5-methylsulfanyl-pyrazol-1-yl]-1- [4-(4-fluoro-
phenyl)-piperazin-1-y!]-ethanone

[0394] Protocol T was followed using 3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column

chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the title
cempound as white solid. !H NMR (400 MHz, CDC13) 8 7.7-7.76 (m, 2H), 6.96-7.1 (m, 4H),
6.88-6.92 (m, 2H), 6.64 (s, 1H), 5.3 (s, 2H), 3.7-3.84 (m, 4H), 3.04-3.2 (m, 4H), 2.5 (s, 3H).
I3C NMR (400 MHz, CDC13) 5 164.8,152,140,127.4,119,118.4,118.2,116.2,116,108,
52.8,52,51.8,45.4,42.2,20.
Synthesis of 2-[4-Chloro-5-(4-Fluoro-phenyl)-3-methyIsulfanyl-pyrazoH-ylJ-1-[4-(4-
fluoro-phenyl)-piperaziii-1-yl]-ethanone

[0395] Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-
pyrazole, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chrornatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the
title compound as white solid. 'H NMR (400 MHz, CDC13) 8 7.82-7.88 (m, 2H), 7.06-7.12
(m, 2H), 6.96-7.1 (m, 2H), 6.88-6.92 (m, 2H), 5.2 (s, 2H), 3.68-3.84 (m, 4H), 3.06-3.18 (m,
4H),2.4 (s, 3H). I3C NMR (400 MHz, CDC13) 8 164.8, 158, 147,135, 127.4,127,119,
112.4, 112.2,110, 108.8, 52.8, 52, 51.8, 45.4, 42.2, 18.6.
Synthesis of 2-[4-Chloro-3-(4-Fluoro-phenyl)-5-methylsuIfanyl-pyrazol-1-yl]-1-[4-(4-
fluoro-phenyl)-piperazin-1-yl]-ethanone

[0396] Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-
pyrazole, K2CO3,2-Chloro-1-[4-(4~fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the
title compound as white solid. *H NMR (400 MHz, CDC13) 8 7.46-7.5 (m, 2H), 7.12-7.18

(m, 2H), 6.96-7.1 (m, 2H), 6.88-6.92 (m, 2H), 4.86 (s, 2H), 3.72-3.78 (m, 2H), 3.56-3.62 (m,
21-1), 3.06-3.18 (m, 4H), 2.54 (s, 3H).
Synthesis of 2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-Chloro-3-
thiophen-2-yl-2H-pyrazole-5-carboxylic acid ethyl ester

[0397J Protocol T was followed using 4-ChIoro-3-Thiophen-2-yl-2H-pyrazole-5-carboxylic
acid ethyl ester, K2CO3,2-Chloro-1-[4-(4-fluoro-pheriyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography vising a solvent mixture (hexane/ ethyl acetate = 1.5/1: Rf= 0.62)
afforded the title compound. 'H NMR (400 MHz, CDC13) 5 7.06-7.36 (m, 1H), 6.96-7.2 (m,
3H), 6.84-6.92 (m, 3H), 54.46 (s, 2H), 4.3-4.4 (q, 2H), 3.6-3.82 (m, 4H), 3.05-3.25 (m, 4H),
1.3-1.42 (m,3H).
Synthesis of 2-(4-Amino-3-heptafluoropropyl-5-methyl-pyrazol-1-yl)-1-[4-(4-fluoro-
phenyl)-piperazin- 1-yl] -ethanone

[0398] Protocol T was followed using 4-Amino-3-heptafluoropropyl-5-methyl-1H-
pyrazole, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the
title compound as colorless oil. 'HNMR (400 MHz, CDC13) 8 6.92-7.02 (m, 4H), 5.14 (s,
2H), 3.64-3.82 (m, 4H), 3.6 (s, 2H), 3.1-3.22 (m, 4H), 2.16 (s, 3H). I3C NMR (400 MHz,
CD6CO) 5 160.4, 158,146,144.2, 119.8, 118.2,52,50.8,50.6,46,42, 12.2.
Synthesis of 2-(5-ButyI-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyI)-
piperazin-1-yI]-ethanone


[0399] Protocol T was followed using 5-n-Butyl-3-trifmoromethyl-1H-pyrazole, K2CO3,2-
Cffioro-1-[4-(4-fluoro-phenyl)-piperazia-1-yl]-ethanone and DMF. Column chromatography
using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title compound as colorless
oil. lK NMR (400 MHz, CDC13) 8 7.18-7.24 (m, 2H), 6.78-6.84 (m, 2H), 6.32 (s, 1H), 5.0 (s,
2H), 3.66-3.78 (m, 4H), 3.08-3.18 (m, 4H), 2.58-2.64 (t, 2H), 1.6-1.7 (m, 2H), 1.38-1.48 (m,
2H), 0.6-1.0 (t, 3H). 13C NMR (400 MHz, CDCI3) 5 160.4, 150, 148,142, 130,126,119.8,
103.2, 52, 50.8, 50.6, 46, 42, 30, 26,22, 14.
Synthesis of 2-(4-Chloro-5-butyl-3-trifluoromethyl-pyrazoH-yl)-1-[4-(4-chloro-phenyl)-
piperazin-1-yl]-ethanone

[0400] Protocol T was followed using 4-Chloro-5-n-butyl-3 -trifluoromethyl-1 H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title
compound as colorless oil. 'H NMR (4O0 MHz, CDC13) 8 7.18-7.24 (m, 2H), 6.78-6.84 (m,
2H), 5.0 (s, 2H), 3.66-3.78 (m, 4H), 3.08-3.2 (m, 4H), 2.58-2.64 (t, 2H), 1.5-1.54 (m, 2H),
1.38-1.48 (m, 2H), 0.6-1.0 (t, 3H). 13C NMR (400 MHz, CDC13) 8 160.4, 148, 142,130, 128,
119.8, 52, 50.8, 50.6, 46, 42, 30.4,26, 23, 14.
Synthesis of 2-(3-Amino-4-bromo-5-pIienyl-pyrazol-1-yl)-1-l4-(4-bromo-3-
methoxyphenyl)-piperazin-1-yI]-ethanone

[0401] Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1.5) afforded the title
compound as white solid. TH NMR (40O MHz, CDCI3) 5 7.78-7.84 (d, 2H), 7.32-7.42 (m,
3H), 7.18-7.22 (d, 1H), 6.44-6.52 (d, 1H), 6.36-6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.84
(s, 3H), 3.76-3.82 (m, 4H), 3.12-3.18 (m, 4H). 13C NMR (400 MHz, CDCI3) 6 164.6, 154.8,
150.2,144.6, 130,128.8,128.6,126.4,109.2,102, 56, 51, 50,49.6,45.6,42.

Synthesis of 2-(4-Bromopyrazol)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone
r

[0402] Protocol T was followed using 4-Bromo-1H-pyrazol, K2CO3, 2-Chloro-1-[4-(4-
fhioro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate =1/1) afforded the title compound as a white solid. lH NMR
(400 MHz, CDC13) 8 7.52-7.58 (d, 1H), 7.48-7.52 (d, 1H), 6.95-7.0 (m, 2H), 6.82-6.92 (dd,
2H), 5.00 (s, 2H), 3.72-3.80 (t, 2H), 3.64-3.72 (t, 2H), 3.02-3.12 (m, 4H). 13C NMR (400
MHz, CDCI3) S 164.6,158.2,156.2, 146.6,141.6, 140.2, 130.5, 129.6, 118.2, 118.0, 115.2,
116.4,94.2, 53.8, 50.8, 50.2,45.4, 42.
Synthesis of 2-(4-Iodopyrazol)-1- [4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

[0403] Protocol T was followed using 4-Iodo-1 H-pyrazol, K2CO3, 2-Chloro-1 -[4-(4-fluoro-
phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture
(hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. 'H NMR (400
MHz, CDCI3) 5 7.58-7.62 (d, 1H), 7.52 (s, 1H), 6.95-7.1 (m, 2H), 6.84-6.92 (dd, 2H), 5.00 (s,
2H), 3.72-3.80 (t, 2H), 3.64-3.72 (t, 2H), 3.02-3.12 (m, 4H). 13C NMR (400 MHz, CDC13) 8
164.6,158.2,156.2, 146.8, 140.8,140.2, 130.5, 129.6,118.2,118.0,115.4,116.8, 96.0, 53.4,
51.2,50.2,45.2,42.
Synthesis of 2-(3,5-Diisopropyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-
ethanone

[0404] Protocol T was followed using 3,5-Diisopropyl-1 H-pyrazole, K2CO3, 2-Chloro-1 -
[4-(4-fiuoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as white solid. *H
NMR (400 MHz, CDCI3) 5 6.92-7.0 (m, 2H), 6.80-6.88 (dd, 2H), 5.88 (s, 1H), 4.92 (s, 2H),

3.70-3.80 (t, 4H), 2.90-3.10 (m, 4H), 1.40-1.60 (m, 12H). ,3CNMR (400 MHz, CDC13) 8
166.6,158.2,150.2,119.2,118.0,100.0, 50.8, 50.5, 50.2,45.2,42, 28.2,26.0,22.4.
Synthesis of l-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyI}-3-trifluoromethyl-
lH-pyrazole-4-carboxylic acid ethyl ester

|0405] Protocol T was followed using 3-Trifmoromethyl-1H-pyrazole-4-carboxylic acid
ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the
title compound as colorless oil. 'H NMR (400 MHz, CDC13) 8 8.15 (s, 1H), 6.98-7.04 (m,
2H), 6.86-6.92 (m, 2H), 5.1 (s, 2H), 4.28-4.38 (q, 2H), 3.78-3.84 (m, 2H), 3.62-3.74 (m, 2H),
3.04-3.2 (m, 4H), 1.3-1.4 (t, 3H). ,3C NMR (400 MHz, CDC13) 8 163.4, 160.5, 159.2,156.2,
147,137.2,119,118.8, 116,115.8,61, 54,50.8, 50.0,45.0,42.2,14.2.
Synthesis of 1-[4-(4-Fluoro-phenyI)-piperazin-1-yl]-2-(4-iodo-3,5-dimethyl-pyrazol-1-
yl)-ethanone

[0406] Protocol T was followed using 4-Iodo-3,5-dimethyl-pyrazole, K2CO3, 2-Chloro-l -
[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. *H
NMR (400 MHz, CDC13) 8 6.95-7.1 (m, 2H), 6.84-6.92 (dd, 2H), 5.00 (s, 2H), 3.62-3.82 (m,
4H), 3.02-3.12 (m, 4H), 2.22-2.32 (d, 6H). ,3C NMR (400 MHz, CDC13) 8 165,158.2,156.2,
150.2, 146.8, 141.8,118.8,115.4,115.2, 52.8, 51.6, 50.2, 45.2, 42, 14.8, 12.6.
Synthesis of2-(3-Chloro-indazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone


[0407] Protocol T was followed using 3-Chloro-l H-indazole, K2CO3,2-Chloro-l -[4-(4-
fiuoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1/4) afforded the title compound as a white solid. 'H NMR
(400 MHz, CDC13) 8 7.64-7.70 (m, 1H), 7.38-7.48 (m, 2H), 7.18-7.26 (m, 2H), 6.94-7.0 (m,
2H), 6.82-6.88 (dd, 2H), 5.2 (s, 2H), 3.72-3.82 (m, 4H), 3.02-3.08 (m, 4H). 13C NMR (400
MHz, CDCI3) 5 165,158.2,142.8,134.8,128.8, 128.4, 122,121.6, 118.8,118.6, 115.4,
115.2,110.6,110.0,51.8,50.6,50.2,45.2,42.
Synthesis of 2-{2- [4-(4-Fluoro-phenyl)-piperazin-1-yl] -2-oxo-ethyl}-5-propyI-2H-
pyrazole-3-carboxylic acid ethyl ester

[0408] Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester,
K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title
compound as a white solid. 'H NMR (400 MHz, CDC13) 8 6.94-7.0 (m, 2H), 6.82-6.90 (dd,
2H), 6.7 (s, 1H), 5.5 (s, 2H), 4.26-4.32 (q, 2H), 3.62-3.82 (m, 4H), 3.04-3.18 (m, 4H), 2.58-
2.64 (t, 2H), 1.64-1.74 (m, 2H), 1.34-1.38 (t, 3H), 0.96-1.0 (t, 3H). 13C NMR (400 MHz,
CDCI3) 8 165,160,156.2,152.4, 146.8, 132.8, 118.2, 118.1, 115.8, 115.4, 110.2, 61, 53,
50.6, 50.2, 45, 42, 30,22.8, 14.2, 14.
Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-propyl-2H-
pyrazole-5-carboxylic acid ethyl ester

[0409] Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester,
K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazm-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =1/1) afforded the title
compound as white solid. ]H NMR (400 MHz, CDC13) 8 6.94-7.0 (m, 2H), 6.82-6.90 (dd,
2H), 6.2 (s, 1H), 5.06 (s, 2H), 4.34-4.40 (q, 2H), 3.62-3.8 (m, 4H), 3.02-3.12 (m, 4H), 2.54-
2.60 (t, 2H), 1.64-1.78 (m, 2H), 1.34-1.38 (t, 3H), 0.98-1.4 (t, 3H). 13C NMR (400 MHz,

CDC13)5 165,160,156.4,152.2,146.6,132.8,118.4,118.2, 115.8,115.4,113.2, 61,53,
50.6,50.2,45.2,42,28,21.8,14.2,14.
Synthesis of 2-(3,5-Bis-trifluororaethyl-pyrazoI-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-
yl]-ethanone

[0410] Protocol T was followed using 3,5-Bis-trifluoromethyl-1H-pyrazole, K2CO3,2-
Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography
using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white
solid. 'H NMR (400 MHz, CDC13) 5 6.94-7.0 (m, 2H), 6.92 (s, 1H), 6.82-7.90 (dd, 2H), 5.2
(s, 2H), 3.72-3.8 (t, 2H), 3.58-3.66 (t, 2H), 3.12-3.18 (t, 2H), 3.02-3.12 (t, 2H). I3C NMR
(400 MHz, CDCI3) 5 162.2,158.2,156.4,146.5,118.4,116.2, 115.8,113.2,60.4, 53.2, 50.6,
50.2,45.2,42.2,21.2,14.2.
Synthesis of l-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazoIe-3,5-
dicarboxylic acid diethyl ester

[0411] Protocol T was followed using lH-Pyrazole-3,5-dicarboxylic acid diethyl ester,
KaCOa, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title
compound as a white solid. *H NMR (400 MHz, CDC13) 5 7.38 (s, 1H), 6.94-7.0 (m, 2H),
6.82-7.90 (dd, 2H), 5.54 (s, 2H), 4.36-4.42 (q, 2H), 4.26-4.32 (q, 2H), 3.60-3.80 (m, 4H),
3.02-3.20 (m, 4H), 1.22-1.42 (m, 6H). 13CNMR (400 MHz, CDC13) 8 164.2,162.2, 158.2,
157.4,156.2, 148.5,144.4,134.2,118.4, 116.2,115.8,114.2, 62, 61.8, 54.2, 50.6, 50.2, 45.2,
42.2,14.6,14.2.

Synthesis of 2-(3-Amino-4-f-butyI-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-
ethanone

[0412] Protocol T was followed using 5-tert-Butyl-1H-pyrazol-3-ylamine, K2CO3) 2-
Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography
using a solvent mixture (hexane/ ethyl acetate = 3/7: Rf = 0.49) afforded the title compound
as colorless oil. lH NMR (400 MHz, CDC13) 5 6.92-7.98 (t, 2H), 6.82-6.88 (dd, 2H), 4.84 (s,
2H), 3.95 (s, 2H), 3.70-3.90 (m, 4H), 2.95-3.10 (m, 4H), 1.25 (s, 9H).
Synthesis of 2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-chloro-5-propyl-
2H-pyrazole-3-carboxylic acid ethyl ester

[04131 Protocol T was followed using 4-Chloro-5-Propyl-2H-pyrazole-3-carboxylic acid
ethyl ester, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate =3/7) afforded the
title compound as a white solid. 'H NMR (400 MHz, CDCI3) 8 6.94-7.0 (m, 2H), 6.82-6.90
(dd, 2H), 5.0 (s, 2H), 4.36-4.40 (q, 2H), 3.62-3.82 (m, 4H), 3.04-3.18 (m, 4H), 2.58-2.66 (t,
2H), 1.64-1.76 (m, 2H), 1.34-1.38 (t, 3H), 0.94-1.0 (t, 3H). 13CNMR (400 MHz, CDC13) 5
165,160.2,156.2,152.4, 147,133,118.4, 118.2, 115.8,115.4, 112.2, 61, 53, 50.6, 50.2, 45,
42, 30, 22.8, 14.4, 14.2.
Synthesis of 2-(3-tert-Butyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-
piperazin-1-yl]-ethanone

[0414] Protocol T was followed using 5-tert-Butyl-3-trifiuoromethyl-1H-pyrazole, K2CO3,
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column

chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title
compound as a colorless oil. 'H NMR (400 MHz, CDC13) 8 6.92-7.08 (t, 2H), 6.82-6.88 (dd,
2H), 6.52 (s, 1H), 5.08 (s, 2H), 3.70-3.80 (m, 2H), 3.58-3.68 (m, 2H), 3.05-3.15 (m, 4H), 1.3
(s,9H). 13CNMR(400MHz,CDCl3)8 164,161.2, 158.2,156.4, 147.2,118.4, 118.2, 115.8,
115.4,108.2, 54, 50.6,50.2,45,44, 30.
Synthesis of 2-(5-Amino-3-furan-2-yl-pyra2ol-1-yI)-1-[4-(4-fluoro-phenyl)-piperazin-1-
yl]-ethanone

[0415] Protocol T was followed using 3-Furan-2-yl-2H-pvrazol-5-ylamine, K2CO3, 2-
CMoro-1-[4-(4-fluoro-phenyi)-piperazin-1-yl]-ethanone and DMF. Column chromatography
using 100% ethyl acetate afforded the title compound as a white solid. *H NMR (400 MHz,
CD6CO) 8 7.48-7.52 (m, 1H), 6.98-7.06 (m, 2H), 6.52-6.56 (m, 2H), 6.44-6.48 (m, 2H), 5.74
(s, 1H), 4.98 (s, 2H), 3.68-3.88 (m, 4H), 3.12-3.24 (m, 4H). MS (ES) M+H) expected =
369.4, found 370.1.
Synthesis of 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(4-bromo-3,5-dimethyl-pyrazol-1-
yl)-ethanone

[0416] Protocol T was followed using 4-Bromo-3, 5-dimethyl-pyrazole, K2CO3,2-Chloro-
1-[4-(4-fiuoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. *H
NMR (400 MHz, CDC13) 5 6.95-7.1 (m, 2H), 6.84-6.92 (dd, 2H), 4.90 (s, 2H), 3.62-3.82 (m,
4H), 3.02-3.12 (m, 4H), 2.24-2.34 (d, 6H). 13C NMR (400 MHz, CDCI3) 8 165,158.4, 156.6,
150.6,146.8,141.4,119, 115.6, 115.2, 52.6, 51.6, 50.4, 45.2, 42.2, 14.8, 12.6.

Synthesis of 2-[4-CWoro-3-(5-chloro-thiophen-2-yl)-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-
piperazin-1-yl]-ethanone

[0417] Protocol T was followed using 4-Chloro-3-(5-chloro-thiophen-2-yl)-l H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanoneand DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the title
compound as yellow solid. *H NMR (400 MHz, CDC13) 8 7.58 (s, 1H), 7.38-7.42 (d, 1H),
6.94-7.1 (m, 2H), 6.84-6.88 (dd, 2H), 4.96 (s, 2H), 3.62-3.81 (m, 4H), 3.02-3.14 (m, 4H). 13C
NMR (400 MHz, CDCI3) 8 165, 158.8,156.8, 142.4,131, 126.8, 124.8, 119, 116,115.6,54,
52,51.6,46,42.6.
Synthesis of 4-Chloro-2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
2H-pyrazole-3-carboxylic acid ethyl ester

[0418] Protocol T was followed using 4-Chloro-5-methyl-2H-pyrazole-3-carboxylic acid
ethyl ester, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3) afforded the
title compound as a white solid. 'H NMR (400 MHz, CDCI3) 8 6.94-7.1 (m, 2H), 6.84-6.88
(dd, 2H), 5.04 (s, 2H), 4.38-4.44 (q, 2H), 3.62-3.80 (m, 4H), 3.02-3.14 (rn, 4H), 2.3 (s, 3H),
1.36-1.42 (t, 3H). 13C NMR (400 MHz, CDC13) 5 182,165,119,116.2, 116, 61.4, 52.3, 51,
50.8, 45.8, 42.6,14.4, 10.

Synthesis of 4-ChIoro-5-(5-chloro-thiophen-2-yl)-2-{2-[4-(4-fluoro-phenyl)-piperazin-1-
yfj-2-oxo-ethyl}-2H-pyrazoIe-3-carboxylic acid ethyl ester

[0419] Protocol T was followed using 4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3 -
carboxylic acid ethyl ester, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone
and DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3)
afforded the title compound as a yellow solid. :H NMR (400 MHz, CDC13) 5 7.46-7.48 (m,
1H), 6.94-7.1 (m, 2H), 6.84-6.92 (m, 3H), 5.4 (s, 2H), 4.34-4.4 (q, 2H), 3.62-3.81 (m, 4H),
3.04-3.24 (m, 4H), 1.36-1.44 (m, 3H). MS (ES) M+H) expected = 511.41, found 511.
Synthesis of 2-(3-Amino-4-chIoro-S-methyl-pyrazol-1-yl)-1-[4-(4-chIorophenyl)-
piper azin-1-yl] -ethanone

[0420] Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title
compound as a colorless oil. 'H NMR (400 MHz, CDC13) 8 7.18-7.22 (d, 1H), 6.78-6.84 (d,
2H), 4.8 (s, 2H), 4.4 (s, 2H), 3.72-3.82 (m, 4H), 3.08-3.18 (m, 4H), 2.14 (s, 3H).
Synthesis of 1- [4-(4-Bromo-3-methoxyphenyl)-piperazin-1-yl] -2-(4-chloro-5-phenyl-3-
trifhioromethyl-pyrazol-1-yl)-ethanone

[0421] Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3: Rf = 0.58)
afforded the title compound as a white solid. 'H NMR (400 MHz, CDC13) 5 7.81-7.86 (m,

IH), 7.36-7.44 (m, 4H), 6.42-6.48 (d, IH), 6.34-6.38 (dd, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62-
3.§2 (m, 4H), 3.12-3.22 (m, 4H).
Synthesis of 1-[4-(4-FluorophenyI)-piperazin-1-yl]-2-(3-trifluoromethy!-pyrazol)-
ethanone

[0422] Protocol T was followed using 3 -trifmoromethyl-1 H-pyrazole, K2CO3,2-Chloro-1 -
[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. 'H
NMR (400 MHz, CDC13) 5 7.54-7.60 (m, IH), 6.94-7.0 (m, 2H), 6.80-6.88 (m, 2H), 6.52-
6.58 (d, IH), 5.2 (s, 2H), 3.72-3.80 (t, 2H), 3.62-3.72 (t, 2H), 3.02-3.12 (m, 4H). MS (ES)
M+H expected 356.33, found 357.1.
Synthesis of 1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-methyl-pyrazol)-ethanor*e

[0423] Protocol T was followed using 3-methyl-1H-pyrazole, K2CO3,2-Chloro-1-|[4-(4-
fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. ' ti NMR
(400 MHz, CDC13) 5 7.38-7.41 (m, IH), 6.94-7.0 (m, 2H), 6.80-6.88 (m, 2H), 6.08-6.10 (d,
IH), 4.95 (s, 2H), 3.74-3.82 (t, 2H), 3.62-3.72 (t, 2H), 3.0-3.1 (m, 4H), 2.28 (s, 3H). MS
(ES) M+H expected 302.05, found 303.1.
Synthesis of l-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole-4-
carboxylic acid ethyl ester

[0424] Protocol T was followed using lH-Pyrazole-4-carboxylic acid ethyl ester, KL2CO3,
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =1/1) afforded the title
compound as a white solid. ]HNMR (400 MHz, CDC13) 5 8.2 (s, IH), 7.92 (s, IH), 6.94-7.0

(m, 2H), 6.82-6.88 (m, 2H), 5.0 (s, 2H), 4.1-4.2 (q, 2H), 3.74-3.82 (t, 2H), 3.62-3.72 (t, 2H),
3T0-3.12 (m, 4H), 1.28-1.42 (t, 3H). MS (ES) M+H expected 360.39, found 361.1.
Synthesis of 1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(4-methyl-pyrazol)-ethanone

[0425] Protocol T was followed using 4-methyl-1H-pyrazole, K2CO3,2-Chloro-1-[4-(4-
fluoro-phenyl)-piperaziii-1-yrj-ethanone and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1/1) afforded the title compound as a white solid. *H NMR
(400 MHz, CDCU) 5 7.26-7.32 (m, 1H), 6.94-7.0 (m, 2H), 6.80-6.88 (m, 2H), 5.0 (s, 2H),
3.62-3.82 (m, 4H), 3.0-3.1 (m, 4H), 2.1 (s, 3H). MS (ES) M+H expected 302.35, found
303.1.
Synthesis of 1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-amino-4-bromopyrazole)-
ethanone
t.
[0426] Protocol T was followed using 4-bromo-3-aminopyrazole, K2CO3,2-Chloro-l -[4-
(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 3/7) afforded the title compound as a white solid. "H
NMR (400 MHz, CDC13) S 7.23 (s, 1H), 6.94-7.0 (m, 2H), 6.80-6.88 (m, 2H), 4.9 (s, 2H), 4.2
(s, 2H), 3 72-3.82 (m, 4H), 3.0-3.14 (m, 4H). MS (ES) M+H expected 382.24, found 382.
Synthesis of 1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-amino-4-cyanopyrazole)-
ethanone

[0427] Protocol T was followed using 3-amino-4-cyano-pyrazole, K2CO3, 2-Chloro-1 -[4-
(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 3/7) afforded the title compound as a solid. 'HNMR
(400 MHz, CDCI3) 5 7.48 (s, 1H), 6.96-7.2 (m, 2H), 6.86-6.92 (m, 2H), 4.96 (s, 2H), 4.88 (s,
2H), 3.78-3.86 (m, 4H), 3.08-3.16 (m, 4H). MS (ES) M+H expected 328.25, found 329.1

Synthesis of 3-Amino-5-cyanomethyl-1-{2-[4-(4-fluoro-phenyI)-piperazin-1-yl]-2-oxo-
etfeyl}-1H-pyrazole-4-carbonitrile

[0428] Protocol T was followed using 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile,
K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 3/2) afforded the title
compound as white solid. !H NMR (400 MHz, CDCI3) 5 6.96-7.2 (m, 2H), 6.86-6.92 (m,
2H), 5.2 (s, 2H), 4.86 (s, 2H), 3.78-3.86 (m, 4H), 3.7 (s, 2H), 3.08-3.16 (m, 4H). MS (ES)
M+H expected 367.39, found 368.1.
Synthesis of 1-[4-(4-FluorophenyI)-piperazin-1-yl]-2-(4-chloro-pyrazol)-ethanone

[0429] Protocol T was followed using 4-chloro-1H-pyrazole, K2CO3,2-Chloro-1-[4-(4-
fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 3/2) afforded the title compound as a white solid. 'HNMR
(400 MHz, CDCI3) 8 7.54-7.56 (d, 2H), 7.46 (s, 1H), 6.94-7.2 (m, 2H), 6.84-6.88 (m, 2H),
4.98 (s, 2H), 3.62-3.82 (m, 4H), 3.0-3.1 (m, 4H). MS (ES) M+H expected 322.77, found
323.1
Synthesis of 2-(3-Amino-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-
ethanone

[0430] Protocol T was followed using 5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-
1-[4-(4-fluoro-phenyl)-piperazm-1-yl]-ethanone and DMF. Column chromatography using a
solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title compound as a colorless oil.
'H NMR (400 MHz, CDC13) 8 7.12-7.18 (m, 3H), 7.0-7.08 (t, 2H), 4.8 (s, 2H), 5.1 (s, 2H),

3.78-3.88 (m, 4H), 3.18-3.38 (m, 4H), 2.28 (s, 3H). MS (ES) M+H expected 317.37, found
318.1
Synthesis of 3-Anmo-1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-m.ethyl-
lH-pyrazole-4-carboxylic acid ethyl ester

[0431] Protocol T was followed using 3-Amino-5-methyl-1H-pyrazole-4-carboxylic acid
ethyl ester, K2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the
title compound as a colorless oil. !H NMR (400 MHz, CDC13) 8 6.94-7.1 (m, 2H), 6.84-6.88
(m, 2H), 5.52 (s, 2H), 4.78 (s, 2H), 4.24-4.32 (q, 2H), 3.74-3.82 (m, 4H), 3.0-3.1 (m, 4H), 2.3
(s, 3H), 1.31-1.38 (t, 3H). MS (ES) M+H expected 389.43, found 390.1.
Synthesis of 2-(3-Amino-4-chloro-5-methyl-pyrazol-1-yI)- 1-[4-(4-fluorophenyl)-
piperazin-1-yl]-ethanone

[0432] Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, KL2CO3,
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4) afforded the title
compound as colorless oil. *H NMR (400 MHz, CDC13) 8 7.02-7.08 (m, 2H), 6.94-7.0 (t,
2H), 4.85 (s, 2H), 4.2 (s, 2H), 3.80-3.88 (m, 4H), 3.14-3.34 (m, 4H), 2.34 (s, 3H). MS (ES)
M+H expected 317.37, found 318.1. MS (ES) M+H expected 351.81, found 352.1.
Synthesis of2-(3-Amino-4-bronto-5-methyI-pyrazol-1-yI)-1-[4-(4-fluorophenyI)-
piperazin- l-yl]-ethanone

[0433] Protocol T was followed using 4-Bromo-5-methyl-1 H-pyrazol-3-ylamine, K2CO3,
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography ethyl acetate afforded the title compound as a colorless oil. *H NMR (400

MHz, CDCI3) 5 6.94-7.02 (m, 2H), 6.82-6.88 (t, 2H), 4.84 (s, 2H), 4.1 (s, 2H), 3.72-3.78 (m,
4H), 3.04-3.08 (m, 4H), 2.16 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES)
M+H expected 396.27, found 396.
Synthesis of 2-(5-tert-Butyl-3-trifluoromethyl-pyrazol-1-yI)-1-[4-(4-fluoro-phenyl)-
piperazin-1-yl]-ethanone

[0434] Protocol T was followed using 5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K2CO3,
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =1/1) afforded the title
compound as a colorless oil. "H NMR (400 MHz, CDC13) 5 6.94-7.08 (t, 2H), 6.82-6.88 (dd,
2H), 6.32 (s, 1H), 5.14 (s, 2H), 3.62-3.80 (m, 4H), 3.05-3.18 (m, 4H), 1.35 (s, 9H). MS (ES)
M+H expected 412.43, found 413.1
Synthesis of 2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-2H-
pyrazole-3-carboxylic acid ethyl ester

[0435] Protocol T was followed using 5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester,
K.2CO3,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =1/1) afforded the title
compound as a white solid. 'H NMR (400 MHz, CDC13) 5 6.94-7.0 (m, 2H), 6.84-6.88 (dd,
2H), 6.58 (s, 1H), 5.04 (s, 2H), 4.3-4.38 (q, 2H), 3.62-3.80 (m, 4H), 3.02-3.14 (m, 4H), 2.3 (s,
3H), 1.32-1.38 (t,3H). I3CNMR(400MHz, CDC13)5 180, 165,119,116.2,116, 109, 61.8,
52, 51.5, 50.8, 45.8, 42.6, 14.4, 10.2.
Synthesis of 2-(3,5-Diisopropyl-4-chloro-pyrazoI-1-yl)-1-[4-(4-fluoro-phenyl>piperazin-
l-yl]-ethanone


[0436] Protocol T was followed using 3,5-Diisopropyl-4—chloro-1H-pyrazole, K2CO3,2-
Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography
using a solvent mixture (hexane/ ethyl acetate = 1/1, Rf= 0.76 ) afforded the title compound
as white solid. MS (ES) M+H) expected = 406.9, found 407.1.
Synthesis of 2-{2-[4-(4-ChIoro-phenyI)-piperazin-1-yl]-2-oxo-ethyI}-5-thiophen-2-yl-2H-
pyrazole-3-carboxylic acid ethyl ester

[0437] Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid
ethyl ester, K2CO3,2-Chloro-1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1.5/1) afforded the
title compound. 'H NMR (400 MHz, CDC13) 6 7.34-7.38 Cm, 1H), 7.24-7.26 (m, 1H), 7.12
(s, 1H), 7.04-7.08 (dd, 1H), 6.96-7.2 (m, 2H), 6.88-6.94 (m, 2H), 4.32-4.42 (q, 2H), 3.52-3.58
(m, 4H), 3.05-3.35 (m, 4H), 1.32-1.42 (m, 3H). 13C NMR. (400MHz, CDC13) 5 164.2, 128,
126.8, 126.6, 120.2, 118.4, 115.2, 62.5, 54.2, 50.5, 42.6, 44, 14.6.
Synthesis of 2-(4-Amino-3-heptafluoropropyl-5-methyl—pyrazol-1-yl)-1-[4-(4-chloro-
phenyl)-piperazin-1-yl]-ethanone

[0438] Protocol T was followed using 4-Amino-3-heptafluoropropyl-5-methyl-1H-
pyrazole, K2CO3,2-Chloro-1-[4-(4-chloro-phenyl)-piperaz:in-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = %, Rf= 0.42)
afforded the title compound as colorless oil. !H NMR (40O MHz, CDC13) 5 6.88-6.94 (d,

2H), 7.22-7.26 (d, 2H), 4.98 (s, 2H), 3.64-3.82 (m, 4H), 3.1-3.22 (m, 4H), 2.98 (s, 2H), 2.18
(s„3H). MS (ES) M+H) expected = 501.82, found 502.1.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-ethyl-3-
trifluoromethyl-pyrazol-1-yI)-ethanone:

[0439] Protocol T was followed using 4-Chloro-5-ethyl-3-trifluoromethyH-H-pyrazol,
K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =2/3, Rf = 0.53) afforded the
title compound as white solid, 'H NMR (400 MHz, CDC13) 8 7.18-7.22 (d, 2H), 6.38-6.48
(m, 2H), 4.98 (s, 2H), 3.86 (s, 3H), 3.66-3.76 (m, 4H), 3.1-3.2 (m, 4H), 2.66-2.74 (q, 2H),
1.18-1.28 (m, 3H). MS (ES) M+H) expected = 464.82, found 465.
Synthesis of 2-(4-Chloro-5-isopropyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone:

[0440] Protocol T was followed using 4-Chloro-5-isopropyl-3 -trifluoromethyl-1 -H-pyrazol,
K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =5.5/4.5, Rf = 0.52) afforded
the title compound as white solid. lH NMR (400 MHz, CDC13) 8 7.19-7.22 (d, 2H), 6.42-
6.48 (m, 2H), 5.18 (s, 2H), 3.88 (s, 3H), 3.56-3.78 (m, 4H), 3.22-3.44 (m, 4H), 3.04-3.14 (m,
1H), 1.44-1.48 (d, 6H). 13C NMR (400MHz, CDC13) 8 164.2,154.8, 151, 130, 109.8, 102,
56.2, 54, 50.5, 50,45.2, 42.6, 26.2, 22.1.
Synthesis of 2-(4-Chloro-3-isopropyl-5-trifluoromethyI-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone:

y
[0441] Protocol T was followed using 4-Chloro-3-isopropyl-5-trifluoromethyl-1-H-pyrazol,
K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazme-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =2/3, Rf = 0.45) afforded the
title compound as white solid. XR NMR (400 MHz, CDC13) 8 7.19-7.22 (d, 2H), 6.38-6.48
(m, 2H), 5 (s, 2H), 3.86 (s, 3H), 3.62-3.78 (m, 4H), 3.08-3.18 (m, 4H), 2.98-3.04 (m, 1H),
1.35-1.41 (d, 6H). 13C NMR (400MHz, CDC13) 8 163.8, 154.8,150.5, 130, 109.8,102,
56.4, 52.8, 50,49.8, 45.2, 42.6, 26.8, 20.
Synthesis of 2-(4-ChIoro-3-n-propyl-5-trifluoromethyI-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyI)-piperazin-1-yl]-ethanone:

[0442] Protocol T was followed using 4-Chloro-3-n-propyl-5-trifluoromethyl-1-H-pyrazol,
K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column
chromatography using a solvent mixture (hexane/ ethyl acetate =3/7, Rf = 0.78) afforded the
title compound as white solid. JH NMR (400 MHz, CDC13) 5 7.22-7.24 (d, 2H), 6.42-6.48
(m, 2H), 5.7 (s, 2H), 3.8 (s, 3H), 3.72-3.78 (m, 4H), 3.22-3.42 (m, 4H), 2.66-2.72 (t, 2H),
1.58-1.68 (m, 2H), 0.98-1.02 (t, 3H). 13C NMR (400MHz, CDC13) 8 164, 154.8, 150.5, 130,
109.8, 102.2, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26, 21.8, 14.
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-bromo-3-phenyl-5-
trifluoromethyl-pyrazol-1-yl)-ethanone


[0443] Protocol T was followed using 4-Bromo-3-phenyl-5-tri£luoromethyl-1H-pyrazole,
K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate =1/1, Rf =0.51)
afforded the title compound as a white solid. *H NMR (400 MHz, CDC13) 8 7.42-7.52 (m,
5H), 7.18-7.22 (d, 1H), 6.38-6.42 (dd, 1H), 6.46-6.48 (d, 1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.5-
3.78 (m,4H), 3.18 (s,4H).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0444] Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole,
K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3, Rf = 0.92)
afforded the title compound as a white solid. lH NMR (400 MHz, CDC13) 5 7.78-7.84 (m,
2H), 7.36-7.52 (m, 4H), 6.38-6.48 (m, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62-3.78 (m, 4H), 3.18-
3.26 (s, 4H). 13C NMR (400 MHz, CDCI3) 164.4, 156,150.4, 130.4,130, 128.6, 110.2,
102.4, 56.4, 52, 50.4,44.6, 42.
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[3-Fluoro-
phenyl]-5-trifluoromethyl-pyrazol-1-yl)-ethanone

[0445] Protocol T was followed using 4-Chloro-3-[3-Fluorophenyl]-5-trifluoromethyI- 1H-
pyrazole, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and
DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3, Rf=
0.51) afforded the title compound as a white solid. *H NMR (400 MHz, CDCI3) 6 7.44-7.52
(m, 1H), 7.18-7.28 (m, 4H), 6.38-6.48 (m, 2H), 4.94 (s, 2H), 3.84 (s, 3H), 3.52-3.78 (m, 4H),
3.12 (s, 4H).

Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)-piperazln-1-yl]-2-(4-chIoro-5-[3-Fluoro-
I*faenyl]-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0446] Protocol T was followed using 4-CMoro-5-[3-Fluorophenyl]-3-trifluoromethyl-1H-
pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and
DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate = 2/3, Rf =
0.59) afforded the title compound as a white solid. ]H NMR (400 MHz, CDC13) 5 7.64-7.68
(d, 1H), 7.56-7.62 (d, 1H), 7.36-7.42 (ra, 1H), 7.22-7.24 (m, 2H), 7.08-7.12 (m, 1H), 6.42-
6.52 (m, 2H), 5.2 (s, 2H), 3.9 (s, 3H), 3.62-3.82 (m, 4H), 3.12-3.22 (m, 4H).
1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-ylj-2-(4-chloro-3,5-ditrifluoromethyl-
pyrazol-1-yl)-ethanone:

[0447] The general protocol T was followed using 4-Chloro-3, 5-ditrifluoromethyl-
pyrazole, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone, and
DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded
the title compound as white solid. lH NMR (400 MHz, CDCI3) 5 7.22-7.24 (m, 2H), 6.42-
6.52 (m, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.58-3.82 (m, 4H), 3.14-3.24 (m, 4H). MS (ES)
(M+H) expected = 505.24, found 506.
1-[4-(4-ChIoro-3-methoxyphenyl)-piperazin-1-yl]-2-(3-methyI-4,5-dibromopyrazol-1-yl)-
ethanone:


[0448] The general protocol T was followed using 3-Methyl-4, 5-dibromo-py-razole,
K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1) afforded the
title compound as white solid. 'H NMR (400 MHz, CDCI3) 8 7.22-7.23 (m, 1HQ, 6.42-6.50
(m, 2H), 4.95 (s, 2H), 3.90 (s, 3H), 3.68-3.78 (m, 4H), 3.14-3.24 (m, 4H). MS expected = 506.6, found 506.9.
2-(3-Amino-4-chIoro-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyphen.yl)-
piperazin-1-yl]-ethanone:

[0449] The general protocol T was followed using 4-Chloro-5-phenyl-1H-pyxazol-3-
ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone, and
DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/4, Rf=
0.68) afforded the title compound as white solid. !H NMR (400 MHz, CDC13) 5 7.79-7.81 (d,
2H), 7.32-7.42 (m, 3H), 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 4.94 (s,
2H), 4.28 (s, 2H), 3.88 (s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18 (m, 4H). MS (ES} (M+H)
expected = 460.36, found 460.
1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chIoro-3,5-dimethyl-pyrazol-1-
yl)-ethanone:

[0450] The general protocol T was followed using 4-Chloro-3, 5-dimethyl-pyrazole,
K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone, and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1, Rf= 0.28)
afforded the title compound as white solid. lH NMR (400 MHz, CDCI3) 5 7.19-7.22 (m, 2H),
6.39-6.49 (m, 2H), 4.86 (s, 2H), 3.84 (s, 3H), 3.64-3.78 (m, 4H), 3.1-3.18 (m, 4-H), 2.12-2.42
(d, 6H). MS (ES) (M+H) expected = 397.3 , found 397.

1-[4-(4-Chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(4-chloro-3-phenyl-5-
fcrifluoromethyl-pyrazol-1-yl)-ethanone:

[0451] The general protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-
lH-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-
yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 2/3, Rf= 0.6) afforded the title compound as white solid. 'H NMR (400 MHz,
CDCI3) 5 7.4-7.52 (m, 5H), 7.19-7.22 (d, 1H), 6.38-6.48 (d, 2H), 4.78-5.22 (m, 3H), 4.4-4.42
(m, 2H), 4.0 (s, 1H), 3.88 (s, 3H),3.42-3.58 (m, 2H), 3.32-3.38 (d, 1H), 3.15 (s, 1H), 2.72-
2.96 (m, 3H) 1.28-1.38 (m, 4H). MS (ES) (M+H) expected = 527.4, found 527.
1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(3-methyl-4-chloro-5-bromo
pyrazol-1-yl)-ethanone:

[0452] The general protocol T was followed using 3-Methyl-4-chloro-5-bromo-pyrazole,
K.2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate =1/1) afforded the
title compound as white solid. 'H NMR (400 MHz, CDC13) 5 7.22-7.23 (m, 1H), 6.42-6.50
(m, 2H), 4.92 (s, 2H), 3.90 (s, 3H), 3.70-3.80 (m, 4H), 3.12-3.22 (m, 4H). MS (ES) (M+H)
expected = 462.17, found 462.9.
1-[4-(4-Chloro-3-methoxy-phenyI)-2-(S)-methyl-piperazin-1-yI]-2-(3-methyl-4-chloro-5-
bromopyrazol-1-yl)-ethanone:


[0453] The general protocol T was followed using 3-Methyl-4-chloro-5-bromo-pyrazole,
K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone,
and DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/1)
afforded the title compound as white solid. fH NMR (400 MHz, CDCI3) 5 7.18-7.22 (m, 1H),
6.38-6.46 (m, 2H), 4.78-5.22 (m, 3H), 4.38-4.42 (m, 1H), 4.2 (s, 1H), 3.85 (s, 3H), 3.8 (s,
1H), 3.42-3.58 (m, 2H), 3.32-3.38 (d, 1H), 3.15 (s, 1H), 2.72-2.96 (m, 3H) 1.26-1.38 (m, 4H).
MS (ES) (M+H) expected = 476.19, found 476.9.
1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[2-fluoro-phenyl]-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0454] The general protocol T was followed using 4-Chloro-5-[2-fluorophenyl]-3-
trifluoromethyl-1 H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 2/3, Rf= 0.6) afforded the title compound as white solid. 'H NMR (400 MHz,
CDCI3) 5 7.44-7.56 (m, 2H), 7.26-7.32 (t, 1H), 7.18-7.26 (m, 2H), 6.44-6.46 (d, 1H), 6.36-
6.42 (dd, 1H), 4.95 (s, 2H), 3.86 (s, 3H), 3.5-3.68 (m, 4H), 3.02-3.14 (s, 4H). MS (ES)
(M+H) expected = 531.3, found 531.
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-phenyl-
pyrazol-1-yl)-ethanone:

[0455] The general protocol T was followed using 4-Chloro-5-methyl-3-phenyl-pyrazole,
K.2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
Column chromatography using a solvent mixture (hexane/ ethyl acetate = 1/3, Rf = 0.7)
afforded the title compound as white solid. 'H NMR (400 MHz, CDCI3) 5 7.82-7.88 (m, 2H),
7.38-7.42 (t, 2H), 7.32-7.36 (m, 1H), 7.18-7.22 (d, 1H), 6.38-6.48 (m, 2H), 4.99 (s, 2H), 3.88

(s, 3H), 3.72 (m, 4H), 3.08-3.18 (m, 4H), 2.34 (s, 3H). MS (ES) (M+H) expected = 459.38,
found 459.
1-[4_(4-Chloro-3-methoxyphenyI)-piperazin-1-yl]-2-(4-chloro-3-[2-fluoro-phenyl]-5-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0456] The general protocol T was followed using 4-Chloro-5-[2-fluorophenyi]-3-
trifluoromethyl-1H-pyrazole, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 2/3, Rf = 0.6) afforded the title compound as white solid. 'H NMR (400 MHz,
CDCI3) 5 7.52-7.58 (m, 1H), 7.38-7.46 (m, 1H), 7.14-7.26 (m, 3H), 6.44-6.51 (m, 2H), 5.22
(s, 2H), 3.84 (s, 3H), 3.62-3.82 (m, 4H), 3.12-3.24 (m, 4H). MS (ES) (M+H) expected =
531.0, found,531.
1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chIoro-3-[4-trifluoromethyl-
phenyl]-5-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0457] The general protocol T was followed using 4-Chloro-5-[4-trifluoromethylphenyl]-3-
trifluoromethyl-1H-pyrazole, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/3, Rf= 0.91) afforded the title compound as colorless oil. ]H NMR (400 MHz,
CDCI3) § 7.99-8.12 (d, 1H), 7.66-7.71 (d, 1H), 7.22-7.24 (m, 1H), 6.44-6.52 (m, 2H), 5.22 (s,
2H), 3.85 (s, 3H), 3.62-3.82 (m, 4H), 3.16-3.24 (m, 4H). MS (ES) (M+H) expected = 581.35,
found 581.

1-[4-(4-ChIoro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[4-trifluoromethyl-
phenyl]-3-trifluoromethyl-pyrazol-1-yI)-ethanone:

[0458] The general protocol T was followed using 4-Chloro-3-[4-trifluoromethylphenyl]-5-
trifluoromethyl-1H-pyrazole, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/3, Rf = 0.85) afforded the title compound as white solid. 'H NMR (400 MHz,
CDCI3) 8 7.78-7.8 (d, 1H), 7.62-7.66 (d, 1H), 7.20-7.22 (m, 1H), 6.40-6.48 (m, 2H), 4.92 (s,
2H), 3.88 (s, 3H), 3.60-3.78 (m, 4H), 3.16-3.20 (m, 4H). MS (ES) (M+H) expected = 581.35,
found 581.
1-[4-(4-ChIoro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[4-methoxyphenyl]-5-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0459] The general protocol T was followed using 4-Chloro-5-[4-methoxyphenyl]-3-
trifluoromethyl-1 H-pyrazole, K2CO3, 2-Chloro-l -[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 3/7, Rf= 0.45) afforded the title compound as colorless oil. 'H NMR (400 MHz,
CDCI3) 8 7.76-7.78 (d, 1H), 7.22-7.24 (d, 1H), 6.94-6.96 (d, 1H), 6.42-6.52 (m, 2H), 4.98 (s,
2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.62-3.82 (m, 4H), 3.16-3.24 (m, 4H). MS (ES) (M+H)
expected = 543.38, found 543.
1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chIoro-5-[4-methoxyphenyl]-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:


[0460] The general protocol T was followed using 4-Chloro-5-[4-methoxyphenyl]-3-
trifluoromethyl-1 H-pyrazole, K2CO3,2-Chloro-l -[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 3/7, Rf = 0.36) afforded the title compound as colorless oil. *H NMR (400 MHz,
CDC13) 5 7.36-7.39 (d, 1H), 7.20-7.22 (d, 1H), 6.88-7.22 (d, 2H), 6.38-6.48 (m, 2H), 4.92 (s,
2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.56-3.78 (m, 4H), 3.14-3.18 (m, 4H). MS (ES) (M+H)
expected = 543.38, found 542.9.
2-[4-Chloro-5-(4-fluoro-phenyl)-3-methylsulfanyl-pyrazol-1-yl]-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone:

[0461] The general protocol T was followed using 4-Chloro-5-(4-fluoro-phenyl)-3-
methylsulfanyl-pyrazol-1-yl, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/4, Rf = 0.77) afforded the title compound as colorless oil. *H NMR (400 MHz,
CDCI3) 5 7.82-7.88 (m, 2H), 7.21-7.25 (m, 1H), 7.04-7.14 (t, 2H), 6.42-6.51 (m, 2H), 5.4 (s,
2H), 3.9 (s, 3H), 3.7-3.8 (m, 4H), 3.25-3.52 (m, 4H), 2.4 (s, 3H). 13C NMR (400 MHz,
CDC13)8 164.8, 158, 152,147,135, 131, 130, 119, 115.4, 115, 110, 104, 56.5, 52.8, 50.8, 50,
45.4,42.2,18.6.
1-[4-(4-ChIoro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[4-fluorophenyl]-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0462] The general protocol T was followed using 4-Chloro-3-[4-fluorophenyl]-5-
trifluoromethyl-1 H-pyrazole, K.2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 3.5/6.5, Rf= 0.83) afforded the title compound as white solid. *H NMR (400 MHz,
CDCI3) 8 7.44-7.49 (m, 2H), 7.14-7.22 (m, 3H), 6.38-6.48 (m, 2H), 4.9 (s, 2H), 3.89 (s, 3H),

3.54-3.78 (m, 4H), 3.14 (s, 4H). I3C NMR (400 MHz, CDC13) 5 164.8, 162, 155,152,143,
132, 131,122,115.4,115,110,100, 56.2, 52.2, 50.8, 50, 45.4,42.2.
2-[4-Chloro-3-(5-chloro-thiophen-2-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chIoro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone:

[0463] The general protocol T was followed using 4-Chloro-3-(5-chloro-thiophen-2-yl)-5-
methyl-pyrazol-1 -yl, K2CO3,2-Chloro-1 -[4-(4-chloro-3-methoxy-phenyl)-piperazin-1 -yl]-
ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate
= 1/ 4, Rf= 0.8) afforded the title compound. *H NMR (400 MHz, CDC13) 5 7.39-7.41 (d,
1H), 7.21-7.24 (m, 1H), 6.86-6.88 (d, 1H), 6.42-648 (dd, 1H), 6.48-6.51 (m, 1H) 4.95 (s, 2H),
3.88 (s, 3H), 3.72-3.82 (m, 4H), 3.11-3.21 (m, 4H), 2.3 (s, 3H).
2-[4-Chloro-3-(2-thiophene)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy phenyl)-
piperazin-1-yl]-ethanone:

[0464] The general protocol T was followed using 4-Chloro-3-(5-chloro-thiophen-2-yl)-5-
methyl-pyrazol-1-yl, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-l -yl]-
ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate
= 1/ 4, Rf= 0.8) afforded the title compound. JH NMR (400 MHz, CDC13) 8 7.62-7.66 (m,
1H), 7.24-7.26 (m, 1H), 7.18-7.22 (d, 1H), 7.45-7.8 (m, 1H), 6.39-6.48 (m, 2H), 4.95 (s, 2H),
3.86 (s, 3H), 3.70-3.78 (m, 4H), 3.09-3.18 (m, 4H), 2.3 (s, 3H).
2-(4-Chloro-5-hydroxymethyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone:


[0465] The general protocol T was followed using 4-Chloro-5-hydroxymethyl-3-
*rifluoromethyl-pyrazol-l -yl, K2CO3, 2-Chloro-l -[4-(4-chloro-3-raethoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 8, Rf= 0.5) afforded the title compound. ]H NMR (400 MHz, CDC13) 5 7.21-7.28
(m, 1H), 6.41-6.51 (m, 2H), 5.18 (s, 2H), 4.66 (s, 2H), 3.86 (s, 3H), 3.70-3.78 (m, 4H), 3.11-
3.24 (m,4H).
2-(4-Chloro-5-methoxymethyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone:

[Q466] The general protocol T was followed using 4-Chloro-5-methoxymethyl-3-
trifluoromethyl-pyrazol-1 -yl, K2CO3,2-Chloro- 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 4, Rf= 0.65) afforded the title compound. 'H NMR (400 MHz, CDC13) 5 7.15-
7.18 (d, 1H), 6.65-6.68 (d, 1H), 6.51-6.58 (dd, 1H), 5.32 (s, 2H), 4.58 (s, 3H), 4.52 (s, 2H),
3.86 (s, 3H), 3.70-3.75 (m, 4H), 3.18-3.28 (m, 4H). MS (ES) (M+H) expected = 481.31,
found 481.2.
4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyI-
lH-pyrazole-3-carboxylic acid ethyl ester:

[0467] The general protocol T was followed using 4-Chloro-5-methyl-1H-pyrazole-3-
carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-
yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 4, Rf= 0.81) afforded the title compound. 'H NMR (400 MHz, CDC13) 5 7.18-
7.21 (d, 1H), 6.66-6.68 (d, 1H), 6.52-6.55 (dd, 1H), 5.42 (s, 2H), 4.30-4.36 (q, 2H), 3.85 (s,
3H), 3.70-3.77 (m, 4H), 3.18-3.28 (m, 4H), 2.22 (s, 3H), 1.32-1.38 (t, 3H). MS (ES) (M+H)
expected = 455.34, found 455.2.

4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-
}H-pyrazole-5-carboxylic acid ethyl ester:

[0468] The general protocol T was followed using 4-Chloro-3 -methyl- lH-pyrazole-5-
carboxylic acid ethyl ester, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-
yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 4, Rp 0.75) afforded the title compound. 'H NMR (400 MHz, CDC13) 8 7.19-
7.22 (d, 1H), 6.64-6.66 (d, 1H), 6.54-6.58 (dd3 1H), 5.44 (s, 2H), 4.30-4.35 (q, 2H), 3.85 (s,
3H), 3.70-3.77 (m, 4H), 3.20-3.28 (m, 4H), 2.24 (s, 3H), 1.34-1.38 (t, 3H). MS (ES) (M+H)
expected = 455.34, found 455.2.
2-(4-Chloro-5-cyclopropyl-3-trifIuoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone:

[0469] The general protocol T was followed using 4-Chloro-5-cyclopropyl-3-
trifluoromethyl-pyrazol-1-yl, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 5, Rf= 0.88) afforded the title compound. JH NMR (400 MHz, CDC13) 5 7.20-
7.24 (d, 1H), 6.48-6.50 (d, 1H), 6.42-6.46 (dd, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.58-3.78 (m,
4H), 3.14-3.24 (m, 4H), 1.86-1.94 (m, 1H), 0.51-0.59 (m, 4H). MS (ES) (M+H) expected =
477.32, found 477.2.
4-Chloro-1-{2-[4-(4-chIoro-3-methoxy-phenyl)-2-methylpiperazin-1-yl]-2-oxo-ethyl}-5-
methyl-1H-pyrazole-3-carboxylic acid ethyl ester:

[0470] The general Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazole-3-
carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-

methyl-piperazin-1-yl]-ethanone, and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1/ 4, Rf= 0.81) afforded the title compound: HPLC retention
time = 4.51 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
2-(4-Chloro-3-(3-Methoxyphenyl)-5-trifluoromethyl-pyrazol-1-yI)-1-[4-(4-chIoro-3-
methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone:

[0471] The general protocol T was followed using 4-Chloro-3-(3-Methoxyphenyl)-5-
trifluoromethyl-pyrazol-1-yl, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
1 -yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 5, Rf= 0.82) afforded the title compound. !H NMR (400 MHz, CDC13) 8 7.42-
7.48 (m, 2H), 7.28-7.34 (m, 1H), 7.19-7.22 (d, 1H), 6.86-6.91 (dd, 1H), 6.39-6.47 (m, 2H),
4.99 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72-3.8 (m, 4H), 3.12-3.18 (m, 4H), 2.3 (3H). MS
(ES) (M+H) expected = 491.34, found 491.2. 13C NMR (400 MHz, CDC13) 5 164.8,160,
156,152, 145, 140,132,131, 120, 115.4,115,110,108, 100, 56.2, 52.2, 50.8, 50,45.4,42.2,
20.
4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methylpiperazin-1-yl]-2-oxo-ethyl}-3-
methyl-1H-pyrazole-5-carboxylic acid ethyl ester:

[0472] The general protocol T was followed using 4-Chloro-3-methyl-1 H-pyrazole-5-
carboxylic acid ethyl ester, K2CO3,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-
methyl-piperazin-1-yl]-ethanone, and DMF. Column chromatography using a solvent
mixture (hexane/ ethyl acetate = 1/ 4, Rt= 0.75) afforded the title compound: HPLC retention
time = 4.74 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5|i, 35°C) using a 4.5 minute

gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
2-(4-Chloro-3-cyclopropyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl J-ethanone:

[0473] The general protocol T was followed using 4-Chloro-3-cyclopropyl-5-
trifluoromethyl-pyrazol-1-yl, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-
l-yl]-ethanone, and DMF. Column chromatography using a solvent mixture (hexane/ ethyl
acetate = 1/ 5, Rf= 0.83) afforded the title compound. 'H NMR (400 MHz, CDC13) 8 7.20-
7.24 (d, 1H), 6.46-6.49 (d, 1H), 6.42-6.46 (dd, 1H), 5.1 (s, 2H), 3.88 (s, 3H), 3.65-3.78 (m,
4H), 3.14-3.24 (m, 4H), 1.65-1.72 (m, 1H), 1.01-1.12 (m 2H), 0.51-0.59 (m, 2H). MS (ES)
(M+H) expected = 477.32, found 477.22.
2-(4-Chloro-5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chIoro-3-methoxy-
phenyl)-2-methyl-piperazin-1-yl]-ethanone:

[0474] The general protocol T was followed using 4-Chloro-5-cyclopropyl-3-
trifiuoromethyl-pyrazol-1-yl, K2CO3, 2-Chloro-l -[4-(4-chloro-3-methoxy-phenyl)-2-(S)-
methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture
(hexane/ ethyl acetate = 1/ 5, Rf= 0.68) afforded the title compound. !H NMR (400 MHz,
CDCI3) 5 7.19-7.22 (d, 1H), 6.41-6.49 (m, 2H), 4.94-5.26 (m, 2H), 4.8 (s, 1H), 4.41-4.44 (d,
1H), 4.0 (s, 1H), 3.91 (s, 3H), 3.52-3.58 (d, 2H), 3.36-3.42 (m, 1H), 3.2 (s, 1H), 2.8 (s, 1H),
1.84-1.94 (m, 1H), 1.3-1.5 (m, 3H), 0.51-0.59 (m, 4H). MS (ES) (M+H) expected = 491.34,
found 491.2.

2-(4-Chloro-3-cyclopropyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chIoro-3-methoxy-
phenyl)-2-methy!-piperazin-1-yl]-ethanone:

[0475] The general protocol T was followed using 4-Chloro-3-cyclopropyl-5-
trifluoromethyl-pyrazol-1 -yl, K2CO3,2-Chloro-1 - [4-(4-chloro-3 -methoxy-phenyl)-2-(S)-
methyl-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture
(hexane/ ethyl acetate = 1/ 5, Rf= 0.62) afforded the title compound. !H NMR (400 MHz,
CDCI3) 8 7.19-7.22 (d, 1H), 6.39-6.48 (m, 2H), 5.01-5.21 (m, 2H), 4.75 (s, 1H), 4.38-4.42 (d,
1H), 4.18 (s, 1H), 3.92 (s, 3H), 3.53-3.59 (d, 2H), 3.42-3.48 (m, 1H), 3.25 (s, 1H), 2.8 (s,
1H), 1.84-1.94 (m, 1H), 1.3-1.5 (m, 3H), 0.98-1.41 (d, 2H), 0.51-0.59 (m, 2H). MS (ES)
(M+H) expected = 491.34, found 491.2.
PROTOCOL U: for the KiCQ* mediated coupling reaction of chloroacetvl substituted
arvlpiperazines with novel heterarvl ring systems
Synthesis of 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-[5-nitro-indazol-1-yl]-ethanone

[0476] 2-Chloro-1-[4-(4-fiuoro-phenyl)-piperazin-l -yl]-ethanone (0.834 g, 3.3 mmol) was
taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g, 11.6 mmol) was added to it
and the reaction mixture stirred at room temperature for lh under nitrogen. 5-Nitro-1H-
indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added to the mixture through a syringe.
The reaction was heated at 70°C for 14h, cooled and then quenched with water and extracted
with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration
afforded material that on purification on neutral alumina column (pet ether/ethyl acetate)
gave title compound as a pale yellow solid.

Synthesis of 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-[7-nitro-indazol-1-yll-ethanone
r
[0477] 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3 mmol) was
taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g, 11.6 mmol) was added to it
and the reaction mixture stirred at room temperature for lh under nitrogen. 7-Nitro-1H-
indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added to the mixture through a syringe.
The reaction was then heated at 70°C for 14h, cooled and then quenched with water and
extracted with ethyl acetate. Drying of the organic layer with Na2SC>4 followed by
concentration afforded material that was purified on neutral alumina column (pet ether/ethyl
acetate). The resulting solid was recrystallized from DCM/pet ether to obtain pure product as
a pale yellow solid.
Synthesis of 2-Benzoimidazol-1-yl-1-[4-(4-chloro-phenyI)-piperazin-1-yl]-ethanone

[0478] Benzimidazole (0.785 g, 0.7 mmol) was taken in dry DMF (15 mL) and dry
potassium carbonate (340 mg) and KI (20 mg) was added to it and the reaction mixture
stirred at room temperature for lh under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-
piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 mL) was then added to the mixture
through a syringe. The reaction was then heated at 140°C for 14h, cooled and then quenched
with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4
followed by concentration gave material that on purification by flash chromatography
(CHCl3/MeOH) afforded pure product: 'H NMR (300 MHz, CDC13) 5 8.10-7.65.(m, 4H),
7.26 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.79-3.66 (m, 4H), 3.14 (br, 4H).

Synthesis of 1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(2,4-dimethyl-imidazoI-1-yl)-
"ethanone

[0479] 2,4-dimethylimidazole (0.633 g, 0.7 mmol) was taken up in dry DMF (15 mL) and
dry potassium carbonate (340 mg) and KI (20 mg) was added and the reaction mixture was
stirred at room temperature for lh under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-
piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 mL) was then added to the mixture
through a syringe. The reaction was then heated at 140°C for 14h, cooled and quenched with
water and extracted with ethyl acetate. Drying of the organic layer with Na2SC>4 followed by
concentration gave material that was purified on a silica gel column (CHCl3/MeOH) 5 >H
NMR (300 MHz, CDC13) 8 7.25 (d, 2H), 6.80 (d, 2H), 6.53 (s, 1H), 4.62 (s, 2H), 3.78 (br,
2H), 3.59 (br, 2H), 3.21 (br, 4H), 2.31 (s, 3H), 2.17 (s, 1H).
Synthesis of 2-(5-Amino-3-methylsulfany1-[l,2,4]triazol-1-yl)-1-[4-(4-chloro-phenyl>-
piperazin-1-yI]-ethanone

[0480] 5-Methylsulfanyl-2H-[l,2,4]triazol-3-ylamine (0.216 g, 1.7 mmol) was taken in dry
DMF (15 mL) and dry potassium carbonate (800 mg) and KI (20 mg) was added to it and the
reaction mixture stirred at room temperature for lh under nitrogen. 2-Chloro-1-[4-(4-chloro-
phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 mL) was then added to the
mixture through a syringe. The reaction was then heated at 140°C for 14h ,cooled and then
quenched with water and extracted with ethyl acetate. Drying of the organic layer with
Na2SO4 followed by concentration afforded crude product that was purified by column
chromatography (CHCl3/MeOH) 5 *H NMR (300 MHz, T>MSO-d6) 5 7.24 (d, 2H), 6.98 (d,
2H), 6.24 (s, 2H), 4.84 (s, 2H), 3.57 (m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 2.37 (s, 3H).

Synthesis of 2-[5-(2-Bromo-phenyI)-tetrazoI-1-yl]-1-[4-(4-chloro-phenyl)-piperazin-1-
yl]-ethanone

[0481] 5-phenyl-1H-tetrazole (0.1216 g, 0.832 mmol) was taken in dry DMF (15 mL) and
dry potassium carbonate (400 mg) and KI (20 mg) was added to it and the reaction mixture
stirred at room temperature for lh under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-
piperazin-1-yl]-ethanone (250 mg, 0.92 mmol) in DMF (5 mL) was then added to the mixture
through a syringe. The reaction was then heated at 140°C for 14h, cooled and quenched with
water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by
concentration afforded material that was further purified by flash column chromatography
(ethyl acetate/pet ether): !H NMR (300 MHz, CDC13) 8 8.17 (br, 2H), 7.49 (br, 3H), 7.24 (br,
2H), 6.85 (br, 2H), 5.60 (s, 2H), 3.82 (m, 2H), 3.71 (m3 2H), 3.19 (m, 4H).
Synthesis of 2-[5-(2-Bromo-phenyl)-tetrazol-1-yl]-1-[4-(4-chloro-phenyl)-piperazin-1-
yl]-ethanone

[0482] 5-(2-Bromo-phenyl)-1H-tetrazole (0.374 g, 1.66 mmol) was taken in dry DMF (15
mL) and dry potassium carbonate (800 mg) and KI (20 mg) was added to it and stirred at rt
for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg,
1.8 mmol) in DMF (5 mL) was then added to the mixture through a syringe. The reaction
was then heated at 140°C for 14 h, cooled and quenched with water and extracted with ethyl
acetate. Drying of the organic layer with Na2SC>4 followed by concentration afforded
material that was further purified by flash column chromatography (ethyl acetate/pet ether):
*H NMR (300 MHz, CDC13) 8 7.90 (d, 1H), 7.74 (d, 1H), 7.45 (t, 1H), 7.35 (t, 1H), 7.25 (d,
2H), 6.87 (d, 2H), 5.65 (s, 2H), 3.84 (m, 2H), 3.73 (m, 2H), 3.20 (m, 4H).

Synthesis of 2-(5-methyl-3-trifluoromethyl-l,2,4-triazol-1-yl)-1-[4-(4-chIoro-3-methoxy-
3->henyl)-piperazin-1-yl] -ethanone:

[0483] 0.04 g (0.00026 mol) of 5-Methyl-3-trifluoromemyl-l,2,4-triazole, 0.078 g (0.00026
mol) of l-(chloroacetyl)-4-(4-chloro-3-methoxyphenyl)-piperazine, and 0.04 g (0.0004 mol)
of potassium carbonate in 3 mL dry DMF were heated at 80°C for 14 hours. The reaction
mixture was quenched with water, and was extracted with ethyl acetate. The ethyl acetate
phase was washed once each with water and brine, dried with Na2SC>4, filtered, and
concentrated to give 2-(5-methyl-3-trifluoromethyl-l,2,4-triazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone; 'H NMR (CDCl3,300MHz) 5 7.22 (m, 1H), 6.48
(s, 1H), 6.443 (m, 1H), 5.07 (s, 2H), 3.87 (s, 3H), 3.71 (m, 4H), 3.18 (m, 4H), 2.50 (s, 3H)
ppm; MS (ES) M+H expect = 418.0, found = 418.2.
PROTOCOL V: Preparation of compounds via acid or base-mediated de-protections.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-3-(R)-hydroxymethyl-piperazin-1-yl]-2-
(4-chloro-5-methyI-3-trifluoromethyl-pyrazol-1-yl)-ethanone and Acetic acid l-(4-
chloro-3-methoxy-phenyl)-4-[2-(4-chloro-5-methyI-3-trifluoromethyl-pyrazoI-1-yl)-
acetyI]-piperazin-2-(R)-ylmethyl ester:


[0484] To 620 mg (1.79 mmol) of 2-(R)-Benzyloxymethyl-1-(4-chloro-3-methoxy-phenyl)-
piperazine, 500 mg (2.05 mmol) of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetic acid, and 280 mg (2.05 mmol) of 1-Hydroxybenzotriazole in 6 mL of N,N-
Dimethylformamide at 0°C was added 430 mg (2.24mmol) of 1-[3-(Dimethylamino)propyl]-
3-ethylcarbodiimide hydrochloride. After two hours, the reaction was allowed to warm to
ambient temperature, and was stirred for an additional 12 hours. The solution was partitioned
between water and ethyl acetate, and the phases were separated. The ethyl acetate phase was
washed once each with 1M NaHSO4, water, 1M NaOH, water, and brine, dried over Na2SO4,
filtered, and concentrated to an oil.
[0485] The oil from above was heated in 6 mL of 48% HBr in acetic acid, with an
additional 5 mL of acetic acid, at 70°C for one hour, followed by cooling to ambient
temperature. The mixture was partitioned between ethyl acetate and water, and the phases
were separated. The ethyl acetate phase was washed once each with 1M NaOH and brine,
dried over Na2SC>4 , filtered, and concentrated. The residue was chromatographed to give 1-
[4-(4-Chloro-3-methoxy-phenyl)-3-(R)-hydroxymethyl-piperazin-1-yl]-2-(4-chloro-5-methyl-
3-trifluoromethyl-pyrazol-1-yl)-ethanone as a white foam: 'H NMR (DMSO-d6, 400MHz) 8
7.1 8 (m, 1H), 6.59 (m, 1H), 6.51 (m, 1H), 5.43 (m, 1H), 5.24 (m, 1H), 5.14 (m, 1H), 4.34-
3.90 (m, 2H), 3.18 (s, 3H), 3.17 (par.obscm, 1H), 3.49-3.30 (m, 4H), 3.27-3.07 (m, 3H), 2.18
(m, 3H) ppm (rotomers); MS (ES) M+H expect = 481.0, found = 481.0.
[0486] In addition, Acetic acid l-(4-chloro-3-methoxy-phenyl)-4-[2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-2-ylmethyl ester was also isolated as a
colorless glass: lH NMR (DMSO-d6, 400MHz) 5 7.19 (m, 1H), 6.68 (s, 1H), 6.46 (m, 1H),
5.50 (m, 1H), 5.37(m, 1H), 4.28-3.87 (m, 5H), 3.82 (s, 3H), 3.59-3.10 (m, 4H), 2.18 (s, 3H),
1.84 (m, 3H) ppm (rotomers); MS (ES) M+H expect = 523.0, found = 523.0.

Synthesis of 1-[4-(4-Chloro-3-methylaminomethyl-phenyI)-piperazin-1-yl]-2-(4-chloro-
S-methyl-3-trifluoromethyl-pyrazoI-1-yl)-ethanone:

[0487] 90 mg (0.15 mmol) of (2-Chloro-5- {4-[2-(4-chloro-5-methyl-3-trifluoromethyl-
p>Tazol-1-yl)-acetyl]-piperazin-1-yl}-benzyl)-methyl-carbarnic acid benzyl ester was treated
with an excess of HBr/AcOH at room temperature for several hours, then purified by prep
HPLC to give 1-[4-(4-Chloro-3-methylamiaomethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone: *H NMR (CDCIJ, 400MHz) 5 7.30 (d, 1H),
7.L0 (s, 1H), 6.87 (d, 1H), 5.08 (s, 2H), 4.24 (s, 2H), 3.71 (d, 4H), 3.21 (d, 4H), 2.71 (s, 3H),
2.28 (s, 3H) ppm MS (ES) M+H expect = 464.1, found = 464.0.
Synthesis of 1 -[4-(3-Amino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0488] 284 mg (0.5 mmol) of 1 -[4-(3-tert-Butoxycarbonylamino-4-chloro-phenyl)-
piperazin-1 -yl]-2-(4-chloro-5-methyl-3 -trifluoromethyl-pyrazol-1 -yl)-ethanone was dissolved
in a 1 mL each of acetonitrile, methanol, and 5M HC1 in isopropanol. After several hours, the
title compound was isolated as a solid by filtration: [H NMR (DMSO-d6,400MHz) 8 7.24
(m, 1H), 7.15 (br, 4 H), 6.88 (s, 1H), 6.67 (m, 1H), 5.41 (s, 2H), 3.70 (m, 4H), 3.31 (m, 2H),
3.22 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H expect = 436.0, found = 436.0.

Synthesis of 4-(4-Chloro-3-methoxy-phenyl)-1-[2-(4-chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetyl] -piperazine-2-carboxylic acid:

[0489] Title compound was prepared following the HATU mediated coupling protocol P,
wherein 4-(4-Chloro-3-methoxy-phenyl)-piperazine-2-carboxylic acid (-)-menthol ester and
(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling
components, to give the product as a solid. The product was further treated with a ten-fold
excess of LiOH in 1/1 THF/water for 24 hours, and the reaction was purified by reverse
phase HPLC to give the product as an oil: !H NMR (400 MHz, CDClj) 8 7.27 (s, 1H), 6.79
(d, 1H), 6.59 (d, 1H), 5.22 (m, 2H), 3.91 (s, 3H), 3.05- 2.99 (m, 3H), 3.32- 3.19 (m, 4H), 2.29
(m, 3H), 2.06 (m, 1H) MS (ES) (M+H) expected = 495.1, found = 495.1
PROTOCOL W: Preparation of compounds via borohydride-mediated reductive
alkylation.
Synthesis of 1-[4-(4-Chloro-3-methylamino-phenyI)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazoI-1-yl)-ethanone:

[0490] To 60 mg (0.13 mrnol) ofl -[4-(3-Amino-4-chloro-phenyl)-piperazin-l -yl]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanonein 1 mL methanol was added 13
mg (0.19 mmol) of sodium cyanoborohydride and 14 microliters (0.16 mmol) of a 12.3M
solution of formaldehyde in water. After 3 hours, the reaction was quenched by adding 50
microliters concentrated HC1. After 30 minutes, the solution was partitioned between ether
and water, and the phases were separated. The aqueous phase was basified with 1M NaOH,

and was extracted twice with ethyl actate. The combined ethyl acetate phases were washed
©nee with brine, dried over Na2SO4 , filtered, and concentrated to an oil. The oil was
dissolved in methanol, acidified with 2 M HC1 in ether, and diluted with ether to give the
product as a solid: MS (ES) M+H expect = 450.0, found = 450.0; HPLC retention time = 4.89
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-(4-Chloro-3-dimethyIamino-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yI]-ethanone:

[0491] 120 ing (0.30 mmol) of 2-(4-Chloro-3-amino-5-methyl-pyrazol-1-yl)-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone was dissolved in 5 mL of
tetrahydrofuran, and 0.10 mL of 0.1M H2SO4 was added. To this, 0.75 mL (9 mmol) of 37%
formaldehyde in water was added, followed by 113 mg (3 mmol) of sodium borohydride.
After 4 hours, the solution was quenched with 50 microliters of concentrated HC1. The
mixture was then partitioned between 1/lether/hexanes and water, and the phases were
separated. The aqueous phase was basified to pH > 10 with 1 M NaOH, and was extracted
twice with ethyl acetate. The combined ethyl acetate phases were washed twice with water,
once with brine, dried over Na2SO4, filtered, and concentrated to an oil. The oil was purified
by chromatography to give the product as a solid: *H NMR (CDC13,300MHz) 6 7.20 (d, 1H),
6.48 (s, 1H), 6.42 (d, 1H), 4.84 (s, 2H), 3.86 (s, 3H), 3.74 (m, 2H), 3.63 (m, 2H), 3.17 (m,
4H), 2.79 (s, 6H), 2.16 (s, 3H) ppm; MS (ES) M+H expect = 426.0, found = 426.0.

Synthesis of 1-[4-(4-Chloro-3-dimethyIamino-phenyI)-piperazin-1-y]]-2-(4-chloro-5-
jnethyl-3-trifIuoromethyI-pyrazol-1-yI)-ethanone:

[0492] To 80 mg (0.17 mmol) of1-[4-(3-Amino-4-chloro-phenyl)-piperazin-1-yl]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone in 1 mL methanol was added 30
mg (0.39 mmol) of sodium cyanoborohydride and 32 microliters (0.39 mmol) of a 12.3M
solution of formaldehyde in water. After 3 hours, the reaction was quenched by adding 50
microliters concentrated HC1. After 30 minutes, the solution was partitioned between ether
and water, and the phases were separated. The aqueous phase was basified with 1M NaOH,
and was extracted twice with ethyl actate. The combined ethyl acetate phases were washed
once with brine, dried over Na2SO4 , filtered, and concentrated to an oil. The oil was
dissolved in methanol, acidified with 2 M HC1 in ether, and diluted with ether to give the
product as a solid: 'H NMR (DMSO-d6, 400MHz) 8 7.35 (m, 1H), 7.14 (s, 1H), 6.89 (m,
1H), 5.41 (s, 2H), 3.68 (m, 4H), 3.35 (m, 2H), 3.25 (m, 2H), 2.91 (br s, 6H), 2.20 (s, 3H)
ppm; MS (ES) M+H expect = 464.0, found = 464.0.
PROTOCOL X: Preparation of compounds via Acylation or sulfonylation.
Synthesis of N-(2-Chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-
acetyll-piperazin-1-yI}-phenyl)-methanesulfonamide:

[0493] To 50 mg (0.1 mmol) of 1-[4-(4-Chloro-3-dimethylamino-phenyl)-piperazin-1-yl]-
2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone in 1.5 mL dichloromethane
were added 39 mg (0.5 mmol) of pyridine and 21 mg (0.12 mmol) of methansulfonic

anhydride. After 20 hours, the solution was partitioned between ethyl acetate and water, and
the phases were separated. The ethyl acetate phase was washed once with brine, dried over
Na2SO4, filtered, and concentrated to an oil. The oil was triturated with ether to give the title
product as a solid: lH NMR (DMSO-d6,400MHz) 8 9.33 (s, 1H), 7.34 (m, 1H), 6.97 (m,
1H), 6.90 (m, 1H), 5.39 (s, 2H), 3.63 (m, 4H), 3.26 (m, 2H), 3.17 (m, 2H), 3.03 (s, 3H), 2.20
(s, 3H) ppm; MS (ES) M+H expect = 514.0, found = 514.0.
Synthesis of N-(2-Chloro-5-{4- [2-(4-chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yI)-
acetyl]-piperazin-1-yl}-phenyl)-acetamide:

[0494] To 50 mg (0.1 mmol) of 1-[4-(4-Chloro-3-dimethylamino-phenyl)-piperazin-1-yl]-
f
2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone in 1.5 mL dichloromethane
were added 39 mg (0.5 mmol) of pyridine and 11 mg (0.12 mmol) of acetic anhydride. After
20 hours, the solution was partitioned between ethyl acetate and water, and the phases were
separated. The ethyl acetate phase was washed once with brine, dried over Na2SC>4 , filtered,
and concentrated to an oil. The oil was triturated with ether to give the title product as a solid:
'HNMR (DMSO-i6, 400MHz) 8 9.38 (s, 1H), 7.33 (s, 1H), 7.29 (m, 1H), 6.81 (m, 1H), 5.39
(s, 2H), 3.61 (m, 4H), 3.22 (m, 2H), 3.13 (m, 2H), 2.19 (s, 3H), 2.07 (s, 3H) ppm; MS (ES)
M+H expect = 478.0, found = 478.0.
Synthesis of N-(2-Chloro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetyl]-piperazin-1-yl}-phenyl)-formamide:


[0495] To 50 mg (0.1 mmol) of 1-[4-(4-Chloro-3-dimethylamino-phenyl)-piperazin-1-yl]-
2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone in 1.5 mL N,N-
Dimethylformamide were added 22 mg (0.2 mmol) of triethylamine and 30 microliters (0.25
mmol) of Formic acid cyanomethyl ester, and the mixture was heated at 90° C for 18 hours.
The solution was partitioned between ethyl acetate and water, and the phases were separated.
The ethyl acetate phase was washed once with brine, dried over Na2SO4, filtered, and
concentrated to an oil. The oil was triturated with ether to give the title product as a solid: 'H
NMR (DMSO-d6, 400MHz) S 9.76 (s, 1H), 8.34 (s, 1H), 7.79 (m, 1H), 7.32 (m, 1H), 6.79
(m, 1H), 5.40 (s, 2H), 3.61 (m, 4H), 3.23 (m, 2H), 3.14 (m, 2H), 2.20 (s, 3H) ppm; MS (ES)
M+H expect = 464.0, found = 464.0.
PROTOCOL Y; Preparation of compounds via alkylation.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-3-(R)-methoxymethyI-piperazin-1-yl]-2-
(4-chloro-5-methyI-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0496] To 53 mg (0.11 mmol) of 1 -[4-(4-Chloro-3-methoxy-phenyl)-3-(R)-hydroxymethyl-
piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone and 19 mg
(0.13 mmol) of methyliodide in 0.7 mL of N,N-dimethylformamide was added 9 mg
(0.22 mmol) of 60% sodium hydride in oil. After 1 hour, the reaction was quenched with
water, and was extracted with ethyl acetate. The ethyl acetate phase was washed with brine,
dried over Na2SO4 , filtered, and concentrated to give the title product as a foam: MS (ES)
M+H expect = 495.0, found = 495.0; HPLC retention time = 5.08 minutes (Agilent Zorbax
SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1
minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(R)-methoxymethyl-piperazin-1-yl]-2-
(4-chIoro-5-methyl-3-trifluoromethyI-pyrazoI-1-yl)-ethanone:

[0497] Title compound was prepared following the HATU mediated coupling protocol P,
wherein l-(4-Chloro-3-methoxy-phenyl)-3-(R)-methoxymethyl-piperazine and (4-Chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to
give the product as a solid: *H NMR (DMSO-JO", 400MHZ) 5 7.20 (m, 1H), 6.63 (m, 1H),
6.49 (m, 1H), 5.50 (m, 1H), 5.25 (m, 1H), 4.21 (m, 1H), 3.82 (s, 3H), 3.81-3.40 (m, 5H), 3.25
(s, 3H), 3.08-2.82 (m, 2H), 2.63 (m, 1H), 2.16 (m, 3H) ppm (rotamers); MS (ES) M+H
expect = 495.0, found = 495.0.
PROTOCOL Z: Preparation of compounds via peroxyacid-mediated N-oxidation.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyI)-4-oxy-piperazin-1-yI]-2-(4-chioro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0498] To 103 mg (0.23 mmol) of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone in 3 mL dichloromethane at 0°C
was added 60 mg (O.34mmol) of meta-Chloroperoxybenzoic acid. After 30 minutes, the
reaction was partitioned between 1/1 ether/ethyl acetate and water, and the phases were
separated. The organic phase was washed once each with 1M NaOH, water, brine, dried over
Na2SO4, filtered, and the product precipitated as a solid: *H NMR (DMSO-d6,400MHz) 8
8.09 (s, 1H), 7.70 (m, 1H), 7.52 (m, 1H), 5.40 (m, 2H), 4.28 (m, 1H), 4.10 (m, 2H), 3.98 (m,
1H), 3.90 (s, 3H), 3.85 (par.obs.rn, 1H), 3.66 (m, 1H), 2.90 (m, 2H), 2.20 (s, 3H) ppm; MS

(ES)M+H expect = 467.0, found = 467.0.
PROTOCOL AA: Synthesis of tri-substituted Pyrazoles via Suzuki coupling.
4-Chloro-3-methyI-5-phenyI-pyrazole:

[0499] 4-ChIoro-3 -methyl-5 -bromopyrazole (1.27 mmole) was taken into dry DMF
(20 mL) and Pd(PPH3)4 (0.44 rnmole) was added, followed by addition of Na2CO3 (344.1 mg
in 1 mL of water) and phenylboronic (1.41 mmole) acid. The mixture was then refluxed at
150°C for 22h, cooled to room, temperature, and then inorganic salts were removed by
filtration. 20 mL of dichloromethane was added to it and was washed with water to remove
any DMF. The organic layer was then dried in Na2SO4 and removed to get the crude product
which was then chromatographed to obtain the pure compound.
Other pyrazoles prepared via protocol AA:

PROTOCOL BB: Triazole via cvclocondensation of acylhvdrazine and thioamide.
5-Methyl-3-trifluoromethyl-l,2,4-triazole

[0500] 2.3 g (0.03125 mol) o f thioacetamide and 4 g (0.03125 mol) of trifluoroaceticacid
hydrazide were heated at 150 °C for 2 days. The white solid obtained were washed with ether,
and dried under vacuum to give 5-Methyl-3-trifluoromethyl-l,2,4-triazole.

Preparation of compounds with modified linker regions
a-substituted acetyl linkers
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-1-[4-(4-fluoro-
phenyI)-piperazin-1-yI]-propan-1-one

[0501] l-(4-Fluorophenyl)-piperazine (1 g, 5.5 mmol) dissolved in dry CH2C12 (20 inL)
was cooled to 0°C and triethylamine (1.66 g, 16.5 mmol) was added to it. 2-bromopropionyl
chloride (1.14 g, 6.6 mol) was added slowly and the reaction mixture stirred for another lh at
the same temperature. The mixture was washed with sodium bicarbonate and brine and dried
(Na2SO4). Evaporation of the solvent afforded the intermediate alkyl bromide (0.68 g,
3.7 mmol) which was taken into dry DMF (20 mL). Potassium carbonate (2.1 g) was added.
After stirring for lh at room temperature under nitrogen, 3-Methyl-4-chloro-5-
trifluoromethyl- (lH)-pyrazole (1.3 g, 4.1 mmol) in DMF (5 mL) was then added to the
mixture through a syringe. The reaction was then heated at 70°C for 14h, cooled and
quenched with water and extracted with ethyl acetate. Drying of the organic layer over
Na2SC>4 followed by concentration afforded material that was purified on a neutral alumina
column (chloroform/methanol).
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-
phenyl)-piperazin-1-yl]-2-phenyl-ethanone

[0502] To 4-Chloro-5-methyl-3-(trifluoromethyl)-l^'-pyrazol-1-yl] phenylacetic acid (0.1
g, 0.00036 mol) and l-(4-chlorophenyl) piperazine (0.060 g, 0.00031 mol) in 20 mL of dry
CH2CI2 was added 0.2 mL of triethylamine and the reaction mixture stirred at room
temperature for 30 min. TBTU (0.1 g, 0.00031 mol) was then added and the reaction mixture

was stirred at room temperature for 17 h. The reaction mixture was diluted with 60 rtiL of
GH2CI2 and washed with saturated aqueous NaHCC>3 (2x50 mL), brine and then dried over
sodium sulfate. The crude product obtained after concentration was purified by column
chromatography to give the product as an off white solid: 'H NMR (CDC13, 300MHz) 7.40-
6.61 (m, 10H), 3.99 (m, 1H), 3.80 (m, 1H), 3.50-2.81 (m, 6H), 1.90 (s, 3H) ppm; MS (ES)
M+H expected = 497.1, found 497.2.
Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-
phenyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-ethanone

[0503] AIBN (10 mg) was added to a solution of (3-Methoxy-phenyl)-acetic acid methyl
ester (2 g, 11 mmol) in CC14 (30 mL). The solution was then heated to reflux and NBS
(2.3 g, 13 mmol) was added in portions. After complete addition the reaction mixture was
refluxed for 4h. After cooling, solid residue was filtered off and the filtrate concentrated to
yield product Bromo-(3-mcthoxy-phenyl)-acetic acid methyl ester, that was washed
repeatedly with pet ether.
[0504] 4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole (610 mg, 3.3 mmol) was taken
into dry CH3CN (15 mL), dry potassium carbonate (1.15 g) was added to this and the
resulting mixture stirred at room temperature for lh under nitrogen. Bromo-(3-methoxy-
phenyl)-acetic acid methyl ester (900 mg, 2.8 mmol) in CH3CN (5 mL) was then added to the
mixture through a syringe. The reaction was then heated at reflux for lOh, cooled and then
filtered through a celite filter bed. The filtrate was concentrated to obtain (4-Chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid ethyl ester that was
purified by column chromatography on silica (pet ether/ethyl acetate)

[0505] (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-aceticacid
methyl ester was then dissolved in THF (20 mL) and LiOH (0.39 g) in water (5 mL) were
added. The mixture was stirred at room temperature for 4h. After this period the THF was
completely evaporated from the reaction mixture under vacuum. The remaining aqueous
layer was extracted with ethyl acetate (3x 5 mL) and the organic layer was discarded. The
aqueous layer was cooled in ice and neutralized by using concentrated HC1. This neutral
aqueous layer was extracted with ethyl acetate (3x10 mL), the organic layer dried over
Na2SC>4, concentrated and purified by flash chromatography (CHClj/MeOH) to yield (4-
Chloro-5-methyl-3 -trifluoromethyl-pyrazol-1 -yl)-(3 -methoxy-phenyl)-acetic acid
[0506] This compound (90 mg, 0.275 mmol) was taken into dry CH2CI2 (10 mL) and
cooled to 0°C. To this cold mixture was first added 4-chlorophenyl-piperazine (0.059 g,
0.31 mmol) followed by the addition of T3P (0.35 g, 0.55 mmol, 50% solution in EtOAc).
The reaction was left overnight at room temperature. The mixture was diluted with CH2CI2,
and then washed sequentially with saturated NaHCO3 solution, brine, dried over Na2SC>4, and
concentrated to afford the crude product. Purification by column chromatograhpy on neutral
alumina yielded 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1 -[4-(4-chloro-
phenyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-ethanone: 'H NMR (300 MHz, CDC13) 5
7.37-7.21 (m, 3H), 6.96-6.79 (m, 4H), 6.60 (s, 1H), 5.31 (s, 1H), 3.99 (m, 1H), 3.80 (s, 3H),
3.79 (m, 1H), 3.46 (m, 2H), 3.24 (m, 1H), 3.13 (m, 2H), 2.91 (m, 1H), 1.95 (s, 3H).

EXAMPLE 2
[0507] Protocols referred to within the following example are the protocols described
within Example 2.
PROTOCOL A: Metal catalysed arylation reactions of secondary amines
Synthesis of 1-[4-(4-chIoro-3-methoxy-phenyl)-[l,4]diazepane-1-carboxylic acid t-butyl
ester:

[0508] A mixture of 5-bromo-2-chloroanisole (1.10 g, 5 mmol , 1.0 equiv), N-Boc-
homopiperazine (1.0 g, 1 equiv), NaOtBu (0.72 g, 1.5 eq), racemic-BINAP (58 m g, 0.015
equiv) and Pd2Dba3 (28 m g, 0.0O5 eq) in 3 mL of toluene was heated at 90 oC overnight.
After cooling to room temperature, the residue was taken up in EtOAc and washed with water
and brine. The organic layer was dried over Na2SO4, filtered, evaporated and subjected to
flash column (1:4 EtOAc/hexane) to give 1-[4-(4-chloro-3-methoxy-phenyl)-[l,4]diazepane-
1-carboxylic acid t-butyl ester. 1H NMR (400 MHz, CDC13) 8 7.13 (d, 1H), 6.22 (d, 1H),
6.20 (dd, 1H), 3.86 (s, 3H), 3.45 (m, 6H), 3.32 (m, 2H), 3.20 (m, 2H), 1.95 (m, 2H), 1.20 (s,
9H). LCMS observed for (M+H-Boc)+: 241.
l-(4-chloro-3-propoxy-phenyl)-piperazmedihydrochloride

[0509] Following Protocol A, 4-bromo-1-chloro-2-propoxybenzene N-Boc-piperazine were
coupled to give the Boc-protected intermediate.
[0510] The Boc-protected intermediate was treated with 4M HC1 in p-dioxane to give the
title compound.

l-(4-chloro-3-(2,2,2-trifluoro)ethoxy-phenyl)-piperazinedihydrochloride

[0511] Following Protocol A, 4-bromo-1-chloro-2-(2,2,2-trifluoro)ethoxybenzene and N-
Boc-piperazine were coupled to give the corresponding Boc-protected intermediate.
[0512] The Boc-protected intermediate was treated with 4M HCl in p-dioxane to give the
title compound.
l-(4-chloro-3-(2-fluoro)ethoxy-phenyl)-piperazinedihydrochIoride

[0513] Following Protocol A, 4-bromo-1-chloro-2-(2-fluoro)ethoxybenzene N-Boc-
piperazine were coupled to give the corresponding Boc-protected intermediate.
[0514] The Boc-protected intermediate was treated with 4M HCl in p-dioxane to give the
title compound.
l-(4-Chloro-3-methoxy-phenyl)-3-trifluoromethyl-piperazine

[0515] Following Protocol A, 2-trifluomethylpiperazine and 5-Bromo-2-chloro-anisole
were coupled to give the title compound.

(S)-1-(3-Methoxy-phenyl)-3-methyI-piperazine

[0516] Took 467mg 3-bromoanisole (2.5 mmol, 1 .Oeq), 300mg (S)-2-methylpiperazine
(2.99 mmol, 1.2eq), 27mg Pd2dba3 (0.03 mmol , 0.0 leq), 50mg BINAP (0.08 mmol,
0.03eq), 336mgNaOtBu (3.5 mmol, 1.4eq), and 5 mL toluene in a 25 mL flask. The mixture
was stirred in an 85°C oil bath under N2 overnight, then the solvents were removed under
vacuum and the crude material treated with aqueous HC1 to get the dihydrochloride.
l-(4-Chloro-3-methoxy-phenyl)-2,3-(cis)-dimethyl-piperazine

[0517] Stepl; 26gm of ethylene diamine (0.43 mole) and 37.2gm of 2,3-but-dione (0.433
mole) were dissolved in 1.21 of dry diethyl ether, and the reaction mixture was stirred
overnight. The solvent was removed, and the oily residue was distilled to obtain 22 gm
(45%) of the intermediate diimine.
[0518] Step 2: To a solution of LAH (1.86 gm, 0.049 mole) in dry THF (10 ml) was added
the intermediate diimine (5gm, 0.047mole) dissolved in THF (5ml) at 0°C. The reaction
mixture was then refluxed overnight at 70°C. The reaction was cooled to room temperature,
was quenched with 5 mL 15% NaOH, and was filtered through celite. The Filtrate was
concentrated to obtain the intermediate cis-2,3-dimefhylpiperazine.
[0519] Step 3; Following Protocol A, 2,3-dimethylpiperazine and 5-Bromo-2-chloro-
anisole were coupled to give the title compound.

Synthesis of l-(7-Chloro-benzofuran-4-yl)-piperazine:
r
[0520] Step 1: Following Protocol A, mono-BOC-piperazine and 4-Bromo-7-chloro-
benzofuran were coupled to give the Boc-protected intermediate.
[0521] Step 2: 0.139g (0.41 ramol) of the Boc-protected intermediate from above was
dissolved in dry ether, and 2 mL of 1M HC1 in ether was added. After nine hours the solids
were isolated by filtration, and washed with dry diethyl ether to give the title compound.
l-(4-Chloro-3-methoxy-phenyl)-cis-2,5-dimethyl-piperazine

[0522] Following Protocol A, Cis-2,5-dimethylpiperazine and 5-Bromo-2-chloro-anisole
were coupled to give the title compound.
Synthesis of l-(4-Chloro-3-methoxy-phenyl)-trans-2,5-diitxethyl-piperazine:

[0523] Step 1; Following Protocol A, trans-2,4-dimethyl piperazine and 5-Bromo-2-
chloroanisole were coupled to give the crude title compound. Purification was not possible,
so the mixture was taken on to Step 2:
[0524] Step 2: 0.159g (0.624 mmol s) of the impure title compound, 0.204g (0.936 mmol
s) of BOC-anhydride, and 0.26 mL (1.87 mmol s) of triethylamine were dissolved in dry
dichloromethane (10ml), and the solution was stirred for 4 hours. The solution was then
washed twice with 10%citric acid, once with 10% NaHCCb, dried over Na2SC>4, and
concentrated. The residue was purified by column chromatography.

[0525] Step 3: To 150mg (0.42 mmol) of the above BOC-intermediate in methanol was
added 5m HC1 in ether under N2 atmosphere, and the mixture was stirred for 7 hours. The
solids formed were isolated by filtration to give the title compound as the HC1 salt (0.110 g,
85%).
PROTOCOL B: Piperazine ring formation via cyclization reactions
Synthesis of l-(4-Fluoro-3-methoxy-phenyl)-piperazine:

[0526] Step 1; Concentrated HC1 (54.26 g, 1.486 mol) was added to 2-methoxy-4-
nitroaniline (50 g, 0.29mols) in a 3 Lt 3-necked round bottom flask. Reaction mixture was
heated at 80°C for half an hour. Then it was cooled to -10°C. An aqueous solution of
sodium nitrate (24.62 g, 0.356mol) was added to it. Hexafluorophosphoric acid (86.82 g,
0.594mol) was then added while maintaining the temperature within -2 to 0°C and was
stirred for half an hour. Solid separates. The solid was filtered and washed with cold water
followed by 50% methanol in ether. Then the solid was dried under high vacuum overnight
atrt.
[0527] The solid was added to hot mineral oil (170°C) and was stirred for half an hour at
170°C, then it was cooled tort and satd. Sodium carbonate solution (300 mL) was added
and steam-distilled to obtain 4-fluoro-3-methoxy nitro benzene (3.5 g, 6.8%).
[0528] Step 2: Raney nickel (0.6 g) was added to a solution of 4-fiuoro-3-methoxy nitro
benzene (3.5 g, 0.02046 mol) in dry methanol, and this was shaken for 12 hours in a par-
shaker under 10 PSI of hydrogen. The Raney nickel was then filtered off, and the filtrate was
concentrated to obtained the crude compound. This material was purified by column
chromatography using pet-ether:Ethyl acetate (100:3) as eluent to give 4-fluoro-3-methoxy
aniline as a reddish liquid (1.4 g, 48%).
[0529] Step 3: 4-fluoro-3-methoxy aniline (0.5 g, 0.0O354mol) dissolved in n-butyl alcohol
(10 mL), and this was added to a stirring solution of Bis(2-chloro ethyl)amine hydrochloride
(0.632 g, 0.00354 mol) in n-butyl alcohol at rt. The reaction mixture was then refluxed for 2
days, cooled to rt, and anhydrous sodium carbonate (1.12 g, 0.01062 mol) was added. The

mixture was refluxed for an additional 2 days, after which the solvent was evaporated. The
residue was dissolved in ethyl acetate, washed with water, brine solution, dried over Na2SO4,
and concentrated. The crude residue was purified by column chromatography using
chloroform:methanol as eluent (100:5) to give the title compound as off white solid (58m g,
7%).
PROTOCOL D: Synthesis and addition of elaborated piperazines to arvl and heteroaryl
halides via arvl-halogen displacement methodologies
2-Chloro-5-piperazin-1-yI-benzoic acid ethyl ester:

[0530] Step 1: To 5-Chloro-2-nitrobenzoic acid (15 g, 0.07mol) in ethanol (200ml) was
added thionylchloride (27ml, 0.37mol) drop wise at 0°C. The reaction mixture was refluxed
at 85°C overnight. The reaction was cooled to ambient temperature, the methanol was
removed under vacuum, and the residue was added to ice water. The resulting mixture was
basified using solid NaHCO3, and was extracted with ethyl acetate. The ethyl acetate layer
was washed with water, brine, dried over Na2SO,j, and concentrated to give the corresponding
ethyl ester.
[05311 Step 2: Ethyl 5-Chloro-2-nitrobenzoate (15 g, 0.0655mol), benzylpiperazine (28.8
g, 0.16 mol), dry K2CO3 (9 g, 0.16mol), tetrabutylammonium iodide (1.5 g) in dry DMSO
(150ml) was heated at 120°C overnight. The mixture was cooled to ambient temperature,
quenched with water, and extracted with ethyl acetate. The ethyl acetate layer was extracted
with 1.5N HC1, and was discarded. The acid layer was washed with ether, basified with
NaHCCh, and extracted with fresh ethyl acetate. The ethyl acetate layer was washed with
water and brine, dried over Na2SO4, and concentrated to give 2-Nitro-5-piperazin-1-yl-
benzoic acid ethyl ester.

[0532] Step 3; To 2-Nitro-5-piperazin-1-yl-benzoic acid ethyl ester (22 g, 0.059 mol) in
methanol (150 ml) was added Palladium on carbon (2.2 g, 10 %) under nitrogen. The
reaction mixture was stirred under H2 for 2 hours. The mixture was filtered and concentrated
to give the corresponding aniline.
[0533] Step 4: To cupric chloride (3.0 g, 0.017mol) in acetonitrile (5 0ml) was added t-
butylnitrite (1.7ml, 0.015mol) slowly, and the mixture was heated to 60°C for 15 minutes.
The aniline from above (5.0 g, 0.015mol) in acetonitile (10ml) was added slowly, and the
mixture was stirred 30 minutes at 60°C. The reaction was cooled to ambient temperature,
quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed
with water and brine, dried over Na2SO4, and concentrated. The crude was purified by
column chromatography to give 2-Chloro-5-piperazin-1-yl-benzoic acid ethyl ester.
[0534] Step 5: To 2-Chloro-5-piperazin-1-yl-benzoic acid ethyl ester (0.8 g, 0.0022mol) in
dry dichloroethane (20 ml) was added 1-chloroethyl chloroformate (0.3ml, 0.0026mol), and
the mixture was heated at 85°C for 3.0 hours. The solvent was removed under vacuum, the
residue was dissolved in methanol (10ml), and the solution was refluxed for 1 hour at 85°C.
The solution was cooled to ambient temperature, the methanol was removed under vacuum,
and the residue was dissolved in water. The solution was washed with ether and chloroform.
The water layer was then basified with NaHCCb, extracted with dichlorornethane, dried over
Na2SC>4, and concentrated. The residue was purified by chromatography to give the title
compound.
l-(2-Bromo-4-chloro-5-methoxy-phenyl)-piperazine

[0535] Stepl: 2,5-Dichlorophenol (25 g, 0.15mot), methyliodide (108 g, 0.76mol), and dry
K2CO3 (105 g, 0.76mol) were combined in dry acetone (250ml), and the mixture was stirred
at for 12 hours. The reaction mixture was concentrated. The residue was slurried in ethyl
acetate, washed with water and brine, dried over Na2SO4, and concentrated to give 2,5-
dichloroanisole.

[0536] Step 2: To 2,5-Dichloroanisole (17.5 g, 0.099mol) in acetic acid (50ml) was added
a,mixture of concentrated nitric acid (9ml) and concentrated Sulfuric acid (13ml) at 0°C. The
reaction mixture was stirred for 2 hours. The solids were isolated by filtration, washed with
water, and dried. The mixture was washed with pet ether to remove the ortho-isomer, and the
remaining solids were clean 2,5-Dichloro-4-nitroanisole.
[0537] Step 3: 2,5-Dichloro-4-nitroanisole (6.0 g, 0.027mol), benzylpiperazine (9.5 g,
0.05mol), and dry K2CO3 (9.36 g, 0.067mol) were combined in dry DMSO (150ml).
Tetrabutylammonium iodide (0.6 g) was added, and the mixture was heated at 120°C for 12
hours. The reaction was cooled to ambient temperature, quenched with water, and extracted
with ethyl acetate. The ethyl acetate phase was dried over NaaSCU, and concentrated to give
the N-benzylpiperazine intermediate.
[0538] Step 4: To the intermediate from Step 3 (11 g, O.033mol) in dry methanol was
added iron powder (7.38 g, 0.13mol), follwed by ammonium chloride (12.7 g, 0.23mol) in
water (100 ml) drop wise, and the mixture was heated at 75°C for 14 hours. The reaction
mixture was cooled to ambient temperature, filtered, and concentrated. The residue was
dissolved in ethyl acetate, washed with water and brine, dried over Na2SC>4, and concentrated
to give 2-(4-Benzyl-piperazin-1-yI)-5-chloro-4-methoxy-phenylamine.
[0539] Step 5; Following Protocol G, 2-(4-Benzyl-piperazin-1-yl)-5-chloro-4-methoxy-
phenylamine was treated with cupricbromide and tert-butylnitrite to give l-Benzyl-4-(2-
bromo-4-chloro-5-methoxy-phenyl)-piperazine.
[0540] Step 6: To l-Benzyl-4-(2-bromo-4-chloro-5-methoxy-phenyl)-piperazine (1.0 g,
0.0025 mol) in dry 1,2-dichloroethane (20ml) was added 1-chloroethyl chloroformate (0.3ml,
0.0026mol), and the reaction was heated at 85°C for 3.0 hours. The solvent was removed
under vacuum, methanol (10ml) was added, and the solution was refluxed for 1 hour. The
methanol was removed under vacuum, the residue was dissolved in water, and the aqueous
layer was washed with ether. The water layer was basified with NaHCO3, and was extracted
with dichloromethane. The dichlormethane phase was dried over Na2SC>4, and was
concentrated. The crude was purified by chromatography to give the title compound.

PROTOCOL E; Selected examples of halogenation of aromatic systems after
attachment of the pipcrazinc ring system
l-(2,4-Dichloro-5-methoxy-phenyl)-3-(S)-methyI-piperazine

[0541] Took 500mg 1 -(3-Methoxy-phenyl)-3-(S)-methyl-piperazine (1.79 mmol, 1 .OOeq)
in 5 mL of 1:1 DCM:AcOH in a 25 mL flask. The mixture was cooled to 0°C in an ice water
bath, then 550mg NCS (3.58 mmol, 2.00eq) was added to the stirring solution at once. The
ice bath was removed and the mixture allowed to stir at room temperature for approximately
one hour. LC/MS revealed a mixture of chlorinated products which were isolated by
preparative HPLC.
(S)-1-(4-Bromo-3-methoxy-phenyI)-3-methyl-piperazine

[0542] Took 500mg (S)-1-(3-Methoxy-phenyl)-3-methyl-piperazine (1.79 mmol, 1 .OOeq)
in 5 mL of 1:1 DCM: AcOH in a 25 mL flask. The mixture was cooled to 0°C in an ice water
bath, then 91uL of Br2 (1.79 mmol, l.OOeq) was added to the stirring solution at once. The
ice bath was removed and the mixture allowed to stir at room temperature for approximately
one hour. LC/MS revealed a mixture of brominated products which were isolated by
preparative HPLC.

PROTOCOL F: Selected examples of demethvlation / etherification of aromatic
precursors for attachment of the piperazine ring system to access key arvlpiperazine
moieties
Synthesis of 4-Bromo-7-chloro-benzofuran:

[0543] Step 1; 1.46g (6.99 mmol s) of 3-Bromo-6-chlorophenol, 1.93g (13.98 mmol s) of
anhydrous K2CO3, and 2.07g (10.48 mmol s) of bromoacetaldehyde diethyl acetate were
combined and heated at 140°C for 3 hours. The reaction was then cooled to ambient
temperature, partitioned between ethyl acetate and water, and the phases were separated. The
ethyl acetate layer was washed once each with water and brine, dried over Na2SO4, and
concentrated to give the crude acetal (2.3 g, 99%).
[0544] Step 2: 2.29g of the crude acetal from above and 4g of polyphosphoric acid were
combined in 20 mL of toluene, and the mixture was heated at 90°C for 3 hours. The reaction
was then cooled to ambient temperature, partitioned between ethyl acetate and water, and the
phases were separated. The ethyl acetate layer was washed once each with water, 10%
NaHCO3, and brine, dried over Na2SO4, and concentrated. The residue was purified by
column chromatography to give the title compound (0.550 g, 31%).
4-bromo-1-chloro-2-(2,2,2-trifluoro)ethoxybenzene

[0545] 14.7gof 5-bromo-2-chlorophenol (71 mmol, l.Oeq), 18.6gtriphenylphosphine(71
mmol, l.Oeq), and 200 mL dry THF were combined in a 500 mL round botton flask fitted
with an N2 inlet. The mixture was cooled in an ice water bath, then 12.4g
diethylazodicarboxylate (71 mmol , l.Oeq) was added. After one hour of stirring, 5.7 mL of
2,2,2-trifluoroethanol (78 mmol , 1.1 eq) was added, and the flask was removed from the ice
bath and allowed to stir at room temperature overnight. The reaction was quenched with a

small amount of water, and the solvents removed under vacuum. The residue was dissolved
in 150 mL DCM, and diluted with hexane until it became cloudy. The solution was placed in
freezer for several hours, the crystalline triphenylphosphine oxide by-product was discarded
and the mother liquor was concentrated under vacuum and purified by column
chromatography (EtOAc/ Hexane).
4-bromo-1-chIoro-2-(2-fluoro)ethoxybenzene

[0546] 14.7g 5-bromo-2-chlorophenol (71 mmol , l.Oeq), 18.6g triphenylphosphine
(71 mmol, l.Oeq), and 200 mL dry THF were combined in a 500 mL round botton flask
fitted with an N2 inlet. The mixture was cooled in an ice water bath, then 12.4 g
diethylazodicarboxylate (71 mmol, 1 .Oeq) was added. After one hour of stirrin g, 4.6 mL of
2-fluoroethanol was added, and the flask was removed from the ice bath and allowed to stir at
room temperature overnight. The reaction was quenched with a small amount of water, and
the solvents removed under vacuum. The residue was dissolved in 150 mL DCM, and
diluted with hexane until it became cloudy. The solution was placed in freezer for several
hours, the crystalline triphenylphosphine oxide by-product was discarded and the mother
liquor was concentrated under vacuum and purified by column chromatography (EtOAc/
Hexane).
4-bromo-1-chIoro-2-propoxybenzene

[0547] 1.2g of 5-bromo-2-chlorophenol (5.9 mmol, l.Oeq), 1.6g of K2CO3 (11.8 mmol,
2.0eq), l.Og of iodopropane (5.9 mmol, l.Oeq) and 16 mL acetone were combined in a 50
mL round bottom flask fitted with a reflux con denser and N2 inlet. The mixture was refluxed
overnight under N2: LC/MS showed reaction was complete. Added 5 mL H20 to flask and

the mixture extracted with 2 X 20 mL of 1:1 EtOAc/Hexane. The aqueous phase was
discarded and the combined organics were dried under vacuum to get 1.8 g clean product.
PROTOCOL H: Pyrazole synthesis via addition of hydrazines to a,B-acetylenic ketones;
Synthesis of 2-(5-Methyl-1H-pyrazol-3-yl)-6-trifluoromethylpyridine
i '
[0548] Step 1: To a solution of 2-chloro-6-trifluoromethylpyridine (91 mg), 2-butynol
(0.043 mL), Pd2(PPh3)2Cl2 (17.5 mg) and Cul (4.8 mg) in DMF (1 mL) was added Et3N (0.3
mL). The reaction mixture was stirred at 25 °C for 12 h and residue was purified on
preparative HPLC to afford the coupled alcohol.
[0549] Step 2: The alcohol was dissolved in CH2C12 (2 mL) and Dess-Martin periodinate
(320 mg) was added. The reaction mixture was stirred at 25 °C for 2 h and evaporated in
vacuo. The residue was purified by preparative HPLC to afford the ketone.
[0550] Step 3: The ketone was dissolved in EtOH (10 mL) and hydrazine was added. The
reaction mixture was heated to reflux for 1 h, cooled to room temperature and evaporated in
vacuo. The residue was purified by preparative HPLC to afford the title compound.
5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

[0551] Step 1; To a solution of 2,5-Dibromopyridine (1 Ogm, 0.0422 mole) in DMF
(100ml) under N2 was added Cu(I)CN (2.5 g, 3.4 mole). The reaction mixture was then
heated to 115°C overnight. The reaction mixture was then cooled to ambient temperature,
poured into water, and extracted four times with EtOAc. The combined ethyl acetate phases
were concentrated, and the residue was purified by chromatography to yield 5-bromo-2-
cyanopyridine.

[0552] Steps 2 and 3; To 5-bromo-2-cyanopyridine (1.8 g, 9.84 mmol e) in dry THF (50
ml) was added Et3N (2.75 ml, 19.7 mmol e), 3-butyn-2-ol (1.03 gm, 14.75 mmol e) and
PdCl2(PPh3)2 ( 200 mg), and the reaction mixture was refluxed at 80°C overnight. The
reaction mixture was cooled to ambient temperature, and the THF was removed in vacuo.
The residue was slurried with water and extracted with chloroform. The chloroform layer
was separated, washed once each with water, NaHCO3,1M citric acid, and brine. The
chloroform layer was dried with Na2SC>4 and concentrated. The crude residue was dissolved
in acetone (25 ml), cooled to 0°C, and Jones reagent (4 ml) was added. After 12 hours the
acetone was removed, and residue was washed with water and brine, dried over Na2SO4 and
concentrated to give the corresponding alkynone.
[0553] Step 4: The alkynone intermediate CI.83 g, 10.75 mmol e) was dissolved in dry
THF (30 ml), hydrazine hydrate (0.582 g, 11.83 mmol e) was added, and the solution was
stirred for 3 hours. The reaction mixture was then concentrated and the residue was
partitioned between water and CHCI3. The chloroform layer was washed with water and
brine, dried over NajSO-j, and concentrated. The residue was purified by chromatography to
give the title compound.
6-(5-Methyl-1H-pyrazoL-3-yI)-pyridine-2-carboxylic acid methylamide

[0554] Step 1: Following Protocol X, 6-bromopicolinic acid was coupled with
methylamine to give the corresponding amide.
[0555] Steps 2 and 3: Following the same two step procedure as in the previous example,
the 6-Bromo-N-methylpicolinamide was converted to the corresponding conjugated ketone.
[0556] Step 4: Following the same procedure as in the previous example, the conjugated
ketone was reacted with hydrazine to give the title compound.

6-(5-Methyl-1H-pyrazoW-yl)-pyridine-2-carboxylic acid ethyl ester

[0557] Steps 1 and 2: To Ethyl 6-Bromopicolinate (5.37 g, O.Z3 mole) in dry THF (60
ml) was added Et3N (3 ml, 0.0215 mole), 3-butyn-2-ol (1.5 ml, 0.O214 mole), and
PdCl2(PPh3)2 (200 mg), and the reaction mixture was refluxed at 80°C overnight. The
reaction mixture was cooled to ambient temperature, the solvent was removed, and the
residue was partitioned between water and chloroform. The chloroform layer was washed
once each with water, NaHCO3, 1M citric acid, and brine, dried o> ver Na2SC>4, and
concentrated. The residue was dissolved in acetone (25 ml), cooled to 0°C, and Jones reagent
(25 ml) was added. After stirring overnight, the acetone was removed in vacuo, and the
residue was partitioned between water and CHCI3. The chloroform layer was washed with
water and brine, dried over Na2SC>4, and concentrated to give the corresponding ketone.
[0558] Step 3: Following Protocol H, the intermediate ketone was treated with hydrazine to
give the title compound.
2-Methyl-4-(5-methyl-1H-pyrazoI-3-yl)-pyridine

[0559] Step 1:2-Mefhylpyridine (25 g, 0.268 mole) was dissolved in 150 mL glacial
acetic acid and 20 mL of 50% H202 was added to it. The reaction, mixture was heated to
85°C overnight. When TLC indicates the total consumption of the starting material the

reaction mixture was cooled to ambient temperature and was treated with Pd/C to destroy the
excess H2O2. Then the Pd/C was filtered off and the excess AcOH was rotavaped off. It was
then further treated with toluene and the excess toluene was removed azeotropically to
generate 27g of the N-oxide 1 in 95% yield.
[0560] Step 2: The N-oxide 1 (27 g, 0.247 mole) was dissolved in 62 mL of concentrated
H2SO4 and cooled to 0°C. Then a mixture of 90 mL of H2SO4 and 115 mL HNO3 was added
slowly, and the resultant mixture was heated at 95°C for 12 hours. The solution was cooled
to ambient temperature, basified with aqueous NH3 to pH 3, and was then extracted three
times with CHCI3. The combined CHCI3 layers were washed once each with water and brine,
dried over lN^SC^, and the concentrated to yield the product 2 as a yellow solid (37 g, 96%).
[0561] Step 3; 2-Methyl-4-Nitropyridine-N-oxide 2 (10 g, 0.0649 mole) was cooled and
CfbCOBr (30 ml) was then added to it drop-wise. After complete addition the reaction
mixture was heated at 50°C for 5 hours. The reaction mixture was cooled to ambient
temperature, basified with 10% NaHCC>3, and extracted with CHCI3. The chloroform phase
was washed with water and brine, dried over Na2SC>4, and concentrated. The residue was
purified by chromatography to give 3.
[0562] Step 4: 3 (7 g, 0.0372 mole) was dissolved in CHC13 (45 ml), and the solution was
cooled to 0CC. PCI3 (14 ml) was then added via a dropping funnel, and the reaction mixture
was allowed to for 12 hours. The reaction was then quenched with 10% NaHCO3, and was
extracted with CHCI3. The CHCI3 layer was washed with water and brine, dried over
Na2SO4, and concentrated to obtain the pyridine 4 (5.9 g, 91%).
[0563] Steps 5 and 6: 4 (5.8 g, 0.0337 mole) was dissolved in dry THF (30 ml), e t3N (9.5
ml, 0.0674 mole), 3-butyn-2-ol (3.6 ml, 0.505 mole) and PdCl2(PPh3)2 (400 mg) were added,
and the reaction mixture was refluxed at 75°C overnight. The reaction mixture was cooled to
ambient temperature, and the THF was removed in vacuo. The residue was partitioned
between water and chloroform, and the layers was separated. The chloroform layer was
washed once each with water, NaHCC»3, 1M citric acid, and brine, dried with Na2SO4, and
concentrated.
[0564] The residue from above was dissolved in acetone (25 ml), cooled to 0°C, and Jones
reagent (10 ml) was added. After stirring for 12 hours, the acetone was removed in vacuo,
and the residue was partitioned between water and CHCI3. The chloroform layer was washed

with water and brine, then dried with Na2SO4, and concentrated to give the product 5 in 20%
yield.
[0565] Step 7: Intermediate 5 (0.6 g, 0.0038 mole) was dissolved in ethanol (15 ml),
hydrazine hydrate (3.5ml) was added, and the solution was stirred for 12 hours. The reaction
mixture was concentrated, and the residue was partitioned between water and CHCI3. The
chloroform layer was washed with water and brine, dried over Na2SO4, and then
concentrated. The residue was purified by chromatography to give the title compound.
PROTOCOL I: General procedure for the synthesis of pyrazoles via condensation of
hydrazines with B-diketones:
Synthesis of 3-(2-pyridyI)-5-methylpyrazole:

[0566] Step 1: NaH (9.6 g, 400 mmol ) was added in one portion into a solution of
dibenzo-18-crown-6 (1.24 g, 3.4 mmol ) and 2-acetylpyridine (22.4 mL, 200 mmol ) in
THF (80 mL) stirring at room temperature. The mixture was allowed to stir at room
temperature for 30 min and EtOAc (25 mL) was added. The mixture was then heated to
reflux for 2 hr and allowed to cool to room temperature. More EtOAc (300 mL) was added
and the reaction mixture was quenched by saturated aqueous NaHCO3 solution (150 mL).
The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 100
mL). The combined organic solvents was dried (Na2SO4), filtered and evaporated in vacuo.
The crude mixture was used as it was.
[0567] Step 2: A solution of crude mixture from last step in denatured EtOH (500 mL) was
stirring at room temperature and hydrazine hydrate (15 mL) was added. The solution was
then heated to reflux for 1 hr, cooled to room temperature and evaporated in vacuo. The
residue was dissolved in EtOAc (300 mL) and washed by saturated aqueous NaCl solution (3
x 50 mL). The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The
crude mixture was used as it was.

Synthesis of 3-(3-pyridyI)-4-chIoro-5-methyIpyrazole:

[0568] Following the same procedure as in the above example, 3-acetylpyridine first
converted to the corresponding diketone, and this was then treated with hydrazine in
methanol to give the pyrazole. This intermediate was treated with N-chlorosuccinimide to
give the title compound.
Synthesis of 2-(5-trifluoromethyl-2H-pyrazol-3-yl)-pyridine:

[0569J The above pyrazole was prepared by following the first two steps in the previous
example, to give the title compound: LC MS (M+l) = 214.1.
4-(4-Chloro-5-methyl-1H-pyrazol-3-yl)pyridine

[0570] The title compound was obtained by following the same procedures used to prepare
3-(3-pyridyl)-4-chloro-5-methylpyrazole, starting from 4-acetylpyridine.
Synthesis of 2-Methyl-6-(5-methyl-1H-pyrazol-3-yl)-pyridine:

[0571] Step 1: 6-methyl picolinic ethyl ester (10 g, 0.061mol) and acetone (8.91 ml, 0.12
mol) in THF were added to NaOMe (4.19 g, 0.09 lmol) in dry THF(lOml) under nitrogen at

ambient temperature. The reaction mixture was refluxed overnight at 65 °C. The reaction
was then cooled to -10°C, diluted with water (150 ml) and THF was removed under vacuum.
The pH was adjusted to 3.5 using acetic acid, and the mixture was extracted with chloroform.
The chloroform layer was washed once each with water and brine, dried over Na2SO4 and
concentrated to obtain the corresponding diketone.
[0572] Step 2: Following Protocol I, the diketone from Step 1 was treated with hydrazine
to give the title compound.
Synthesis of Pyrimidine-4-carboxylic acid ethyl ester:

[0573] Step 1: To 4-Methyl pyrimidine (5 g, 0.05 mol) in pyridine (50 ml) was added
selenium dioxide portion wise with stirring over 10 minutes. The reaction mixture was
heated at 60°C for 2 hours, it was then cooled to ambient temperature and stirred for 12
additional hours. The solution was concentrated and brown solid obtained was washed with
water and dried under vacuum to give 8gm of 4-pyrimidine carboxylic acid.
[0574] Step 2: To 4-Pyrimidine carboxylic acid (8 g, 0.06 mol) in absolute ethanol (150
ml) was added sulphuric acid (3.16 ml), and the mixture was refluxed for 12 hours. The
reaction mixture was concentrated, partitioned between 10 % sodium bicarbonate and ethyl
acetate, and the phases were separated. The ethyl acetate layer was washed with water, brine,
dried over sodium sulphate and concentrated to give 7.7gm of the title compound.
Synthesis of 4-(5-Methyl-1H-pyrazoI-3-yl)-pyrimidine:

[0575] Step 1: To sodium methoxide (0.02 mol) in dry THF (15 ml) under nitrogen
atmosphere was added dry acetone (0.07mol), and the solution was stirred for 30 minutes.
Pyrimidine-4-carboxylic acid ethyl ester (3.0 g, 0.02 mol) in dry THF (20 ml) was added
drop wise. The reaction mixture was stirred for 30 minutes, followed by heating at reflux for
1 hour. The reaction mixture was cooled to room temperature, neutralised with acetic acid,
and extracted with ethyl acetate. The ethyl acetate layer was washed once each with water
and brine, dried over sodium sulphate, and concentrated to give the corresponding diketone.

[0576] Step 2: Following Protocol I, the diketone from Step 1 was treated with hyrdazine
to give the title compound. *
5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

[0577] Step 1: Following the procedure used in the previous example, Methyl-2-cyano-
nicotinate was reacted with acetone to give the corresponding diketone intermediate.
[0578] Step 2: To a solution of the diketone intermediate (1.85 gm) in 50 mL of ethanol
was added 2.5 mL of concentrated HC1. The reaction mixture was heated at 100°C for 12
hours. The solvent was rotavaped off, and 10% NaHCC>3 was added until the reaction pH
was >8. The mixture was extracted with CHCI3. The chloroform layer was then washed with
water, dried over Na2SC>4, and concentrated to give the corresponding ethyl ester.
[0579] Step 3: Following Protocol I, the intermediate from Step 2 was reacted with
hydrazine to give the title compound.
Pyrimidine-2-carboxylic acid methyl ester:

[0580] 2-Cyanopyrimidine (3 g, 0.0285 mol) in dry methanol was sparged with HC1 gas
for 2 hours. The reaction vessel was stoppered and kept at 4°C for 3 days. The reaction
mixture was concentrated and the residue was basified using 10% sodium bicarbonate
solution and extracted with dichloromethane. The dichloromethane layer was washed with
water brine, dried over sodium sulphate, and concentrated to give the title compound.
Synthesis of 2-(5-Methyl-1H-pyrazol-3-yl)-pyrimidine:


[0581] Step 1: Sodium methoxide (0.86 g, 0.0159 mol) in dry THF (20 ml) was added dry
acetone (0.9 g, 0.015 mol) and stirred for about 30 minutes. Pyrimidine-2-carboxylic acid
methyl ester (1.1 g, 0.007 mol) in dry THF (20 ml) was added drop wise. The reaction
mixture was stirred for 30 minutes, followed by heating at reflux for 1 hour. The reaction
mixture was cooled to room temperature, neutralised with acetic acid, and extracted with
ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over
sodium sulphate, and concentrated to give the corresponding diketone.
[0582] Step 2: Following Protocol I, the diketone from Step 1 was treated with hydrazine
hydrate to give the title compound.
1-Oxy-isonicotinic acid methyl ester:

[0583] To methyl isonicotinate (44 g, 0.2913 mol) in acetic acid (135 ml) was added H2O2
(44 ml) drop wise, and the mixture was heated at 90°C for 12 hours. The mixture was cooled
to ambient temperature, Pd/C (0.5 g) was added slowly, and the mixture was stirred for 15
minutes. The reaction mixture was then filtered through Celite, and the filtrate was
concentrated to give the title compound.
Synthesis of 4-(5-Methyl-1H-pyrazol-3-yl)-pyridine 1-oxide:

[0584] Stepl: To NaOMe (19.4 g, 0.3592 mol) in dry ether (300 ml) was added dry
acetone (27.7 g, 0.4790 mol) and the reaction mixture was stirred for 20 minutes. 1 -Oxy-
isonicotinic acid methyl ester (40 g, 0.2395) in 300 mL of ether was added slowly, the
mixture was warmed to reflux, and was stirred for one hour. The reaction mixture was
cooled to ambient temperature, neutralised with acetic acid, and extracted with ethyl acetate.
The ethyl acetate layer was washed once each with water and brine, dried over Na2SO4, and
concentrated to give the corresponding diketone.

[0585] Step 2: Following Protocol I, the diketone from Step 1 was treated with hydrazine
hydrate to give the title compound.
Synthesis of 4-(5-Methyl-1H-pyrazoI-3-yl)-pyridine-2-carbonitrile:

[0586] To 4-(5-Methyl-1H-pyrazol-3-yl)-pyridine 1-oxide (7.0 g, 0.024mol) in water/1,4-
dioxane mixture (140/175 ml) was added NaCN (3 g, 0.0614 mol). The reaction mixture
was stirred for 14 hours, followed by extraction with ethyl acetate. The ethyl acetate layer
was washed once each with water and brine, dried over Na2SO4, and concentrated. The crude
residue was purified by column chromatography to give the title compound.
Synthesis of 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-pyridine:

[0587] Step 1: Sodium methoxide (1.5 g, 0.027mol) in dry THF (20 ml) was added dry
acetone (3.2 g, 0.055mol), and this was stirred for about 30 minutes. 6-Methyl-nicotinic acid
methyl ester (2.3 g, 0.027 mol) in dry THF (20 ml) was added drop wise. The reaction
mixture was stirred for 30 minutes, followed by heating at reflux for 1 hour. The reaction
mixture was cooled to room temperature, neutralised with acetic acid, and extracted with
ethyl acetate. The ethyl acetate layer was washed once each with water and brine, dried over
sodium sulphate, and concentrated to give the corresponding diketone.
[0588] Step 2: Following Protocol I, the diketone from Step 1 was treated with hydrazine
hydrate to give the title compound.
Synthesis of 4-(5-Methyl-2H-pyrazoI-3-yl)-pyridine:


[0589] Step 1; To sodium methoxide (5.9 g, 0.1 mol) in dry THF (100ml) under nitrogen
atmosphere was added dry acetone (12.7 g, 0.2mol), and stirred for 30 minutes. Methyl
isonicotinate (15 g, O.lmol) in dry THF (100ml) was added drop wise. The reaction mixture
was stirred for 30 minutes, followed by heating at reflux for 1 hour. The reaction mixture
was cooled to room temperature, neutralised with acetic acid, and extracted witii ethyl
acetate. The ethyl acetate layer was washed once each with water and brine, dried over
sodium sulphate, and concentrated to give the corresponding diketone.
[0590] Step 2; Following Protocol I, the diketone from Step 1 was treated with hydrazine
hydrate to give the title compound.
Synthesis of 2-Chloro-5-(5-methyl-1H-pyrazol-3-yl)-pyridine:

[0591] Step 1:5g (0.0269mols) of 6-chloro nicotinic ethyl ester was dissolved in dry THF,
and was added to 2.18g (0.041mols) of sodium methoxide in dry THF. To this was added
3.96 mL (0.054mols) of acetone under N2 atmosphere, and the mixture was refiuxed at 65°C
for 12 hours. The reaction mixture was cooled to ambient temperature, and was quenched
with water. The THF was removed in vacuo, the pH ws adjusted to 3.5 using acetic acid, and
the mixture was extracted with chloroform. The chloroform phase was washed once each
with water and brine, dried over Na2SC>4, and concentrated. The resulting residue was a
mixture of l-(6-chloropyridine-3-yl) butane-1.3-dione and l-(6-ethoxypyridine-3-yl) butane-
1.3-dione.
[0592] Step 2: Following Protocol I, the above mixture was treated with hydrazine hydrate
to give the crude pyrazole.
[0593] Step 3:1.7g of the above crude pyrazole was dissolved in 20 mL of dry dioxane, 10
mL POCI3 was added to it, and the mixture was heated at 80°C for 12 hours. The reaction
mixture was cooled to -20°C, 50 mL water was added to it, and the pH was adjusted to 9
using NaHCO3 solution. The mixture was extracted with chloroform. The chloroform phase
was washed three times with water, once with brine, dried over Na2SC>4, and concentrated.

The residue was purified by column chromatography using pet ether/ethyl acetate as eluent,
to, give the title compound.
5-Furan-2-yI-3-trifluoromethyl-1H-pyrazole

[0594] The above compound was synthesized following Protocol I using the commercially
available diketone: [H NMR (400 MHz, CDC13): 5 6.51 (dd, J = 1.8 & 3.3 Hz, 1H), 6.67-6.68
(m, 1H), 6.71 (s, 1H), 7.48-7.49 (m, 1H).
PROTOCOL L: chlorination or bromination of pyrazoles with N-chlorosuccinimide
(NCS) or N-bromosuccinimide (NBS):
4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0595] Following Protocol L, 5-methyl-1H-pyrazole-3-carboxylic acid ethyl was treated
with NCS to give the title compound.
(4-Chloro-5-methyl-1H-pyrazol-3-yl)-methanoI

[0596] 3.0g of 4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (15.9 mmol,
1 .Oeq) was dissolved in 17 mL dry THF, and the solution was cooled in an ice water bath.
1.2g of UAIH4 (31.8 mmol, 2.0eq) was added in portions under N2, taking care that the
reaction did not become too vigorous. The grey slurry was refluxed for three hours. The
mixture was cooled in an ice water bath and carefully quenched with 1M NaOH. The

solvents were removed under vacuum, and the solids washed with hot MeOH and discarded.
The methanol solution was concentrated under vacuum and purified by preparative HPLC.
S-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridiiie-2-carbonitriIe

[0597] Following Protocol L, 5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile was
treated with N-Chlorosuccinimide to give the target compound.
Synthesis of 2-(4-chloro-5-trifluoromethyl-2H-pyrazoI-3-yl)-pyridine:

f
[0598] Following Protocol L, 2-(5-trifluoromethyl-2H-pyrazol-3-yl)-pyridine was treated
with N-chlorosuccinimide. The crude product was purified by recrystallisation from hexane
and ethyl acetate (9:1): lH NMR (400 MHz, CDC13): 5 7.35-7.38 (m, 1H), 7.85-7.90 (m, 1H),
8.20 (d, J= 8.1 Hz, 1H), 8.63 (d, J= 4.0 Hz, 1H).
6~(4~Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid methylamide

[0599] Following Protocol L, 6-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid
methylamide was treated with N-Chlorosuccinimide to give the title compound.

4-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrUe

[0600] Following Protocol L, 4-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carbomtrile was
treated with NCS to give the title compound.
2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-6-trifluoromethyl-pyridine ,

[0601] Following Protocol L, 2-(5-methyl-1H-pyrazol-3-yl)-6-trifluoromethyl-pyridine was
treated with NCS to give the title compound.
3-Bromoindazole

[0602] Following Protocol L, Indazole was converted to 3-Bromoindazole.
Synthesis of 3-(2-pyridyl)-4-chloro-5-methylpyrazole:

[0603] Following Protocol L, 3-(2-pyridyl) -5-methylpyrazole was treated with N-
chlorosuccinimide to give the title compound as a pale yellow solid.
Synthesis of 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-6-methyl-pyridine:


[0604] Following Protocol L, 2-Methyl-6-(5-methyl-1H-pyrazol-3-yl)-pyridine was treated
with N-chlorosuccinimide to give the title compound.
Synthesis of2-(4-Bromo-5-methyl-1H-pyrazol-3-yl)-6-methyl-pyridine:

[0605] Following Protocol L, 2-Methyl-6-(5-methyl-1 H-pyrazol-3-yl)-pyridine was treated
with N-bromosuccinimide to give the title compound.
Synthesis of 3-methyl-4-iodo-5-(trifluoromethyl) pyrazole

[0606] 3-Methyl-5(trifluoromethyl)pyrazole(1.5 g, lOmmol),
[Bis(trifluoroacetoxy)iodo]benzene (4.8 g, 11 mmol ) and Iodine(2.8 g, 11 mmol) were
mixtured in 120 mL DCM and stirred at r.t. for 2 hrs. 0.5L EtOAc was added into the
mixture, washed it with 1M Na2S205] brine, dried over anhydrous sodium sulfate, and
concentrated to afford the brown solid. The solid was washed with Hexane to afford the title
compound: HPLC retention time = 3.52 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5|i,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); MS (ES) M+H expect =276.9, found =277.1.

Synthesis of 3-methyl-4-floro-5(trifluoromethyI) pyrazole

[0607] 3-Methyl-5-(trifluoromethyl)pyrazole (0.30 g, 2 mmol), select-fluor reagent (3.54
g, 10 mmol) were mixtured in DMF and stirred at 60°C overnight, e tOAc was added, the
mixture was filtered, and the filtrate was washed with Sat. NaHCC>3, Brine, dried over
Na2SO4, and concentrated to afford the product.
6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

[0608] Following Protocol L, 6-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid
ethyl ester was treated with N-chlorosuccinimide to give the title compound.
Synthesis of 4-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyrimidine:

[0609] Following protocol L, 4-(5-Methyl-1H-pyrazol-3-yl)-pyrimidine was treated with
N-chlorosuccinimide in acetonitrile to give the title compound.
Synthesis of 4-Chloro-3-iodo-5-methyl-1H-pyrazole:

[0610] 7.0gm (60 mmol) of 4-Chloro-3-methylpyrazole3 34gm (78 mmol) of Bis-
(trifluoroacetoxy)iodobenzene, and 20gm (78 mmol) of iodine were added to 350 mL
dichloromethane in a flask with a large stirbar. After 14 hours, the mixture was partitioned

between 3M sodium metabisulfite and hexane, and the phases were separated. The hexane
phase was washed once each with 3M sodium metabisulfite and brine, dried over sodium
sulfate, filtered, and concentrated. The residue was crystallized from hexane to give the title
compound.
Synthesis of 4-(4-Bromo-5-methyl-2H-pyrazol-3-yl)-pyridine:

[0611] Following protocol X, 4-(5-methyl-2H-pyrazol-3-yl)-pyridine was treated with NBS
in acetonitile to give the title compound.
Synthesis of 4-(4-Chloro-5-methyI-2H-pyrazol-3-yI)-pyridine:

[0612] Following protocol X, 4-(5-methyl-2H-pyrazol-3-yl)-pyridine was treated with NCS
in acetonitile to give the title compound.
Synthesis of 2-(4-ChIoro-5-Methyl-1H-pyrazol-3-yl)-pyrimidine:

[0613] Following Protocol L, 2-(5-Methyl-1H-pyrazol-3-yl)-pyrimidine was treated with
N-chlorosuccinimide at 60°C for one hour. The reaction mixture was cooled to rt,
concentrated, and the residue was partitioned between ethyl acetate and water. The phases
were separated, and the aqueous phase was back-extracted twice with ethyl acetate. The
combined ethyl acetate phases were washed with 1M NaOH, brine, dried over Na2SO4, and
concentrated. The residue was slurried in ether, and the solids were isolated by filtration to
give the title compound.

Synthesis of 2-Methyl-5-(4-chloro-5-methyl-2H-pyrazoI-3-yl)-pyridine:

[0614] Following protocol L, 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-pyridine was treated
with N-chlorosuccinimide in acetonitrile to give the title compound.
4-Chloro-3,5-dipyridin-2-yl-pyrazoI-1-yl

[0615] The above compound was synthesized following Protocol L using the commercially
available dipyridylpyrazole.
2-Methyl-4-(4-chloro-5-methyl-1H-pyrazol-3-yl)-pyridine

[0616] Following Protocol L, 2-Methyl-4-(5-methyl-1H-pyrazol-3-yl)-pyridine was treated
with N-Chlorosuccinimide to give the title compound.
5-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid ethyl ester

[0617] Following Protocol L, 5-(5-Methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid
ethyl ester was treated with NCS to give the title compound.

Synthesis of 3-Bromo-4-chloro-5-methyl-1H-pyrazole:

[0618] 5.0 mL (61 mmol) of 3-methylpyrazole and 8.95gm (67.1 mmol) of N-
chlorosuccinimide in 50 mL of glacial acetic acid were heated at 60°C for two hours in a
sealed vessel. Following this, 5.5gm (74 mmol) of sodium acetate, 40 mL of water, and 3.2
mL (61 mmol) of bromine were added, the vessel was sealed, and the dark mixture was
heated at 100°C for three hours. The light orange solution was cooled to ambient
temperature, and 100 mL of water was added slowly. The solids were isolated by filtration,
washed with water, and dried to give the title compound.
PROTOCOL M: General procedure for reduction of Nitropyrazoles
Synthesis of 3-methyl-4-nitro-5(trifluoromethyI) pyrazole:

[0619] 3-Methyl-5(trifluoromethyl)pyrazole (3.0 g, 20 mmol) was dissolved in 2 mL
concentrated H2SO4 with vigorous stirring. 6 mL of nitric acid was added slowly into it. The
reaction mixture was stirred at 60°C overnight. The reaction mixture was cooled to room
temperature, poured into 50 mL saturated NaHCO3 in ice-bath, and the resulting mixture was
extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with
brine, dried over anhydrous sodium sulfate, and concentrated to afford the title compound (
3.9 g, yield: 100%). HPLC retention time = 4.55 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile). MS (ES) M+H expect = 196.0, found = 196.1.

Synthesis of 3-methyl-4-amino-5(trifluoromethyl)pyrazole:
■4
[0620] Following Protocol M, 3-Methyl-4-nitro-5(trifluoromethyl)pyrazole was treated
with Zinc in acetic acid to afford the title compound: MS (ES) M+H expect = 166.0, found =
165.0.
PROTOCOL P: Couplings of arylpiperazines with pyrazolyl-acetic acid derivatives -
compounds prepared by HATTJ mediated coupling:
2-(4-Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-1-[4-(2,4-dichloro-5-methoxy-
phenyl)-piperazin-1-yl]-ethanone

[0621] Following Protocol P, l-(2,4-Dichloro-5-methoxy-phenyl)-piperazine and (4-
Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using HATU to
give the title compound: HPLC retention time = 4.96 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5n, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).

1-[4-(4-CMoro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethytpyrazol-1-yl)-ethanone

[0622] Following Protocol P, l-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazine and (4-
Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using HATU to
give the title compound: HPLC retention time = 7.38 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5]i, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 469
(M+H).
2-(4-Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[(S)-4-(2,4-dichloro-5-methoxy-
phenyl)-2-methyl-piperazin-1-yl]-ethanone

[0623] Following Protocol P, (S)-1 -(2,4-Dichloro-5-methoxy-phenyl)-3-methyl-piperazine
and (4-Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using
HATU to give the title compound: HPLC retention time = 6.86 minutes (Agilent Zorbax SB-
C18,2.1X50 mm, 5\x, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)- = 463
(M-Br).

2-(4-Bromo-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-1-[(S)-4-(4-bromo-5-methoxy-
phenyl)-2-methyI-piperazin-1-yl]-ethanone

[0624] Following Protocol P, (S)-1-(4-Bromo-5-methoxy-phenyl)-3-methyl-piperazine and
(4-Bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using HATU to
give the title compound: HPLC retention time = 7.32 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)- = 473
(M-Br).
1-[4-(4-Chloro-3-methoxy-phenyl)-cis-2,3-dimethyl-piperazin-1-ylJ-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yI)-ethanone

[0625] Following HATU mediated coupling Protocol P, 1 -(4-Chloro-3 -methoxy-phenyl)-
2,3-cis-dimethyl-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-l -yl)-acetic
acid were coupled to give the title compound: HPLC retention time = 7.5 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5\x, 35°C) using a 2.0 minute isocratic period of 20% B,
followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile);

2-ChIoro-5-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyll-piperazin-
1-yIJ-benzoic acid ethyl ester

[0626] Following Protocol P, 2-Chloro-5-piperazin-1-yl-benzoic acid ethyl ester and (4-
Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using HATU to
give the title compound: HPLC retention time = 7.38 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1 % formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
1-[4-(2-Bromo-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chIoro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0627] Following Protocol P, l-(2-Bromo-4-chloro-5-methoxy-phenyl)-piperazine and (4-
Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using HATU to
give the title compound: HPLC retention time = 7.82 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5 p., 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

5-Chloro-2- {4- [2-(4-chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-acetyl] -piperazin-
lryI}-4-methoxy-benzoic acid methyl ester

[0628] Following Protocol P, 5 -Chloro-4-methoxy-2-piperazin-1 -yl-benzoic acid methyl
ester and (4-Qiloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using
HATU to give the title compound: HPLC retention time = 7.44 minutes (Agilent Zorbax SB-
C18,2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)- = 506.9
(M-H).
Synthesis of racemic 1-[4-(4-Chloro-3-methoxyphenyl)-2-trifluoromethylpiperazin-1-
yl]-2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yI)ethanone

[0629] The title compound was obtained by following Protocol P: LCMS (ES): M+H
519.0; HPLC retention time = 5.57 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5n, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-ChIoro-3-methoxyphcnyI)-cis-2,5-dimethylpiperazin-1-yl]-2-(4-
ciiloro-5-methyl-3-trifluoromethylpyrazol-1-yl)ethanone

[0630J The title compound was obtained by following Protocol P: LCMS (ES): M+H
479.1; HPLC retention time = 5.49 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of racemic 1-[4-(4-Chloro-3-methoxyphenyl)-trans-2,5-dimethylpiperazin-1-
yI]-2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)ethanone

[0631] The title compound was obtained by following Protocol P: LCMS (ES): M+H
479.1; HPLC retention time = 5.47 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-(3-cyano-4-chIoro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-[l,4]diazepan-1-yl]-ethanone:

[0632] Step 1: A sample of 1-[4-(4-chloro-3-methoxy-phenyl)-[l,4]diazepane-1-carboxylic
acid t-butyl ester (68 m g, 0.2 mmol , 1 equiv) was treated with 2 mL of 4N HC1 in dioxane
at room temperature for 2 hours and evaporated.

[0633] Step 2: To the solution of the residue in 1 mL of DMF were added (4-chloro-5-
methyl-3-trifluomethyl-pyrazol-1-yl)-acetic acid (48 m g, 1 equiv), HATU (84 m g, 1.1
equiv), TEA (84 uL, 3 equiv) at room temperature overnight. The mixture was diluted with
EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried
over Na2SC>4, filtered, evaporated and subjected to reverse phase HPLC (acetonitrile-HaO
with 0.1% TFA as eluent) to yield the title compound: NMR signals from the major isomer
are !H NMR (400 MHz, CDC13) 8 7.33 (d, 1H), 6.76 (d, 1H), 6.60 (dd, 1H), 5.00 (s, 2H), 3.84
(s, 3H), 4.00-3.50 (m, 8H), 2.33 (m, 2H), 2.08 (s, 3H). LCMS observed for (M+H)+: 466.
4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yI]-2-oxo-ethyl}-5-methyl-
lH-pyrazoIe-3-carboxylic acid methylamide

[0634] Following Protocol P, 4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-
yl]-2-oxo-ethyl}-5-rnethyl-1H-pyrazole-3-carboxylic acid and methylamine hydrochloride
were coupled using HATU to give the title compound: HPLC retention time = 4.78 minutes
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20%
B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)+ = 440.1 (M+H).

4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
MI-pyrazole-3-carboxylic acid dimethylamide

[0635] Following Protocol P, 4-Chloro-l - (2-[4-(4-chloro-3-tnethoxy-phenyl)-piperazin-l -
yl]-2-oxo-ethyl}-5-methyl-1H-pyrazole-3-carboxylic acid and dimethylamine were coupled
using HATU to give the title compound: HPLC retention time = 4.899 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B,
followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)+ = 454.1 (M+H).
4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
lH-pyrazoIe-3-carboxylic acid ethylamide

[0636] Following Protocol P, 4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-
yl]-2-oxo-ethyl}-5-methyl-1H-pyrazole-3-carboxylic acid and ethylamine were coupled using
HATU to give the title compound: HPLC retention time = 5.02 minutes (Agilent Zorbax SB-
CIS, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 454.1
(M+H).

Synthesis of 2-(4-Chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)-1-[4-(2,4-dimethyI-
phenyl)piperazin-1-yl] ethanone

[0637] The title compound was obtained by following Protocol P: LCMS (ES): M+H
415.1; HPLC retention time = 5.374 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0:08% formic acid / 99.9%
acetonitrile).
1-[4-(4-Chloro-3-methoxy-phenyl)-trans-2,5-dimethyl-piperazin-1-yl]-2-(4-chloro-5-
methyI-3-pyridin-2-yl-pyrazol-1-yI)-ethanone

[0638] Following Protocol P, the title compound was prepared: 'H NMR (400 MHz,
CDC13) 8 8.87-8.92 (m, 3H), 6.02-6.95 (s, 2H), 5.11 (s, 2H), 4.18 (q, 1H), 3.68 (q, 1H), 3.41
(q, 1H), 2.45 (s, 3H), 1.52 (t, 3H), 1.42 (d, 3H), 1.21 (d, 3H); LCMS (ES) M+H=488.4, RT
4.364min (acetonitrile/H20 20-95% method).
1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chloro-5-methyI-3-(l-oxypyridin-
4-yl)pyr azol-1-yl] ethanone


[0639] The title compound was obtained by following Protocol P: LCMS (ES): M+H
476.0; HPLC retention time = 4.00 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-ChIoro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-ylI-2-[4-chloro-
5-methyI-3-(l-oxypyridin-4-yl)pyrazol-1-yl]ethanone

[O640] The title compound was obtained by following Protocol P: LCMS (ES): M+H
490.1; HPLC retention time = 4.36 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5n, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-[4-chloro-
5-methyl-3-(l-oxy-pyridin-3-yI)-pyrazol-1-yI]-ethanone:

[0641] Following Protocol P, sodium [4-chloro-5-methyl-3-(l-oxy-pyridin-3-yl)-pyrazol-1-
yl]-acetate and l-(4-Chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine were coupled to give
the title compound: MS (M+H+): 490.1; HPLC retention time = 4.06 minutes (Agilent Zorbax
SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1
minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-ChIoro-3-methoxy-phenyl>piperazin-1-yl]-2-[4-chIoro-5-methyl-3-
|l-oxy-pyridin-3-yl)-pyrazol-1-yl]-ethanone:

[0642] Following Protocol P, sodium [4-chloro-5-methyl-3-(l -oxy-pyridin-3-yi)-pyrazol-1-
yl]-acetate and l-(4-Chloro-3-methoxy-phenyl)-piperazine were coupled to give the title
compound: MS (M+H1): 476.1; HPLC retention time = 3.80 minutes (Agilent Zorbax SB-
CIS, 2.1X50 mm, 5p., 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute
wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic
acid / 99.9% acetonitrile).
1-[4-(4-ChIoro-3-methoxybenzyl)piperazin-1-yI]-2-(4-chloro-5-methyl-3-
trifluoromethylpyrazol-1-yl)ethanone

[0643] The title compound was obtained by following Protocol P: LCMS (ES) M+H: M+H
= 465.0: HPLC retention time = 3.733 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5[i,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).

4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
lH-pyrazole-3-carboxylic acid isopropylamide

[0644] Following Protocol P, 4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-
yl]-2-oxo-ethyl}-5-methyl-1H-pyrazole-3-carboxylic acid and isopropylamine were coupled
using HATU to give the title compound: HPLC retention time = 5.23 minutes (Agilent
Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B,
followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile);;.(M/Z)+ = 468.1 (M+H).
1-[4-(4-Chloro-3-methoxy-phenyl)-2-pyrrolidin-1-ylmethyl-piperazin-1-yl]-2-(4-chloro-
5-methyI-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0645] Approximately 0.28 mmol of4-(4-Chloro-3-methoxy-phenyl)-2-pyrrolidin-1-
ylmethyl-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL of 1/1
dichloromethane and trifluoroacetic acid. After 30 minutes, the solution was concentrated to
a residue. The crude residue was dissolved in 500uL DMF, 82mg of 4-chloro-3-
trifluoromethyl-5-methylpyrazole-1-acetic acid (0.34 mmol), 293uL of DIEA (1.7 mmol),
and 128mg of HATU (0.34 mmol) were added sequentially. The vial was stirred at room
temperature for several hours, then placed in a 60°C oil bath overnight. The crude mixture

was purified by preparative HPLC. LC/MS(ES) (M+H) 534.5; HPLC retention time = 6.47
minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period
of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at
95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
1-[4-(4-Chloro-3-methoxy-phenyl)-2-morpholin-4-ylmethyl-piperazin-1-yl]-2-(4-chloro-
5-methyl-3-trifluoromethyI-pyrazol-1-yl)-ethanone

[0646] Approximately 0.28 mmol of 4-(4-Chloro-3-methoxy-phenyl)-2-morpholin-4-
ylmethyl-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL of 1/1
dichloromethane and trifluoroacetic acid. After 30 minutes, the solution was concentrated to
a residue. The residue was dissolved in 500uL DMF, and 82mg 4-chloro-3-trifluoromethyl-
5-methylpyrazole-1-acetic acid (0.34 mmol ), 293uL DIEA (1.7 mmol), and 128mg HATU
(0.34 mmol) were added sequentially. The vial was stirred at room temperature for several
hours, then placed in a 60°C oil bath overnight. The crude mixture was purified by
preparative HPLC. LC/MS(ES) (M+H) 550.5; HPLC retention time = 6.33 minutes (Agilent
Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B,
followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).

1-[4-(4-Chloro-3-methoxy-phenyl)-2-(4-methyI-piperazin-1-ylmethyI)-piperazin-1-yl]-2-
(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0647] Approximately 0.28 mmol of 4-(4-Chloro-3-methoxy-phenyl)-2-(4-methyl-
piperazin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL of
1/1 dichloromethane and trifluoroacetic acid. After 30 minutes, the solution was
concentrated to a residue. The residue was dissolved in 500uL DMF, and 82mg 4-chloro-3-
trifluoromethyl-5-methylpyrazole-1-acetic acid (0.34 mmol), 293uL DIEA (1.7 mmol), and
128mg HATU (0.34 mmol) were added sequentially. The vial was stirred at room
temperature for several hours, then placed in a 60°C oil bath overnight. The crude mixture
was purified by preparative HPLC. LC/MS(ES) (M+H) = 563.5; HPLC retention time =
7.25 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic
period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash
at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(morpholine-
4-carbonyl)-pyrazol-1-yl]-ethanone

[0648] Following Protocol P, 4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-
yl]-2-oxo-ethyl}-5-methyl-1H-pyrazole-3-carboxylic acid and morpholine were coupled

using HATU to give the title compound: HPLC retention time = 4.90 minutes (Agilent
Zorbax SB-C18, 2.1X50 mm, 5\i, 35°C) using a 2.0 minute isocratic period of 20% B,
followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)+ = 496.1 (M+H).
PROTOCOL S: preparation of chloroacetvl arvlpiperazines
4-chloromethylcarbonyl-1-(4-chIoro-3-(2-fluoro)ethoxy-phenyI)-piperazine

[0649] Following Protocol S, l-(4-chloro-3-(2-fluoro)ethoxy-phenyl)-piperazine
dihydrochloride
[0650] (1.53 mmol, 1 .Oeq), 1.0g K2CO3 (7.5 mmol, 5.0eq) were combined in a vial with 4
mL NMP. The vial was cooled in an ice water bath, then 197uL chloroacetyl chloride (1.8
mmol, 1.2eq) was added and the mixture allowed to stir at room temperature overnight. The
material was purified by column chromatography to get lOOmg clean product.
4-chloromethylcarbonyl-1-(4-chloro-3-(2,2,2-trifluoro)ethoxy-phenyl)-piperazine

[0651] Following Protocol S, l-(4-chloro-3 -(2,2,2-trifluoro)ethoxy-phenyl)-piperazine
dihydrochloride was reacted with chloroacetyl chloride to give the title compound.

4-chloromethylcarbonyl-1-(4-chloro-3-propoxy-phenyI)-piperazine
■4

[0652] Following Protocol S, l-(4-chloro-3-propoxy-phenyl)-piperazinedihydrochloride
was reacted with chloroacetyl chloride to give the title compound.
PROTOCOL T: K2CQ3 mediated coupling reaction of chloroacetvl arvlpiperazines
with pyrazoles
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-S-methyl-3-pyridin-4-yI-
pyrazol-1-yl)-ethanone

[0653] The title compound was prepared following Protocol T, using l-(4-Chloro-3-
methoxy-phenyl)-piperazine: HPLC retention time = 5.57 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5jj, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 460.1
(M+H).

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(S-hydroxy-3-methyl-
pyrazol-1-yl)-ethanon.e and 1-[4-(4-ChIoro-3-methoxy-phenyl)-piperazin-1-yI]-2-(3-
hydroxy-5-methyl-pyrazol-1-yl)-ethanone

[0654] Title compounds were prepared following Protocol T, wherein (3-Methyl-5-
(hydroxyl) pyrazole was used: 1-[4-(4-Chtoro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-
hydroxy-5-methyl-pyrazol-1-yl)-ethanone: HPLC retention time = 2.89minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a
1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 365.1, found = 365.4. 1-[4-(4-
ChIoro-3-methoxy-phenyl)-piperazin-1-yI]-2-(5-hydroxy-3-methyl-pyrazol-1-yl)-
ethanone: HPLC retention time = 3.33 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5\i,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); MS (ES) M+H expect = 365.1, found = 365.4; 'H NMR (DMSO, 400MHz) 7.20
(d, 1H), 70(s 1H), 6.52(d, 1H), 5.50 ( s 1H), 4.84 (s, 2H), 3.83 (s, 3H), 3.5-3.6 ( Par. Obsc.s,
4H), 3.1-3.3 (d, 4H), 2.15(s, 3H) ppm.
1-[4-(4-Chloro-3-meth.oxy-phenyl)-2-methyl-piperazin-1-yl]-2-[4-chloro-5-methyI-3-(4-
methyl-pyridin-2-yl)-pyrazoI- 1-yl] -ethanone


[0655] Following Protocol T, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-
methylpiperazin-1-yl]-ethanoneand2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-4-methyl-
pyridine were combined to give the title compound: HPLC retention time = 6.76 minutes
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20%
B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)+= 488.1 (M+H).
4-(l-{2-[4-(4-Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-5-
methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

[0656] Following Protocol T, the title compound was prepared: HPLC retention time =
6.90 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic
period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); (M/Z)+ = 465.3 (M+H).
4-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yI]-2-oxo-ethyl}-5-methyI-
lH-pyrazol-3-yl)-pyridine-2-carbonitrile


[0657] Following Protocol T, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-
ethanone and 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-4-methyl-pyridine were combined to
give the title compound: HPLC retention time = 7.14 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 486.2
(M+H).
4-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-
5-methyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile

[06581 Following Protocol T, 2-Chloro-1 -[4-(4-chloro-3 -methoxy-phenyl)-2-(S)-methyl-
piperazin-1-yl]-ethanone and 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-4-methyl-pyridine were
combined to give the title compound: HPLC retention time = 7.42 minutes (Agilent Zorbax
SB-C18, 2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a
5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ =
499.2 (M+H).

l_{4-[4-Chloro-3-(2-fluoro-ethoxy)-phenyl]-piperazin-1-yl}-2-(4-chloro-5-methyl-3-
pyridin-2-yl-pyrazol-1-yl)-ethanone

[0659] Following Protocol T, the title compound was prepared: LC/MS(ES) (M+H) 492.4;
HPLC retention time = 5.91 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5|i, 35°C) using
a 2.0 minute isocratic period of 20°/o B, followed by a 5.0 minute gradient of 20% to 95% B
with a 2.5 minute wash at 95% B (A. = 0.1% formic acid / 5% acetonitrile / 94.9% water, B =
0.08% formic acid / 99.9% acetonitrile)
2-(4-Chloro-5-methyl-3-pyridin-2-yl-pyrazoI-1-yl)-1-{4-[4-chloro-3-(2,2,2-trifluoro-
ethoxy)-phenyl]-piperazin-1-yI}-ethanone

[0660] Following Protocol T, the title compound was prepared: LC/MS(ES) (M+H) 528.4;
HPLC retention time = 6.47 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using
a 2.0 minute isocratic period of 20°/o B, followed by a 5.0 minute gradient of 20% to 95% B
with a 2.5 minute wash at 95% B (A. = 0.1% formic acid / 5% acetonitrile / 94.9% water, B =
0.08% formic acid / 99.9% acetonitrile).

2-(4-Chloro-5-methyI-3-pyridin-2-yl-pyrazol-1-yl)-1-[4-(4-chloro-3-propoxy-phenyl)-
piper azin- l-yl]-ethanone

[0661] Following Protocol T, the title compound was prepared: LC/MS(ES) (M+H) 488.4;
HPLC retention time = 6.52 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5p, 35°C) using
a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B
with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B =
0.08% formic acid / 99.9% acetonitrile).
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yll-2-(S-methyl-3-trifluoromethyl-
pyrazol-1-yl)-ethanone

[0662] Following Protocol T, 2-Chloro-1-[4-(4-chloro-3-methox.y-phenyl)-piperazin-1-yl]-
ethanone and 3-methyl-5-trifluoromethylpyrazole were coupled to give the title compound:
HPLC retention time = 7.18 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using
a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B
with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B =
0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 417.2 (M+H).
[0663] 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(5-methyl-3-
trifluoromethyl-pyrazol-1 -yl)-ethanone


[0664] Following Protocol T, 2-Chloro-1-[4-(4-chloro-6-fluoro-3-methoxy-phenyl)-
piperazin-1-yl]-ethanone and 3-methyl-5-trifluoromethylpyrazole were reacted to give the
title compound: HPLC retention time = 7.35 minutes (Agilent Zorbax SB-C18, 2.1X50 mm,
5|i, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 435.2 (M+H).
2-(4-Chloro-3-hydroxymethyl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yl]-ethanone

[0665] Following Protocol T, (4-Chloro-5-methyl-1H-pyrazol-3-yl)-methanol and 2-
Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone were coupled to give the
title compound: HPLC retention time = 6.45 minutes (Agilent Zorbax SB-C18, 2.1X50 mm,
5 p., 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 413.2 (M+H).

1-[4-(4-Chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chIoro-5-methyI-3-
pyridin-4-ylpyrazol-1-yI)ethanone

[0666] The title compound was obtained by following Protocol T: LCMS (ES): M+H
474.1; HPLC retention time = 3.645 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).
6-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
lH-pyrazol-3-yI)-pyridine-2-carboxylic acid methylamide

[0667] The title compound was made by following Protocol T: LCMS (ES) M+H= 518.4;
HPLC RT = 4.308 min (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yI]-2-(4-chloro-5-methyI-3-
pyridin-2-yl-pyrazol-1-yl)ethanone


[0668] The title compound was obtained by following Protocol T: LCMS (ES): M+H
460.1; HPLC retention time = 3.77 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
6-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
lH-pyrazol-3-yI)-pyridine-2-carboxylic acid dimethylamide

[0669] The title compound was made by following Protocol T: ' H NMR (400 MHz,
CDC13) 5 8 7.98-7.41 (m, 3H), 6.47 (m, 3H), 5.05 (s, 1H), 3.89 (q, 2H), 3.89 (s, 3H), 3.21-
3.13 (dt, 2H), 2.34 (s, 3H), 2.18 (s, 3H), 1.63 (s, 1H); LCMS (ES) M+H= 531.5; HPLC RT =
4.113 min (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95%*B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-(3-methylsuIfonyI-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-2 (S)-methyl-piperazin-l -yl] -ethanone

[0670] Following Protocol T, 2-chloro-l -[4-(4-chloro-3-methoxy-phenyl)-2(S)-methyl-
piperazin-1-yl]-ethanone and 3-methylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl were coupled
to give the title compound: *H NMR (400 MHz, CDC13) 5 7.30 (d, 1H), 7.18 (br, 1H), 6.80
(br, 1H), 6.05 (bt, 3H), 5.50 (br, 1H), 4.95 (br, 1H), 4.42 (br, 1H), 3.90 (s, 3H), 3.42 (br, 3H),
3.18 (s, 3H), 2.30 (s, 3H), 1.70 (d, 1.5H), 1.58 (d, 1.5H); LCMS observed for (M+H)+: 475.

1-[4-(4-Chloro-3-methoxyphenyl)-2-(S)-methyIpiperazin-1-yl]-2-(4-chloro-5-methyI-3-
pyridin-2-ylpyrazol-1-yl)ethanone

[0671] The title compound was prepared following Protocol T: LCMS (ES) M+H = 474.1;
HPLC retention time = 4.95 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-
methyl-3-pyridin-2-ylpyrazol-1-yl)ethanone

[0672] The title compound was obtained by following Protocol T: LCMS (ES): M+H
478.1; HPLC retention time = 3.92 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyI)-2-raethylpiperazin-1-yl]-2-[4-chIoro-5-
methyl-3-(6-methylpyridin-3-yl)pyrazol-1-yl]ethanone


[0673] The title compound was obtained by following Protocol T: LCMS (ES): M+H
488.1; HPLC retention time = 4.32 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-ChIoro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-pyridiii-2-
yl-3-trifluoromethyl-pyrazol-1-yl)-ethanoneand 1-[4-(4-Chloro-3-methoxy-phenyl)-
piperazin-1-yl]-2-(4-chloro-3-pyridin-2-yl-S-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0674) The above two isomers were synthesized by the same Protocol T. These isomers
were purified by preparative TLC (50% EtOAc: n-Hexane).
[0675] l-(4-(4-Chloro-3-methoxyphenyI)-piperazin-1-yl)-2-(4-chloro-5-pyridin-2-yl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone (Major isomer): LC MS 514 (M+, 20-95 method,
RT = 4.99 min); !H NMR (400 MHz, CDC13): 5 3.06 (t, /= 4.7 Hz, 2H), 3.19 (t, J= 4.7 Hz,
2H), 3.63 (apparent q, J= 7.5 Hz, 4H), 3.87 (s, 3H), 5.63 (s, 2H), 6.39 (dd, J= 2.6 & 8.8 Hz,
1H), 6.46 (d, J= 2.6 Hz, 1H), 7.20 (d, J= 8.8 Hz, 1H), 7.29-7.32 (m, 1H), 7.81 (dt, J= 1.8 &
8.1 Hz, 1H), 7.92 (d, J= 7.7 Hz, 1H), 8.60 (d, J= 5.1 Hz, 1H).
[0676] l-(4-(4-Chloro-3-methoxyphenyI)-piperazin-1-yl)-2-(4-chIoro-3-pyridin-2-yl-5-
trifluoromethyl-pyrazol-1-yI)-ethanone (Minor isomer): LC MS 514 (M+, 20-95 method,
RT = 4.68 min); 'H NMR (400 MHz, CDC13): 8 3.06 (t, J= 4.3 Hz, 2H), 3.21 (t, J= 4.3 Hz,
2H), 3.60 (apparent q, J= 6.5 Hz, 2H), 3.76 (apparent q, J= 6.5 Hz, 2H) 3.85 (s, 3H), 5.24
(s, 2H), 6.39 (dd, /= 2.6 & 8.8 Hz, 1H), 6.46 (d, J= 2.6 Hz, 1H), 7.20 (d, /= 8.8 Hz, 1H),
7.29-7.32 (m, 1H), 7.76 (dt, 7= 1.8 & 8.1 Hz, 1H), 7.98 (d, J= 1.1 Hz, 1H), 8.74 (d, J= 5.1
Hz, 1H).

Synthesis of 1-[4-(4-ChIoro-3-methoxyphenyl)-2-(S)-metliylpiperazin-1-yl]-2-(4-chloro-
5-methyl-3-pyrimidin-4-ylpyrazol-1-yl)ethanone

[0677] The title compound was obtained by following Protocol T: LCMS (ES): M+H
475.1; HPLC retention time = 4.59 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minxite wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of l-(4-(4-Chloro-3-methoxyphenyl)-2(S)-methylpiperazin-1-yl)-2-(4-chloro-5-
pyridin-2-yI-3-trifluoromethyl-pyrazoI-1-yl)ethanoneanci l-(4-(4-Chloro-3-
methoxyphenyI)-2(S)-methyIpiperazin-1-yI)-2-(4-chIoro-3-pyridin-2-yl-5-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0678] l-(4-(4-Ch!oro-3-methoxyphenyl)-2(5)-methylpiperazin-1-yl)-2-(4-chloro-5-
pyridin-2-yl-3-trifluoromethyl-pyrazol-1-yI)ethanone: Trie above compound was
synthesized by the same Protocol T: LCMS 528 (M+H); HPLC RT = 5.29 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a
1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile).
[0679] l-(4-(4-Chloro-3-methoxyphenyl)-2(5)-methylpiperazin-1-yl)-2-(4-chloro-3-
pyridin-2-yl-5-trifluoromethyI-pyrazoI-1-yl)-ethanone: The above compound was

synthesized by the same Protocol T: LCMS 528 (M^H); HPLC RT = 4.95 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5p., 35°C) using a 4.5 minute gradient of 20% to 95% B with a
1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile)
Synthesis of l-(4-(4-ChIoro-2-fluoro-5-methoxyphenyI)-2(S)-methyIpiperazin-1-yI)- 2-(4-
chloro-5-pyridin-2-yl-3-trifluoromethyl-pyrazoI-1-yl)-ethanone and l-(4-(4-Chloro-2-
fluoro-5-methoxyphenyl)-2(S)-methy]piperazin-1-yl)-2-(4-chloro-3-pyridin-2-yI-5-
trifluoromethyl-pyrazol-1-yl)-ethanone:

[0680J l-(4-(4-Chloro-2-fluoro-5-methoxyphenyl)-2 (^)-methylpiperazin-1-yl)- 2-(4-
chIoro-5-pyridln-2-yl-3-trifluoromethyl-pyrazol-1-yl)-ethanone: The above compound
was synthesized by Protocol T: LC MS 546 (M+H); HPLC RT = 5.52 minutes (Agilent
Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a
1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile).
[0681] l-(4-(4-Chloro-2-fluoro-5-methoxyphenyl)-2(.S,)-methylpiperazin-1-yI)-2-(4-
chloro-3-pyridin-2-yl-5-trifluoromethyI-pyrazol-1-yl) ethanone : The above compound
was synthesized by the same protocol XX. LC MS 546 (M+H); HPLC RT = 5.19 minutes
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-ChIoro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chloro-
5-methyl-3-pyrimidin-2-ylpyrazol-1-yI)ethanone

[0682] The title compound was obtained by following Protocol T: *H NMR: 5 (400 MHz,
CDC13) 8.95 (d, 2H), 7.60 (ddd, 1H), 7.39 (m, 1H), 6.52 (JOT, 2H), 5.28-4.77 (br, 2H), 4.47-
4.18 (br, 2H), 3.89 (s, 3H), 3.78-2.73 (br, 5H), 2.36 (s, 3H), 1.53-0.78 (br, 3H); LCMS (ES):
M+H 475.1; HPLC retention time = 4.41 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5\i,
35°C) using a4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazm-1-yl]-2-(4-fluoro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0683] Title compound was prepared following Protocol T, wherein l-(3-methoxyphenyl-
4-chloro)piperazine-4-chloromethyl-ketonand(3-Methyl-4-fluoro-5-(trifluoromethyl)
pyrazole were used as the coupling components: HPLC retention time = 4.69 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5\i, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 435.1, found = 435.3.

6-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyI-
ip-pyrazol-3-yl)-pyridine-2-carbonitrile

[0684] The title compound was made by following Protocol T: LCMS (ES) M+H=485.4;
HPLC RT = £.859 min (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-
pyrimidin-4-yIpyrazoI-1-yl)ethanone

[0685] The title compound was obtained by following Protocol T: LCMS (ES): M+H
461.1; HPLC retention time = 4.37 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5fi, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of l-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5methyl-
3-trifluoromethyl-1H-pyrazole-4-carbonitrile

[0686] Title compound was prepared following Protocol T, wherein l-(3-methoxyphenyl-
4-chloro)piperazine-4-chloromethyl-ketonand(3-Methyl-4-cyano-5-(trifluoromethyl)

pyrazole were used as the coupling components: HPLC retention time = 4.59 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 442.1, found = 442.4.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-ylJ-2-(4-iodo-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-ethanone

[0687] Title compound was prepared following Protocol T: HPLC retention time = 4.89
minutes, (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 543.2,
found = 543.3.
Synthesis of N-(l-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-
methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetamide

[0688] Title compound was prepared following Protocol T, wherein l-(3-methoxyphenyl-
4-chloro)piperazine-4-chloromethyl-ketonand3-Methyl-4-acetylamino-5-(trifluoromethyl)
pyrazole were used as the coupling components: HPLC retention time = 3.66 minutes,
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 474.1, found = 474.4.

Synthesis of 2-(2-phenylimidazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyI)-piperazin-1-
yl]-ethanone

[0689] Following Protocol T, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-
ethanone and 2-phenylimidazole were coupled to give the title compound: LCMS retention
time: 2.86 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed for
(M+H)+:411.
Synthesis of 2-Benzoimidazol-1-yl-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-
ethanone

[0690] Following Protocol T, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yI]-
ethanone and benzimidazole were reacted to give the title compound: LCMS retention time:
2.57 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed for (M+H)+: 385.
5-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-
ethyl}-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxyIic acid methylamide


[0691] The title compound was made by following Protocol T: *H NMR (400 MHz,
GDClj): 5 9.21-8.12 (m, 3H), 6.47 (m, 3H), 4.64 (s, 2H), 3.81 (q, 2H), 3.89 (s, 1H), 3.89 (d,
2H), 3.79-3.32 (dt, 2H), 2.35 (s, 3H), 2.18 (s, 3H); LCMS (ES) M+H= 531.5; HPLC RT=
4.360min (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
2-[4-Chloro-3-(6-methanesuIfonyl-pyridin-2-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-
methoxy-phenyl>2-(S)-methyl-piperazin-1-yl]-ethanone

[0692] The title compound was made by following Protocol T: !H NMR (400 MHz,
CDCI3) 5 5 8.12-7.82 (m, 3H), 6.47 (m, 3H), 5.51 (s, 2H), 3.89 (s, 1H), 3.89 (s, 3H), 3.81(d,
2H), 3.79 (d, 2H), 3.36 (s, 3H), 3.18-3.13 (dt, 2H), 2.35 (s, 3H), 2.34(s, 3H), 1.60 (s, 1H);
LCMS (ES) M+H=532.5; HPLC RT = 4.582 min (Agilent Zorbax SB-C18, 2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl] -2-(4-chloro-5-
methyl-3-pyrimidin-2-ylpyrazoI-1-yI)ethanone

[0693] The title compound was obtained by following Protocol T: LCMS (ES): M+H
479.1; HPLC retention time = 4.65 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5JJ., 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 %
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

2-[4-Chloro-3-(6-chloro-pyridin-3-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-
pj2enyI)-2-(S)-methyl-piperazin-1-yl]-ethanone

[0694] Following Protocol T, 2-Chloro-1 -[4-(4-chloro-3-methoxy-phenyl)-2-(S)-
methylpiperazin-1 -yl]-ethanone and 2-Chloro-5-(4-chloro-5 -methyl-1 H-pyrazol-3-yl)-
pyridine were coupled to give the title compound: HPLC retention time = 7.83 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u., 35°C) using a 2.0 minute isocratic period of 20%
B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)- = 506 (M-H).
4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-
lH-pyrazole-3-carboxylic acid ethyl ester

[0695] Following Protocol T, 2-Chloro-1 -[4-(4-chloro-3 -methoxy-phenyl)-piperazin-1 -yl] -
ethanone and 4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester were combined to
give the title compound: HPLC retention time = 7.14 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5^, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /

5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ - 455.1
(M+H).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chIoro-5-methyl-3-(6-
methylpyridin-2-yl)pyrazol-1-yl]ethanone

[0696] The title compound was obtained by following Protocol T: LCMS (ES): M+H
474.1; HPLC retention time = 4.39 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyI)-2-(S)-methylpiperazin-1-yl]-2-[4-cliloro-
5-methyl-3-(6-methyIpyridin-2-yl)pyrazol-1-yl]ethanone

[0697] The title compound was obtained by following Protocol T: LCMS (ES): M+H
488.1; HPLC retention time = 4.42 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5U., 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 2-[4-Bromo-5-methyI-3-(6-methylpyridin-2-yI)pyrazol-1-yl]-1-[4-(4-chloro-
3rmethoxyphenyl)piperazin-1-yl]ethanone

[0698] The title compound was obtained by following Protocol T: LCMS (ES): M+H
518.1; HPLC retention time = 4.43 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u., 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of2-[4-Bromo-5-methyl-3-(6-methylpyridin-2-yl)pyrazol-1-yl]-1-[4-(4-chloro-
3-methoxyphenyl)-2-(S)-methyIpiperazin-1-yl]ethanone

[0699J The title compound was obtained by following Protocol T: LCMS (ES): M+H
532.1; HPLC retention time = 4.25 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u., 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyI)piperazin-1-yl]-2-[4-chloro-5-methyI-3-(2-
methylpyridin-4-yl)pyrazol-1-yl]ethanone


[0700] The title compound was obtained by following Protocol T: LCMS (ES): M+H
474.1; HPLC retention time = 3.76 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5\i, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1_ 1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08°/i formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)pipei-azin-1-yl]-2-[4-chloro-5-methyl-3-(6—
trifluoromethylpyridin-2-yl)pyrazoI-1-yl]ethanone

[0701] Following Protocol T, 2-(4-Chloro-5-methyl-1 H-pyrazol-3-yl)-6-trifluoromethyl-
pyridine and 2-Chloro-1-[4-(4-chloro-3-methoxy-phen.yl)-piperazin-1-yl]-ethanone were
combined to give the title compound: LCMS (ES): M+-H 528.1; HPLC retention time = 5.36
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).
1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-m.ethyl-piperazm-1-yI]-2-(4-chIoro-5-
methyl-3-pyridin-2-yl-pyrazol-1-yl)-ethanone

[0702] Following Protocol T, 2-Chloro-1 -[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-
methyl-piperazin-1-yl]-ethanone and 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine were
combined to give the title compound: HPLC retention "time = 6.50 minutes (Agilent Zorbax
SB-C18,2.1X50 mm, 5\i, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a
5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic

acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ =
492.1 (M+H).
Synthesis of 2-(4-Chloro-3-iodo-5-methyI-pyrazoI-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone:

[0703] Following Protocol T, 2-(4-Chloro-5-methyl-1 H-pyrazol-3-yl)-pyridine and 2-
chloro-1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-ethanone were treated with
potassium carbonate in N,N-dimethylformamide to yield the title compound: LCMS (ES)
M+H= 509.0; HPLC retention time = 4.85 minutes (Agilent Zorbax SB-C18, 2.1X50 mm,
5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A
= 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).
Synthesis of 1-[4-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-(4-chloro-5-
methyI-3-pyridin-2-ylpyrazol-1-yl)ethanone:

[0704] Following Protocol T, 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-
chloro-1-[4-(4-chloro-3-ethoxy-2-fluoro-phenyl)-piperazin-1-yl]-ethanone were treated with
potassium carbonate in N,N-dimethylformarnide to yield the title compound: *H NMR (400
MHz, CDC13) 8 8.87-7.12 (m, 3H), 6.47 (d, 3H), 5.11 (s, 2H), 3.8 (q, 2H), 3.21-3.83 (dt, 2H),
2.35 (s, 3H). LCMS (ES) M+H= 492.1, HPLC retention time = 5.469 min (acetonitrile/H20
20-95% method).

Synthesis of l-(4-(4-ChIoro-3-methoxyphenyI)-piperazin-1-yl)-2-(3-trifluoromethyl)-5-
(2-furyI)-pyrazol-1-yl)ethanone:

[0705] The above compound was synthesized following Protocol T: LCMS M+H = 469;
HPLC RT = 4.81 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); ]H NMR (400
MHz, CDC13) 5 3.14-3.21 (m, 4H), 3.65-3.78 (m, 4H), 3.88 (s, 3H), 5.30 (s, 2H), 6.42 (dd, J
= 2.4 & 6.7 Hz, 1H), 6.48-6.50 (m, 2H), 6.70 (d, J= 3.3 Hz, 1H), 6.75 (s, 1H), 7.21 (s, 1H),
7.46 (d, 7= 1.8 Hz, 1H).
Synthesis of 2-(4-Chloro-3,5-dipyridin-2-yl-pyrazol-1-yl)-1-(4-(4-chloro-3-
methoxyphenyl)-piperazin-1-yl)ethanone:

[0706] The above compound was synthesized following Protocol T: LCMS M+H = 523;
HPLC RT = 4.29 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5a, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); *H NMR (400
MHz, DMSO-4,): 8 3.10 (br, 2H), 3.25 (br, 2H), 3.51 (br, 2H), 3.68 (br, 2H), 3.87 (s, 3H),
5.65 (s, 2H), 6.52(dd, /= 2.6 & 8.8 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H). 7.23 (d, /= 8.8 Hz,
1H) 6.48-6.50 (m, 2H), 6.70 (d, J= 3.3 Hz, 1H), 6.75 (s, 1H), 7.21 (s, 1H), 7.46 (d, J= 1.8

Hz, 1H), 7.43-7.50 (m, 2H), 7.90-7.94 (m, 2H), 8.01 (dt, J= 1.8 & 7.7 Hz, 1H), 8.70-8.73 (m,
2H"j.
Synthesis of 2-(4-Chloro-3,5-dipyridin-2-yl-pyrazol-1-yl)-1-(4-(4-chloro-2-fluoro-5-
methoxyphenyl)-2-(S)-methyIpiperazin-1-yl) ethanone:

[0707] The above compound was synthesized following Protocol T: LCMS M+H = 555;
HPLC RT = 4.77 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); [H NMR (400
MHz, DMSO-4;): 5 1.11 (d, 7=6.3 Hz, 1.5H), 1.41 (d,/=6.5 Hz, 1.5 H) 3.25 (br,2H),
2.67- 3.01 (m, 3H), 3.43-3.50 (m, 1H), 3.88 (s, 3H), 4.10-4.13 (m, 1H), 4.28 (br, 1H),
4.45(br, 1H), 5.60 (s, 1H), 5.68 (s, 1H), 6.74 (d, J= 8 Hz, 1H), 7.38-7.56 (m, 3H), 7.90-7.97
(m, 2H), 8.02 (t, J = 7.7 Hz, 1H), 8.71-8.75 (m, 2H).
Synthesis of 1-[4-(4-Chloro-3-ethoxyphenyl)-2-methylpiperazin-1-ylJ-2-(4-chloro-5-
methyl-3-pyridin-2-ylpyrazoI-1-yl)ethanone:

[0708] Following Protocol T, 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-
chloro-1-[4-(4-chloro-3-ethoxyphenyl)-2-(S)-methylpiperazin-1-yl]-ethanone were combined
to yield the title compound; 'H NMR (400 MHz, CDC13) 5 8.87-7.12 (m, 3H), 6.47 (d, 3H),
5.11 (s, 2H), 3.8 (q, 2H), 3.21-3.83 (dt, 2H), 2.35 (s, 3H), 1.52 (d, 3H); LCMS (ES) M+H=
488.1; HPLC RT = 5.993 min (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5

minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5%"acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 6-(4-Chloro-1-{2-[4-(4-chloro-3-ethoxyphenyl)piperazin-1-yl]-2-oxo-ethyl}-
5-methyl-1H-pyrazol-3-yl)pyridine-2-carbonitrile:

[0709] Following Protocol T, 2-(4-Chloro-5-methyl-l H-pyrazol-3-yl)-6-cyanopyridine and
2-chloro-1-[4-(4-chloro-3-ethoxyphenyl)-piperazin-1-yl]-ethanone were treated with
potassium carbonate in N,N-dimethylformamide to yield the title compound: !H NMR (400
MHz, CDC13) 8 8.87-8.92 (m, 3H), 6.57-6.45 (m, 3H), 5.11 (s, 2H), 4.18 (q, 2H), 3.21-3.68
(dt, 4H), 2.45 (s, 3H), 1.52 (t, 3H); LCMS (ES) M+H= 499.2; HPLC RT = 4.807 min.
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 6-(4-Chloro-1-{2-[4-(4-chloro-3-ethoxyphenyl)-2-(S)-methylpiperazin-1-yl]-
2-oxo-ethyl}-5-methyl-1H-pyrazol-3-yl)pyridine-2-carbonitriIe:

[0710J Following Protocol T, 2-(4-Chloro-5-methyl-1 H-pyrazol-3 -yl)-6-cyanopyridine and
2-chloro-1 -[4-(4-chloro-3-ethoxyphenyl)-2-(S)-methylpiperazin-1 -yl]-ethanone were treated
with potassium carbonate in N,N-dimethylformarnide to yield the title compound. *H NMR
(400 MHz, CDCI3) 6 8.87-8.92 (m, 3H), 6.57-6.45 (m, 3H), 5.11 (s, 2H), 4.18 (q, 2H), 3.21-
3.68 (dt, 4H), 2.45 (s, 3H), 1.52 (d, 3H), 1.40 (q, 1H); LCMS (ES) M+H= 513.4; HPLC RT =
5.192 min. (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 2-[4-chloro-1-{2-[4-(4-chloro-3-methoxy-phemyl)-piperazin-1-yI]-2-
oxoethyl}-5-methyl-1H-pyrazoI-3-yI)-isonicotinic acid eth;yl ester

[0711] Title compound was prepared following Protocol T: HPLC retention time = 5.9
minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES> M+H expect = 532.14, found =
532.2.
Synthesis of 2-[4-chloro-3-(6-methanesulfonyI-pyridin-2-yl)-5-mthyl-pyrazol-1-yl]-1-[4-
(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-ethanone

[0712] Title compound was prepared following Protocol T: HPLC retention time = 5.55
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5|i, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES> M+H expect = 538.1, found =
538.1.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
pynmidin-2-yl-pyrazol-1-yl)-ethanone (Isomer I) and 1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yI]-2-(4-chIoro-3-methyl-5-pyrimidin-2-yl-pyrazol-1-yl)-ethanone (Isomer
II)

[0713] Title compounds were prepared following Protocol T: Isomer I: HPLC retention
time = 3.8 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5n, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).MS(ES) M+H expect
= 461.1, found = 461.3.
[0714] Isomer II: HPLC retention time = 4.16 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).MS (ES) M+H expect = 461.1, found = 461.3.
Synthesis of 1-[4-(4-chloro-3-ethoxy-phenyl)-piperazin-1-yl]-2-(4-ch!oro-5-methyl-3-
pyrimidin-2-yl-pyrazol-1-yl)-ethanone (Isomer I) and 1-[4-(4-chloro-3-ethoxy-phenyl)-
piperazin-1-ylI-2-(4-chloro-3-methyl-5-pyrimidin-2-yl-pyrazoI-1-yl)-ethanone (Isomer
II)


[0715] Title compounds were prepared following Protocol T:Isomer I: HPLC retention
time = 4.09minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5n, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); MS(ES) M+H expect
= 475.1, found = 475.4; *H NMR (CDC13,400MHz) 8.88 (d, 2H), 7.31-7.25 (m, 4H),
6.64(s,lH), 6.52(d, 1H), 5.15 (s, 2H), 4.5-4.3,4.08 (q, 2H), 3.83 (m, 4H), 3.25-3.19 (m, 4H),
2.37(s, 3H), 1.47 (t, 3H) ppm; NOESY shows co-relationship between a-H (5.1ppm) and
CH3-in pyrazole(2.4ppm);
[0716] Isomer II: HPLC retention time = 4.45 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5LI, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).MS (ES) M+H expect = 475.1, found = 475.4; lE NMR (CDC13,
400MHz) 1H NMR (CDCI3, 400MHz) 8.80 (d, 2H), 7.2 (m, 4H), 6.62 (s, 1H), 6.61 (d,
1H), 5.64 (s, 2H), 4.10 (d, 2H), 3.77-3.23 (d,d, 8H), 3.17(d, 4H), 2.34(s, 3H), 1.48 (t,
3H) ppm; NOESY shows no co-relationship between -H (5.64ppm) and CH3- in
pyrazole (2.34 ppm).
Synthesis of 1- [4-(4-chloro-3-ethoxy-phenyl)-2-mthyl-piperazin-1-yl] -2-(4-chIoro-5-
methyl-3-pyrimidin-2-yl-pyrazoI-1-yl)-ethanone (Isomer I) and 1-[4-(4-chloro-3-ethoxy-
phenyl)-2-mthyl-piperazin-1-yl]-2-(4-chloro-3-methyl-5-pyrimidin-2-yl-pyrazol-1-yI)-
ethanone (Isomer II)

[07171 Title compounds were prepared following Protocol T: Isomer I: HPLC retention
time = 4.35 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).MS(ES) M+H expect
= 489.2, found = 489.4.

[0718] Isomer II: HPLC retention time = 4.71 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).MS (ES) M+H expect = 461.1, found = 489.4.
Synthesis of 1-[4-(4-chloro-1-{2-[4-(4-chIoro-3-ethoxy-phenyl)-piperazin-1-yl]-2-oxo-
ehtyI}-5-methyl-1H-pyrazol-3-yl)-pyrimidine-2-carbonitrile

[0719] Title compound was prepared following Protocol T: HPLC retention time = 4.94
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid/ 99.9% acetonitrile).MS (ES) M+H expect = 499.1, found =
499.4.
Synthesis of 2-[4-chloro-3(14iydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-1-[4-(3-
methoxy-4-chIoro-phenyI)-piperazin-1-yi]-ethanone (Isomer I) and 2-[4-chloro-5(l-
hydroxy-1-methyl-ethyl)-3-methyI-pyrazol-1-yl]-1-[4-(3-methoxy-4-ch!oro-phenyl)-
piperazin-1-yl]-ethanone (Isomer II):

[0720] Following protocol T, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1 -yl]-
ethanone and 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-propan-2-ol were combined to give the
title compounds. Isomer I: HPLC retention time = 5.34 minutes (Agilent Zorbax SB-C18,

2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile);; MS (ES) M+H expect = 441.1, found = 423.1(-H20); *H NMR (CDC13,
400MHz) 7.63 (s, 3H), 7.32(d 1H), 6.80(s, 1H), 6.65 (d 1H), 5.04 (s, 2H), 3.89 (m, 3H),
3.93-3.85 (Par. Obscm, 4H), 3.38 (t, 2H), 3.30 (t, 2H), 2.27(s, 2H), 1.63 (s, 6H) ppm;
NOESY shows co-relationship between a-H (5.0ppm) and CH3-in pyrazole(2.2ppm).
[0721] Isomer II: HPLC retention time = 5.5minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5\i, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); MS (ES) M+H expect = 441.1, found = 423.1(-H20); *H NMR (CDC13,
400MHz) 9.6 (s, 1H), 7.25(d, 1H), 6.5 (s 1H), 6.45(d, 1H), 4.86 (s, 2H), 3.88 (s, 3H), 3.38
(m, 8H), 2.24(s, 3H), 1.82 (s, 6H) ppm; NOESY shows no co-relationship between a-
H(4.86ppm) and CH3- in pyrazole(2.24ppm).
Synthesis of 2-[4-chIoro-3-isopropyl-5-methyl pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone

[0722] Title compound was prepared following Protocol T: HPLC retention time = 6.0
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u., 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 425.1, found =
425.1.

Synthesis of l-4-(4-chIoro-3-methoxyphenyl)-piperazin-1-yl) -2-(3,5-dipyridin-2-yl-
pyrazol-1-yl)ethanone:

[0723] Following Protocol T, the title compound was prepared: LC MS 489 (M+, 20-95
method, RT = 3.79min); 'HNMR (400MHz, CDC13): 5 3.13 (bs, 2H),3.25 (bs, 2H), 3.74
(bs, 4H), 3.88 (s, 3H), 5.82 (s, 2H), 6.43 (dd, J- 2.6 & 8.5 Hz, 1H), 6.48 (d, J= 2.4 Hz, 1H),
7.17-7.24 (m, 3H), 7.37 (d, J= 1.1 Hz, 1H), 7.68-7.76 (m, 3H), 7.97 (dd, J = 0.7 & 7.3 Hz,
1H), 8.49-8.52 (m, 1H), 8.60-8.62 (m, 1H).
Synthesis of 6-(4-Chloro-1-{2-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-
oxo-ethyl}-5-methyI-1H-pyrazol-3-yl)pyridine-2-carbonitrile:

[0724] Following Protocol T, 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-6-cyanopyridine and
2-chloro-1 -[4-(4-chloro-3 -ethoxy-2-fluorophenyl)-piperazin-1 -yl] -ethanone were combined
to yield the title compound: *H NMR (400 MHz, CDC13) 5 8.87-8.92 (m, 3H), 6.02-6.95 (s,
2H), 5.11 (s, 2H), 4.18 (q, 2H), 3.21-3.68 (dt, 4H), 2.45 (s, 3H), 1.52 (t, 3H). LCMS (ES)
M+H= 517.4, RT = 5.130 min (acetonitrile/H20 20-95% method).
Synthesis of l-{2-[4-(4-Chloro-3-methoxy-phenyJ)-2-methyI-piperazin-1-yl]-2-oxo-
ethyl}-5-methyl-3-(5-methyl-isoxazoI-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester:

[072S] Following Protocol T, 5-Methyl-3-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-
carboxylic acid ethyl ester and 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-

piperazin-1-yl]-ethanone were combined to give the title compound: MS (M+H*): 488.2;
HPLC retention time = 5.21 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using
a 45 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-(3-BromoindazoI-1-yl)-1-(4-(4-chloro-3-methoxyphenyI)-piperazin-1-
yl)ethanone

[0726] Following Protocol T, the title compound was prepared: LCMS M+H = 464; HPLC
RT = 4.73 min. (Agilent Zorbax SB-C18,2.1X50 mm, 5\i, 35°C) using a 4.5 minute gradient
of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile/
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); 'H NMR (400 MHz, CDC13): 5
3.07 (apparent q, J= 4.4 Hz, 4H), 3.75 (apparent q, /= 4.4 Hz, 4H), 3.87 (s, 3H), 5.23 (s,
2H), 6.37 (dd, J= 1.4 & 8.4 Hz, 1H), 6.48 (d, J= 1.8 Hz,lH), 7.18-7.24 (m, 2H), 7.42- 7.45
(m, 2H), 7.59 (d, J= 8.0 Hz, 1H).
5-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yll-2-oxo-ethyl}-5-methyI-
lH-pyrazol-3-yl)-pyridine-2-carboxylic acid dimethylamide

[0727] The title compound was made by following Protocol T: ' H NMR (400 MHz,
CDCI3) 8 8 9.21-8.12 (m, 3H), 6.47 (m, 3H), 4.48 (s, 2H), 3.8 (q, 2H), 3.89 (s, 1H), 3.79-
3.32 (dt, 2H), 2.35 (s, 3H), 2.18 (s, 3H); LCMS (ES) M+H = 532.4; HPLC RT = 4.483 min
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).

5-(4-ChIoro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-2-methyI-piperazin-1-yl]-2-oxo-ethy[}-
5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid dimethylamide

[0728] The title compound was made by following Protocol T: XH NMR (400 MHz,
CDCI3) 8 8 9.21-8.12 (m, 3H), 6.47 (m, 3H), 4.64 (s, 2H), 3.81 (q, 2H), 3.89 (s, 1H), 3.89 (d,
2H), 3.79-3.32 (dt, 2H), 2.35 (s, 3H), 2.18 (s, 3H); LCMS (ES) M+H = 546.5; HPLC RT =
6.887 min (Agilent Zorbax SB-C18,2.1X50 mm, 5ji, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-pyridin-2-yl-pyrazoI-1-yl)-ethanone

[0729] A mixture of 4-chloro-5-methyl-3-pyridylpyrazol (3.61 g,18.7mmol),
phenylpiperazine-carbonylmethylchloride(5.75 g, 19.0mrnol ) and K2CO3 (27.6 g, 200
mmol ) in CH3CN (50 mL) and DMF (5 mL) was heated to 80 °C for 2 hr. The mixture was
tilted and evaporated in vacuo. The remaining residue of DMF was further removed by high
vacuum over night. Recrystallization in hot ethanol afforded the title compound as a white
solid. The solid was dissolved in ethanol (200 mL) and hydrogen chloride in ether (2.0 M,
400 mL) was added slowly with stirring. The resulting precipitate was filtered to afford the
title compound as a white solid. lH NMR: 8 (400 MHz, cf-DMSO) major rotamer: 8.69 (br d,
1H), 8.15 (br, 1H), 8.07 (br d, 1H), 7.59 (br, d, 1H), 7.20 (d, 1H), 6.64 (br, 1H), 6.41 (br d,
1H), 5.55-5.18 (brm, 2H), 3.83 (s, 3H), 3.74-3.48 (br m, 4 H), 3.18-2.59 (br m, 3H), 2.22 (s,
3H), 1.42-1.16 (brm, 3H). MS (M+H+): 474.1

1-[4-(4-Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-raethyl-3-
pyridin-3-yl-pyrazol-1-yl)-ethanone:

[0730] Foliowing Protocol T, 3-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-
Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone were
treated with potassium carbonate in N,N-dimethylformamide to give title compound: MS
(M+H+): 474.1; HPLC retention time = 3.96 minutes (Agilent Zorbax SB-C18,2.1X50 mm,
5\i, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A
= 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).'
1-[4-(4-Chldro-3-methoxy-phenyl)-piperazin-1-ylj-2-(4-chloro-5-methyl-3-pyridin-3-yl-
pyrazol-1-yl)-ethanone:

[0731] Following Protocol T, 3-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine and 2-
Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone were treated with
potassium carbonate in N,N-dimethylformamide to give title compound: MS (M+H*): 460.1;
HPLC retention time = 3.59 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5\i, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

PROTOCOL V: Preparation of compounds via acid or base-mediated de-protections.
4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyi)-piperazin-1-yl]-2-oxo-ethyl}-5-methyI-
lH-pyrazole-3-carboxylic acid.

[0732] 4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-
methyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg) was dissolved in THF (7 ml) and
5 mL of IN NaOH was added to the solution and the reaction mixture was stirred overnight.
It was then acidified with IN HC1 and was the extracted with ethyl acetate. It was then dried
and solvent removed to get a clean product: 1H NMR (CDC13,400MHz) 7.18-7.22 (d, 1H),
6.74-6.76 (d, 1H), 6.54-6.58 (dd, 2H), 5.3 (s, 2H), 3.88 (s, 3H), 3.68-3.82 (m, 4H), 3.22-3.38
(m, 4H), 2.24 (s, 3H) ppm. MS (ES)M+H expected = 427, found = 427.
6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid amide:

[0733] To Ethyl 6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylate (1 .Ogm,
0.78 mmol) in 10 mL of dry THF was added 10 mL of liquid ammonia. It was then heated
to 60°C for next 6h, in which time the reaction was over and the solid product precipitated.
The reaction was cooled and THF was rotavaped off to generate 0.5gm of the title compound.

6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridme-2-carbonitrile:

[0734] 6-(4-Chloro-5-methyl-1 H-pyrazol-3-yl)-pyridine-2-carboxylic acid amide (0.15 gm,
0.63 mmol ) was dissolved in 5 mL of dry CH2C12, and 1 mL of TEA (7.29 mmol) was
added to it. It was then cooled to 0°C and was treated with (CF3CO)20 (0.2ml, 0.952 mmol
). The reaction mixture was slowly warmed to ambient temperature, and was then stirred for
another 4 hours. The mixture was washed once each with 10% NaHCC>3, 5% citric acid, and
finally with saturated brine. The methylene chloride phase was concentrated, and the residue
was purified by chromatography to give the title compound.
6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylic acid:

[0735] Ethyl 6-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-pyridine-2-carboxylate (0.23 gm,
0.78 mmol ) was dissolved in 5 mL of dry THF and 5 mL of water, and LiOH (0.3gm) was
added to it. After 6 hours, the THF was rotavaped off, and the residue was then acidified
with citric acid. The resultant solids were isolated to give the title compound.
PROTOCOL W: Preparation of compounds via borohydride-mediated reductive
alleviation. '
l-(4-Chloro-3-methoxybenzyl)piperazine


[0736] The title compound was obtained by following Protocol W, using 4-chloro-3-
methoxybenzaldehyde and 1-Boc-piperazine, followed by N-Boc cleavage with HC1 in
isorjropanol.
4-(4-Chloro-3-methoxy-phenyl)-2-formyl-piperazine-1-carboxylic acid tert-butyl ester

[0737] 500 mg (1.40 mmol ) of 4-(4-Chloro-3-methoxy-phenyl)-2-hydroxymethyl-
piperazine-1-carboxylic acid tert-butyl ester was dissolved in 5 mL of dichloromethane, the
solution was cooled to 0°C, and 7.3 mL (1.82 mmol) of 0.25M Des-Martin periodinane in
dichloromethane was added slowly. After 2 hours, the mixture was washed with sat. sodium
metabisulfite, brine, and dried over sodium sulfate. The crude aldehyde was used as is.
4-(4-Chloro-3-methoxy-phea.yl)-2-pyrroIidin-1-yImethyl-piperazine-1-carboxylic acid
tert-butyl ester

[0738] To approximately 0.28 mmol of 4-(4-Chloro-3-methoxy-phenyl)-2-formyl-
piperazine-1-carboxylic acid tert-butyl ester in 2.4 mL of dichloromethane was added 0.5 mL
methanol, 0.1 mL (1.1 mmol ) of pyrrolidine, and 35mg (0.56 mmol) of sodium
cyanoborohydride. After 4 hours, the reaction was quenched with 50microliters of acetic
acid. One hour later, the mixture was washed with sat. sodium bicarbonate, brine, dried over
sodium sulfate, and concentrated to a residue.

4-(4-Chloro-3-methoxy-phenyl)-2-morpholin-4-ylmethyl-piperazine-1-carboxyiicacid
tert-butyl ester

[0739] To approximately 0.28 mmol of 4-(4-Chloro-3-methoxy-phenyl)-2-formyl-
piperazine-1-carboxylic acid tert-butyl ester in 2.4 mL of dichloromethane was added 0.5 mL
methanol, 0.1 mL (1.1 mmol ) of morpholine, and 35mg (0.56 mmol) of sodium
cyanoborohydride. After 4 hours, the reaction was quenched with 50microliters of acetic
acid. One hour later, the mixture was washed with sat. sodium bicarbonate, brine, dried over
sodium sulfate, and concentrated to a residue.
4-(4-Chloro-3-methoxy-phenyl)-2-(4-methyl-plperazin-1-ylmethyl)-piperazine-1-
carboxylic acid tert-butyl ester

[0740] To approximately 0.28 mmol of 4-(4-Chloro-3-methoxy-phenyl)-2-formyl-
piperazine-1-carboxylic acid tert-butyl ester in 2.4 mL of dichloromethane was added 0.5 mL
methanol, 0.12 mL (1.1 mmol) of 1-methylpiperazine, and 35mg (0.56 mmol) of sodium
cyanoborohydride. After 4 hours, the reaction was quenched with 50microliters of acetic
acid. One hour later, the mixture was washed with sat. sodium bicarbonate, brine, dried over
sodium sulfate, and concentrated to a residue.

PROTOCOL X: Preparation of compounds via Acvlation or sulfonylation.
N-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyI)-piperazin-1-yl]-2-oxo-ethyl}-5-
methyl-1H-pyrazol-3-yl)-methanesulfonamide

[0741] To2-(3-Amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yl]-ethanone (1.0 g) in dichloromethane (20ml) was added triethylamine (0.7ml)
and MeSOaCI (0.19ml), and the mixture was stirred for 5 hows at 0°C. The disulfonated
compound formed was dissolved in methanol (10ml) and NaOH (0.42g in 5- mL water) was
added and stirred at 60°C for 2 hours. The methanol was removed under vacuum, water was
added, and the pH was adjusted to acidic using citric acid. The solid compound was filtered
and purified by chromatography to give the title compound
Synthesis of 3-methyl-4-acetylamino-5(trifluoromethyl) pyrazole

[0742] To 3-methyl-4-amino-5(trifluoromethyl) pyrazole (165 m g, 1 mmol ) dissolved in
ACN was added 0.1 mL acetic anhydride. A precipitate was formed after addition, and was
isolated by filtration to give the title compound: HPLC retention time = 0.36 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a
1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 208.1, found = 208.2.

PROTOCOL Y: Preparation of compounds via alkvlation.
Synthesis of 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-propan-2-ol

[0743] 4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.14 g, 0.8 mmol )
was dissolved in 6 mL anhydrous THF, cooled to 0°C, and 3 mL (9.0 mmol) of 3M MeMgBr
in ethyl ether was added drop wise. The reaction was then removed from the ice-bath, and
was stirred at ambient temperature For one hour. The reaction mixture was poured into 1M
phosphate buffer (pH = 7)', and the mixture was extracted with EtOAc. The phases were
separated, and the ethyl acetate layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated to afford the title compound: MS (ES) M-OH expect =157.1, found
= 157.1; ]H NMR (CDCL3, 400MHZ) 5 2.25 (s, 3H), 1.64 (s, 6H) ppm.
Synthesis of'4-Chloro-3-isopropyI-5-methyI-1H-pyrazoIe:

[0744] 2-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-propan-2-ol (52 m g, 0.3 mmol ), 2 mL
DCM, 1 mL triethylsilane and 0.1 mL TFA were added together and stirred at 80°C
overnight, then the solvent was removed in vacuo. The residue was dissolved in ethyl
acetate, washed with saturated NaHG03, brine, dried over anhydrous sodium sulfate, and
concentrated to afford the title compound. HPLC retention time = 4.9 minutes (Agilent
Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a
1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile); MS (ES) M+H expect =159.1, found =159.1.

PROTOCOL AA: Synthesis of tri-substituted Pvrazoles via Suzuki coupling.
2-[4-Chloro-3-(5-fluoro-2-methoxy-pyridin-4-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-
3-methoxy-phenyl)-piperazin-1-yl]-ethanone

10745] The title compound was made by following Protocol AA: LCMS (ES) M+H =
509.3; HPLC RT = 4.714min (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
2-[4-Chloro-3-(3-methoxy-phenyl)-5-methyl-pyrazoI-1-yl]-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone.

[0746] Step 1; 3-Methyl-4-chloro-5-bromopyrazol (222.5 mg) was dissolved in DMF
(10ml). To the mixture was added Pd(PPh3)4 (44.6 mg), aq. Na2CO3 (306.16 in 2 mL of
H2O) and finally 3-methoxyphenylboronic acid (190 mg). The reaction mixture was heated
in an oil bath at about 140°C for 14h. Once the starting material is all consumed it was then
cooled and then the solid residue was filtered off. e tOAc was added to the reaction mixture
and was then washed with water to remove the DMF. The organic layer was then dried and
solvent removed to get the crude product.
[0747] Step 2; The product was then dissolved in DMF (7ml) and was treated with K2CO3
(123.2 mg) and 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone A (278
mg). It was then heated at about 8O0C for 16h and then cooled, quenched with water and
extracted with ethyl acetate. The solvent was removed and the crude product was purified by

chromatography to give the title compound: Rf: 0.7; *H NMR (CDC13,400MHz) 7.4-7.48
(2H, m), 7.28-7.34 (t, 1H), 7.2-7.22 (d, 1H), 6.86-6.91 (m, 1H), 6.4-6.48 (m, 2H), 5.0 (2H, s),
3.84 (s, 3H), 3.82 (s, 3H), 3.72-3.8 (m, 4H), 3.12-3.18 (m, 4H), 2.3 (s, 3H) ppm. l3CNMR
(400MHz, CDCI3) 8 161, 160, 158,152, 148, 140, 134,130, 128, 120, 112, 111.5, 110, 109,
100, 58, 56, 54, 50.2, 50, 46,42, 10.
2-(4-Chloro-3-furan-2-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chIoro-3-methoxy-phenyl)-2-
(S)-methyl-piperazin-1-yl]-ethanone

[0748] Following Protocol AA, 2-(3-Bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-
chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone and furan-2-boronic acid
were cross-coupled to give the title compound: HPLC retention time = 7.42 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B,
followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)+ = 463.2 (M+H).
Synthesis of 2-[4-Chloro-3-(2,4-difluoro-phenyl)-5-methyl-pyrazoI-1-yI]-1-[4-(4-chloro-
3-methoxy-phenyl)-2-(S)-methylpiperazin-1-ylI-ethanone:

[0749] Following Protocol AA, 2,4-difluorophenylboronic acid and 2-(3-Bromo-4-chloro-
5-methyI-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-
ethanone were coupled to give the title compound. HPLC retention time = 5.39 minutes

(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0*03% formic acid / 99.9% acetonitrile).
2-[4-Chloro-3-(3-fluoro-pyridin-4-yl)-5-methyl-pyrazoI-1-yI]-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone

[0750] The title compound was made by following Suzuki Protocol AA: LCMS (ES) M+H
= 478.3; HPLC RT = 4.724 min (Agilent Zorbax SB-C18, 2.1X50 mm, 5\x, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
2-[4-Chloro-3-(2-chloro-pyridin-3-yl)-5-methyl-pyrazol-1-yll-1-[4-(4-chIoro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone

[0751] The title compound was made by following Suzuki Protocol AA: ]H NMR (400
MHz, CDC13) 0 8.87-7.12 (m, 3H), 6.47 (d, 3H), 4.64 (s, 2H), 3.89 (s, 1H), 3.21-3.83 (dt,
2H), 2.85 (s, 3H); LCMS (ES) M+H=494.4; HPLC RT= 4.514 min (Agilent Zorbax SB-CIS,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).

2-[4-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0752] The title compound was made by following Suzuki Protocol AA: LCMS (ES) M+H
= 521.4; HPLC retention time = 4.499min (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(l-methyl-1H-
indoI-6-yl)-pyrazol-1-yI]-etb.anone

[0753] The title compound was made by following Suzuki Protocol AA: LCMS (ES)
M+H= 512.4; HPLC RT = 5.038min (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(5-methyl-
furan-2-yl)-pyrazol-1-yl]-ethanone


[0754] The title compound was made by following Suzuki Protocol AA: LCMS (ES) M+H
= 463.4; HPLC retention time = 4.961min (Agilent Zorbax SB-C18,2.1X50 mm, 5|i, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 %
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
2-(4-Chloro-3-furan-3-yl-5-methyI-pyrazol-1-yI)-1-[4-(4-chloro-3-methoxy-phenyl)-2-
(S)-methyl-piperazin-1-yI]-ethanone

[0755] Following Suzuki Protocol AA, 2-(3-Bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-
(4-chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanoneandftiran-3-boronic
acid were cross-coupled to give the title compound: HPLC retention time = 7.49 minutes
(Agilent Zorbax SB-C18, 2.1X50 mm, 5fx, 35°C) using a 2.0 minute isocratic period of 20%
B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); (M/Z)+= 463.2 (M+H).
2-[4-Chloro-3-(4-fluoro-phenyl)-5-methyl-pyrazoI-1-yl]-1-[4-(4-chIoro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone.

[0756] Following Protocol AA, 2-[4-Chloro-3-bromo-5-rnethyl-pyrazol-l -yl]-l -[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 4-Fluoroboronic acid were cross-
coupled to give the title compound: Rf=0.57; 'HNMR^DCU^OOMHz) 7.8-7.9 (2H,m),
7.2-7.22 (d, 1H), 7.05-7.12 (m, 2H), 6.4-6.48 (m, 2H), 5.0 (2H, s), 3.82 (s, 3H), 3.7-3.8 (m,

4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H) ppm. I3CNMR (400MHz, CDC13) 8 162,160,155,152,
148, 140, 134, 130, 118, 112, 110, 109, 100, 58, 56, 54, 52, 46, 42, 10 ppm.
>-
2-[4-Chloro-3-(2-fluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone.

[0757] Following Protocol AA, 2-[4-Chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2-Fluoroboronic acid were coupled
to give the title compound: Rf: 0.521; *H NMR (CDC13,400MHz) 7.5-7.56 (1H, m), 7.32-
7.38 (m, 1H), 7.1-7.21 (m, 3H), 7.12-7.22 (d, 1H), 6.4-6.48 (m, 2H), 5.0 (2H, s), 3.83 (s, 3H),
3.7-3.8 (m, 4H), 3.08-3.18 (in, 4H), 2.3 (s, 3H) ppm. ,3CNMR (400MHz, CDC13) 5 162,160,
158, 155, 138, 131, 130, 124, 118, 112, 110, 109, 100,58,56,54,52,46,42, 10 ppm.
2-[4-ChlorOT3-(3-fluoro-phenyl)-5-methyI-pyrazol-1-yl]-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone.

[0758] Following Protocol AA, 2-[4-Chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 3-Fluoroboronic acid were coupled
to give the title compound: Rf: 0.68; 'H NMR (CDCl3,400MHz) 7.68-7.72 (1H, m), 7.58-
7.62 (m, 1H), 7.32-7.38 (m, 1H), 7.18-7.22 (d, 1H), 6.98-7.04 (m, 1H), 6.38-6.48 (m, 2H),
4.98 (2H, s), 3.88 (s, 3H), 3.7-3.8 (m, 4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H) ppm; 13CNMR
(400MHz, CDCI3) 8 164, 156,150,144, 130, 129, 124, 118,114-116 (m), 110,100, 56, 52,
50,49,46,42, lOppm.

2-[4-Chloro-3-(2,4-difluoro-phenyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-chIoro-3-methoxy-
phenyI)-piperazin-1-y]]-ethanone.

[0759] Following Protocol AA, 2-[4-Chloro-3-bromo-5-methyt-pyrazol-1 -yl]-l -[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2,4-Difluoroboronic acid were
cross-coupled to give the title compound: Rf: 0.7; ]H NMR (CDC13,400MHz) 7.48-7.56
(1H, m), 7.18-7.22 (d, 1H), 6.86-6.94 (m, 2H), 6.38-6.48 (m, 2H), 5.00 (2H, s), 3.88 (s, 3H),
3.68-3.8 (m, 4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H) ppm; 13CNMR (400MHz, CDC13) 5 164,156,
150, 138,132, 130, 122, 118,1 14-116 (m), 102, 56, 52, 50, 49, 46, 42, lOppm.
1-[4-(4-Chloro-3-methoxy-phenyI)-piperazin-1-yl]-2-(4-chloro-5-methyI-3-pyrimidin-5-
yl-pyrazol-1-yl)-ethanone.

[0760] Following Protocol A A, 2-[4-Chloro-3-bromo-5-methyl-pyrazol-l -yl]-l -[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 4-Pyrimidineboronic acid were
cross-coupled to give the title compound: Rf: 0.7; 'H NMR (CDC13) 400MHz) 9.15 (s, 1H),
9.23 (s, 2H), 7.2-7.25 (d, 1H), 6.38-6.48 (m, 2H), 5.02 (s, 2H), 3.88 (s, 3H), 3.72-3.82 (m,
4H), 3.12-3.22 (m, 4H), 2.32 (s, 3H) ppm; MS (ES)M+H expected = 461, found = 461.1.
2-(4-Chloro-3-furan-3-yl-5-methyI-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yl]-ethanone.

[0761] Following Protocol AA, 2-[4-Chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 3-Furanboronic acid were cross-
coupled to give the title compound: Rf: 0.7; !H NMR (CDCI3) 400MHz) 8.00 (s, 1H), 7.42-
7.44 (t, 1H), 7.18-7.22 (d, 1H), 6.82-6.84 (d, 2H), 6.38-6.48 (m, 2H), 4.84 (s, 2H), 3.88 (s,

3H), 3.68-3.8 (m, 4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H) ppm; 13CNMR (400MHz, CDC13) 8 164,
156,151,143, 141, 138, 130, 118, 116,110, 111, 102, 56,52, 50,49, 46,42, lOppm.
2-(4-ChIoro-3-furan-2-yl-5-methyI-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yl] -ethanone.

[0762] Following Protocol AA, 2-[4-Chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-
cMoro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2-Furanboronic were cross-coupled
to give the title compound: Rf: 0.7; *H NMR (CDC13, 400MHz) 7.48-7.52 (d, 1H), 7.18-
7.22 (d, 1H), 6.91-6.92 (d, 1H), 6.38-6.48 (m, 3H), 5.00 (s, 2H), 3.88 (s, 3H), 3.68-3.78 (m,
4H), 3.1-3.2 (m, 4H), 2.3 (s, 3H) ppm; l3CNMR (400MHz, CDC13) 8 164, 156, 151, 146,
142, 138, 130, 114, 111, 109, 108, 100, 56, 52, 50, 49, 46, 42, lOppm.
1-[4-(4-Chloro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
pyrimidin-5-yl-pyrazol-1-yI)-ethanone.

[0763] Following Protocol AA, 2-[4-Chloro-3-bromo-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone and 4-Pvrimidineboronic acid
were cross-coupled to give the title compound: Rf: 0.7; 'H NMR (CDC13,400MHz) 9.15 (s,
1H), 9.23 (s, 2H), 7.2-7.25 (d, 1H), 6.38-6.48 (m, 2H), 4.32-5.2 (m, 5H), 3.88 (s, 3H), 2.52-
3.52 (m, 7H), 2.3-2.4 (s, 4H) ppm; MS (ES)M+H expected = 475, found = 475.1.

1-[4-(4-ChIoro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-S-methyl-3-quinolin-3-yl-
pyrazol-1-yl)-ethanone

[0764J The title compound was made by following Suzuki Protocol AA: !H NMR (400
MHz, CDCI3) 5 9.21-7.43 (m, 6H), 6.47 (d, 3H), 4.64 (s, 2H), 3.89 (s, 1H), 3.21-3.83 (dt,
2H), 2.85 (s, 3H); LCMS (ES) M+H= 510.3, HPLC RT= 4.718min (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-raethoxyphenyl)piperazin-1-ylJ-2-(4-chloro-3-
furan-3-yl-5-methyIpyrazol-1-yI)ethanone

[0765] The title compound was obtained by following Protocol AA: LCMS (ES): M+H
467.1; HPLC retention time = 4.98 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

PROTOCOL CC: One-pot HATU mediated coupling and Azide reduction reactions.
2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazoI-1-yl)-1-[4-(2,4-dichloro-5-
>
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0766] 50mg of l-(2,4-Dichloro-5-methoxy-phenyl)-piperazine di-HCl (0.14 mmol,
l.Oeq), 48mg of (5-Azidomethyl-4-chloro-3-trifluororaethyl-pyrazol-1-yl)-acetic acid (0.17
mmol, 1.2eq), lOOuL of DIEA (0.57 mmol, 4.0eq) and 65mg of HATU (0.17 mmol, 1.2eq)
were combined in 250uL DMF in a 4 mL vial. After four hours, 157mg (0.7 mmol) of
Stannous (II) chloride was added, and the vial was sealed and heated in a 60°C oil bath
overnight. The reaction was purified by preparative HPLC to give the title compound: HPLC
retention time = 5.01 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5\x, 35°C) using a 2.0
minute isocratic period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a
2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile); (M/Z)+ = 496.7 (M+H).
2-(5-Aminomethyl-4-chloro-3-triflaoromethyl-pyrazoI-1-yl)-1-[4-(4-bromo-3-methoxy-
phenyI)-piperazin-1-yl]-ethanone

[0767] Following Protocol CC, l-(4-Bromo-5-methoxy-phenyl)-piperazine di-HCl and (5-
Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled with HATU,
and the crude product was reduced in situ with Stannous (II) chloride to give the title

compound: HPLC retention time = 5.46 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 509.0 (M+H).
2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxy-
phenyl)-2-methyl-piperazin-1-yl]-ethanone

[0768J Following Protocol CC, (S)-1-(4-Bromo-3-methoxy-phenyl)-3-methyl-piperazine
and (5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled with
HATU and the crude mixture was treated with Stannous (II) chloride to give the title
compound: HPLC retention time = 5.58 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)- = 443.9 (M-Br).
2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-2-fluoro-5-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0769] Following Protocol CC, 1 -(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazine and
(5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using
HATU and the crude mixture was treated with Stannous (II) chloride to give the title

compound: HPLC retention time = 5.84 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z)+ = 481.9 (M+H).
2-(5-Aminomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyI)-2-(S)-inethyI-piperazin-1-yl]-ethanone

[0770] Following Protocol CC, (S)-1-(4-chloro-3-methoxy-phenyl)-3-methyl-piperazine
and (5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were coupled using
HATU , and the crude mixture was treated with Stannous (II) chloride to give the title
I:
compound: HPLC retention time = 5.74 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5jx>
35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); (M/Z) = 487.8 (M+H).
PROTOCOL DP: Preparation of compounds via Palladium and Copper mediated
Processes.
Synthesis of 2-(3-morpholino-4-chloro-5-methyI-pyrazol-1-yI)-1-[4-(4-chloro-3-methoxy-
phenyI)-piperazin-1-yll-ethanone

[0771] A mixture of 2-(3-bromo-4-chloro-5 -methyl-pyrazol-1 -yl> 1 -[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone(46 m g, 0.1 mmol , lequiv), morpholine (44 m

g, 45 uL, 5 equiv), racemic-BINAP (20 m g, 0.3 equiv), Pd2(dba)3 (10 m g, 0.1 equiv) and
K3P04«H20 (138 m g, 6 equiv) in 1 mL of DMF were heated at 110 °C overnight and then
ceoled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-HaO with 0.1% TFA as eluent) to yield 2-(3-morpholino-4-chloro-
5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone. lH
NMR (400 MHz, CDC13) 8 7.23 (d, 1H), 6.50 (d, 1H), 6.42 (dd, 1H), 4.95 (s, 1H), 3.90 (s,
3H), 3.78 (m, 8H), 3.20 (m, 8H), 2.30 (s, 3H). LCMS observed for (M+H)+: 468.
Synthesis of 2-(4-chloro-5-methyl-pyrazol-1-yl)- 1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yl]-ethanone

[0772] A mixture of 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (46 m g, 0.1 mmol , 1 equiv), pyrrolidine (42 m g,
42 uL, 5 equiv), racemic-BINAP (20 m g, 0.3 equiv), Pd2(dba)3 (10 m g, 0.1 equiv) and
K3PCM»H20 (138 m g, 6 equiv) in 1 mL of DMF were heated at 110 °C overnight and then
cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered ,
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield 2-(4-chloro-5-methyl-
pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone. 'H NMR (400
MHz, CDC13) 5 7.46 (s, 1H), 7.30 (d, 1H), 6.74 (d, 1H), 6.60 (dd, 1H), 5.08 (s, 1H), 3.90 (s,
3H), 3.88 (m, 2H), 3.80 (m, 2H), 3.34 (m, 2H), 3.25 (m, 2H), 2.20 (s, 3H). LCMS observed
for (M+H)+: 383.
Synthesis of 3-methyl-4-cyano-5(trifluoromethyl) pyrazole

[0773] 3-Methyl-4-iodo-5-(trifluoromethyl)pyrazole (0.28 g, 1 mmol) and Copper(I)
cyanide (0.9 g, 10 mmol ) were mixtured in 1 mL DMF and stirred at 150°C for 1 hour. The

reaction mixture were slowly poured into 30 mL heated EtOAc/MeOH under stirrin g, and
this was filtered to remove the solid. The mixture was partitioned between EtOAc and Sat.
HaHCO3, and the phases were separated. The ethyl acetate phase was washed with Brine,
dried over Na2SC>4 and concentrated to afford the title product.
Synthesis of 1-[4-(4-Chloro-3-roethoxy-phenyI)-piperazin-1-yl]-2-(4-methanesulfonyl-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0774] Title compounds were prepared by mixture 1 -[4-(4-Chloro-3-methoxy-phenyl)-
piperazin-1-yl]-2-(4-iodo-5-methyl-3-trifluorometh.yl-pyrazol-1-yl)-ethanone (109m g, 0.2
mmol), NaSO2Me (61m g, 0.6 mmol) and Cul (114m g, 0.6 mmol) in DMSO (lml) at
110°C for 3 hours. The crude reaction was purified by HPLC: HPLC retention time = 4.21
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 495.1, found =
495.4.
Synthesis of 3-methylsulfonyl-4-chloro-5-methyl-pyrazole

[0775] A mixture of 3-iodo-4-chloro-5-methyl-pyrazole (48 m g, 0.2 mmol , 1 equiv),
NaSO2Me (72 m g, 3 equiv) and Cul (114 m g, 3 equiv) in 1 mL of DMSO were heated at
110 °C for 3 h and then cooled to room temperature, taken up in a 1:1 mixture of methanol
and EtOAc, filtered through a thin pad of celite and concentrated. The residue was dissolved
in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and
concentrated. The crude product was used in the next step without purification.

Synthesis of l-(4-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperaziii-1-yl]-2-oxo-
ethyl}-5-methyl-1H-pyrazol-3-yl)-pyrrolidin-2-one

[0776] A mixture of 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (92 m g, 0.2 mmol , 1 equiv), 2-pyrolidinone (17
m g, 1 equiv), N,N-dimethylethylenediamine (5.3 m g, 0.3 equiv), Cul (12 m g, 0.3 equiv)
and CS2CO3 (130 m g, 2 equiv) in 1 mL of dioxane were heated at 110 °C overnight and then
cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield l-(4-chloro-1-{2-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazol-3-yl)-
pyrrolidin-2-one. 'H NMR (400 MHz, CDC13) 5 7.32 (d, 1H), 6.78 (d, 1H), 6.65 (dd, 1H),
4.93 (s, 2H), 3.90 (s, 3H), 3.88 (m, 6H), 3.35 (m, 2H), 3.28 (m, 2H), 2.60 (m, 2H), 3.30 (s,
3H), 2.24 (m, 2H). LCMS observed for (M+H)+: 466.
Synthesis of 2-(3-methylsulfonyl-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0777] A mixture of 2-(3-bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (46 m g, O.l mmol , 1 equiv), NaSC^Me (36 m g,
3 equiv) and Cul (57 m g, 3 equiv) in 1 mL of DM SO were heated at 110 °C overnight and
then cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield 2-(3-methylsulfonyl-4-
chloro-5-methyl-pyrazol-l -yl)-l -[4-(4-chloro-3-methoxy-phenyl)-piperazin-l -yl]-ethanone.
*H NMR (400 MHz, CDC13) 5 7.38 (d, 1H), 6.82 (d, 1H), 6.70 (dd, 1H), 5.18 (s, 2H), 3.92

(m, 4H), 3.90 (s, 3H), 3.40 (m, 2H), 3.36 (m, 2H), 3.19 (s, 3H), 2.34 (s, 3H). LCMS
observed for (M+H)+: 461.
Synthesis of 2-[4-chloro-3-(2-phenyl)imidazol-1 -yl-5-methyl-pyrazol-1 -yl]-l -[4-(4-chloro-3-
memoxy-phenyl)-piperazin-1-yl]-ethanone

[0778] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone (102 m g, 0.2 mmol , 1 equiv), 2-phenylimidazole (86 m g,
3 equiv), 8-hydroxyquinoline (5.8 m g, 0.2 equiv), Cul (7.6 m g, 0.2 equiv) and K2CO3 (42 m
g, 1.5 equiv) in 1 mL of DMSO were heated at 110°C over two nights and then cooled to
room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin
pad of celite and concentrated. The crude product was purified by reverse phase HPLC to
yield the title compound: LCMS Retention time: 4.04 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); LCMS observed for (M+H)+: 525.
Synthesis of 2-(4-chloro-3-[l,2,3]triazol-1-yl-5-methyl-pyrazoI-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0779] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone (102 m g, 0.2 mmol , 1 equiv), 1,2,3-triazole (42 m g, 3
equiv), 8-hydroxyquinoline (5.8 m g, 0.2 equiv), Cul (7.6 m g, 0.2 equiv) and K2CO3 (42 m
g, 1.5 equiv) in 1 mLof DMSO were heated at 110 °C over two nights and then cooled to
room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin
pad of celite and concentrated. The crude product was purified by reverse phase HPLC to
yield the title compound: LCMS Retention time = 3.93 minutes (Agilent Zorbax SB-C18,

2.1X50 mm, 5|i, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); LCMS observed for (M+H)+: 450.
Synthesis of 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone

[0780] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone (51 m g, 0.1 mmol , 1 equiv) and CuCN (180 m g, 20
equiv) in 1 mL of DMF were heated at 175 °C for 1 h and then cooled to room temperature,
taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin pad of celite and
concentrated. The crude product was purified by reverse phase HPLC (acetonitrile-HaO with
0.1% TFA as eluent) to yield 2-(3-cyano-4-chloro-5-methyl-pvrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone. lHNMR(400 MHz, CDC13) 5 7.30 (d, 1H), 6.65
(d, 1H), 6.56 (dd, 1H), 5.02 (s, 2H), 3.90 (s, 3H), 3.88 (m, 2H), 3.80 (m, 2H), 3.35(m, 2H),
3.28 (m, 2H), 2.32 (s, 3H).
Synthesis of 2-[4-chloro-3-(2-methylimidazol-1-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

[0781] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-piperazin-1-yl]-ethanone (102 m g, 0.2 mmol , 1 equiv), 2-methyl imidazole (32 m
g, 2 equiv), 8-hydroxyquinoline (5.8 m g, 0.2 equiv), Cul (7.6 m g, 0.2 equiv) and K2CO3 (42
m g, 1.5 equiv) in I mL of DMSO were heated at 110 °C over two nights and then cooled to
room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin
pad of celite and concentrated. The crude product was purified by reverse phase HPLC
(acetonitrile-H20 with 0.1% TFA as eluent) to give the title compound: 'H NMR (400 MHz,
CDCI3) 5 8.92 (s, 1H), 7.66 (d, 1H), 7.40 (d, 1H), 7.28 (d, 1H), 7.21 (d, 1H), 6.53 (d, 1H),

6.42 (dd, 1H), 5.00 (s, 2H), 3.90 (s, 3H), 3.80 (m, 2H), 3.71 (m, 2H), 3.28(m, 2H), 3.20 (m,
2H), 2.72 (s, 3H), 2.37 (s, 3H); LCMS observed for (M+H)+: 463.
y
Synthesis of 2-[4-chloro-3-(4-methylimidazoH-yl)-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

[0782] Following the same procedure as the previous example, 2-(3-iodo-4-chloro-5-
methyl-pyrazol-1 -yl)-1 - [4-(4-chloro-3 -methoxy-phenyl)-piperazin-1 -yl]-ethanone and 4-
methyl imidazole were coupled to give the title compound: 'H NMR (400 MHz, CDCI3) 8
8.93 (s, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 6.52 (d, 1H), 6.44 (dd, 1H), 5.00 (m, 2H), 3.90 (s,
3H), 3.80 (m, 2H), 3.73 (m, 2H), 3.28(m, 2H), 3.20 (m, 2H), 2.47 (s, 3H), 2.35 (m, 3H);
LCMS observed for (M+H)+: 463.
Synthesis of2-(4-chloro-3-benzimidazol-1-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0783] Following the same procedure as the previous example, 2-(3-iodo-4-chloro-5-
methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanoneand
benzimidazole were coupled to give the title compound: *H NMR (400 MHz, CDCI3) 5 9.13
(s, 1H), 8.00 (m, 1H), 7.80 (m, 1H), 7.53 (m, 2H), 7.22 (d, 1H), 6.52 (d, 1H), 6.44 (dd, 1H),
5.06 (s, 2H), 3.88 (s, 3H), 3.84 (m, 2H), 3.76 (m, 2H), 3.26(m, 2H), 3.22 (m, 2H), 2.40 (s,
3H); LCMS observed for (M+H)+: 499.

Synthesis of 2-(4-chloro-3-pyrazol-1-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0784] Following the same procedure as the previous example, 2-(3-iodo-4-chloro-5-
methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanoneand
pyrazole were coupled to give the title compound: *H NMR (400 MHz, CDCb) 5 8.00 (br,
1H), 7.63 (br, 2H), 7.40 (d, 1H), 7.18 (d, 1H), 6.42 (br, 1H), 5.40 (br, 2H), 4.40 (br, 2H), 4.24
(br, 2H), 3.90 (s, 3H), 3.55 (br, 2H), 3.36 (br, 2H), 2.36 (s, 3H); LCMS observed for (M+H)+:
449.
Synthesis of 2-[4-chloro-3-(3-methyI)-pyrazol-1-yl-5-raethyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

[0785] Following the previous example, 2-(3-iodo-4-chloro-5-merhyl-pyrazol-1-yl)-1-[4-
(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 3-methylpyrazole were coupled
to give the title compound: 'H NMR (400 MHz, CDC13) o 7.97 (d, 1H), 7.30 (d, 1H), 6.74 (d,
1H), 6.60 (dd, 1H), 6.24 (d, 1H), 5.00 (s, 2H), 3.82 (s, 3H), 3.80 (m, 4H), 3.33 (m, 2H), 3.24
(m, 2H), 2.37 (s, 3H), 2.30 (s, 3H); LCMS observed for (M+H)+: 463.
Synthesis of 2-[4-chloro-3-(3-trifluoromethyl)-pyrazoH-yl-5-methyl-pyrazol-1-yl]-1-[4-
(4-chloro-3-methoxy-phenyl)-piperazin-1-yI]-ethanone


[0786] Following the previous example, 2-(3-iodo-4-chloro-5-methyl-pyrazol-l -yl)-1 -[4-
(4-chloro-3-raethoxy-phenyl)-piperaziii-1-yl]-ethanone and 3-trifluoromethylpyrazole were
coupled to give the title compound: *H NMR (400 MHz, CDC13) 5 8.08 (d, 1H), 7.30 (d, 1H),
6.73 (d, 1H), 6.70 (d, 1H), 6.60 (dd, 1H), 5.10 (s, 2H), 3.90 (s, 3H), 3.89 (m, 4H), 3.30 (m,
4H), 2.38 (s, 3H); LCMS observed for (M+H)+: 517.
Synthesis of l-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyI)-piperazin-1-yl]-2-oxo-
ethyl}-5-methyl-1H-pyrazol-3-yl)-1H-pyridin-2-one

[0787J Following the previous example, 3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and 2-hydroxypyridine were coupled to
give the title compound: *H NMR (400 MHz, CDC13) 8 8.19 (m, 1H), 7.74 (m, 1H), 7.22 (d,
1H), 7.06 (m, 2H), 6.60 (d, 2H), 6.48 (dd, 1H), 4.92 (s, 2H), 3.90 (s, 3H), 3.80 (m, 4H), 3.70
(m, 2H), 3.22 (m, 2H), 2.32 (s, 3H); LCMS observed for (M+H)+: 476.
Synthesis of 1-[4-(4-Chloro-3-hydroxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-
(pyridin-2-yloxy)-pyrazol-1-yl]-ethanone

[0788] The title compound is also obtained from the previous reaction: ]H NMR (400
MHz, CDCI3) 5 7.50-7.00 (m, 5H), 6.58 (d, 1H), 6.23 (d, 1H), 4.95 (s, 2H), 4.20-4.00 (m,
4H), 3.95 (s, 3H), 3.42 (m, 2H), 3.36 (m, 2H), 2.40 (s, 3H). LCMS observed for (M+H)+:
476.

PROTOCOL EE: General procedure for the synthesis of oxazole substitution on
pyrazol:
y
4-ChIoro-1-{2-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-oxethyl}-5-methyl-1H-
pyrazole-3-carbonyl chloride

[0789] To a solution of 4-Bromo-1-{2-[4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-
l-yl]-2-oxethyl}-5-methyl-l#-pyrazole-3-cafboxylic acid obtained from last reaction in
CH2CI2 (1 mL) was added oxalyl chloride (1 mL). The reaction mixture was stirred at 60 °C
for 12 h, cooled to room temperature and evaporated in vacuo to afford the title compound
which was used as it was.
1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yl]-2-(4-chloro-5-methyl-3-oxazol-2-yl-
pyrazol-1-yl)ethanone

[0790] A mixture of 4-Chloro-1-{2-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-
oxethyl}-5-methyl-li/-pyrazole-3-carbonyl chloride obtained from last reaction, 1,2,3-
triazole (0.008 mL) and K2CO3 (41 mg) in tetramethylene sulfone (0.5 mL) was heated to
140 °C for 10 min and cooled to room temperature. The residue was purified on preparative
HPLC to afford the title compound. ]H NMR: 5 (400 MHz, CDC13) (400 MHz, CDCI3) 7.71
(d, 1H), 7.29 (d, 1H), 7.22 (s, 1H), 6.48 (d, 1H), 6.44 (dd, 1H), 5.06 (s, 2H), 3.89 (s, 3H),
3.86 (m, 4H), 3.19 (m, 4H), 2.35 (s, 3H). LCMS (ES): M+H 450.1; HPLC retention time =
4.45 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5 % acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

PROTOCOL FF: General procedure for the synthesis of 1,3,4-oxadiazole substitution
on pyrazol;
y
Synthesis of 1-[4-(4-ChIoro-3-methoxyphenyl)piperazin-1-yI]-2-(4-chloro-5-methyl-3-
[l,3,4]oxadiazol-2-yl-pyrazol-1-yI)ethanone

[0791] Step 1: To a solution of pyrazolecarboxylic ester (140 mg) in MeOH (20 aiL) was
added hydrazine hydrate (2 raL). The reaction mixture was stirred at 25 °C for 12 h. and
evaporated in vacuo to afford the corresponding hydrazide which was used as it was.
[0792] Step 2: The hydrazide was dissolved in trimethylorthoformate (30 mL), stirred and
under a positive nitrogen flow heated to 80 °C for 3 h. The reaction mixture was cooled to
room temperature and evaporated in vacuo. The residue was purified by preparative HPLC
to afford the title compound: :H NMR: 5 (400 MHz, CDC13) 8.46 (s, 1H), 7.22 (d, 1H), 6.49
(s, 1H), 6.35 (dd, 1H), 5.09 (s, 2H), 3.89 (s, 3H), 3.76 (m, 4H), 3.20 (m, 4H), 2.36 (s, 3H).
LCMS (ES): M+H 451.1; HPLC retention time = 4.13 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94,9% water, B = 0.08% formic acid /
99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-(4-chIoro-
5-methyl-3-[l,3,4]oxadiazol-2-ylpyrazol-1-yl)ethanone

[0793] The title compound was obtained by following the same protocol as the previous
example: LCMS (ES): M+H 465.1; HPLC retention time = 5.02 minutes (Agilent Zorbax SB-
CIS, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute
wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic
acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yl]-2-[4-chIoro-5-methyJ-3-(5-
methyI-[l,3,4]oxadiazol-2-yl)pyrazol-1-yl]ethanone

[0794] The title compound was obtained by following the same protocol as in the previous
example, using trimethylorthoacetate: LCMS (ES): M+H 465.3; HPLC retention time = 3.90
minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).
PROTOCOL GG: General procedure for the synthesis of Substituted oxazoles on
pyrazoies:
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)piperazin-1-yI]-2-[4-chloro-5-meth.yl-3-(4-
methyloxazol-2-yl)pyrazol-1-yl]ethanone

[0795] Step 1; The pyrazolcarboxylic acid was coupled with 2-aminopropaldehyde
dimethylacetal by following Protocol P to afford the corresponding amide.
[0796] Step 2: The amide was dissolved in POCl3 and heated to 90 °C for 24 h. The
reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was
purified by preparative HPLC to afford the title compound: LCMS (ES): M+H 464.3; HPLC
retention time = 4.22 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u-, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

PROTOCOL HH: Sonagashira Coupling of Terminal Alkvnes to 3-Halopyrazoles
Synthesis of 2-[4-Chloro-3-(3-hydroxy-prop-1-ynyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-
chIoro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone:

[0797] To lOOmg (0.21 mmol) of 2-(3-Bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-
chIoro-3-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone, 0.12 mL (2.0 mmol) of
propargyl alcohol, 4mg (0.02 mmol) of copper (I) iodide, 43mg (0.30 mmol) potassium
carbonate, and 23mg (0.02 mmol) of palladium (O) tetrakis-triphenylphosphine in 1.4 mL of
1,2-dimethoxyethane and 0.4 mL of water under a nitrogen atmosphere was added 0.2 mL of
triethylaminq, the vessel was sealed, and the mixture was heated at 135°C for four hours.
The mixture-was cooled to ambient temperature, and was partitioned between ethyl acetate
and water. The phases were separated, and the aqueous was back-extracted once with ethyl
acetate. The combined ethyl acetate phases were washed once each with water, pH = 7 1M
phosphate buffer, and brine, dried over sodium sulfate, and concentrated. The residue was
purified by chromatography to give the title compound: LCMS (ES) M+H= 451.2; HPLC
retention time = 4.49 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5^, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-[4-Chloro-3-(3-hydroxy-prop-1-ynyl)-5-methyl-pyrazol-1-yl]-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone:


[0798] Following Protocol HH, 2-(3-Bromo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-
chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone was cross-coupled with propargyl
afeohol to give the title compound: LCMS (ES) M+H= 437.1; HPLC retention time = 4.24
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a4.5 minute gradient of20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).
Syuthesisof2-(4-Chloro-3-ethynyl-5-methyl-pyrazol-1-yl)-1-(4-chloro-3-
methoxyphenyl)-piperazin-1-yl)ethanone

[0799] Following Protocol HH, TMSacetylene was cross-coupled to 2-(4-ChIoro-3-iodo-5-
methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone to give the
TMS-protected terminal alkyne: LC MS 479 (M\ 20-95 method, RT = 5.43 min); *H NMR
(400 MHz, CDC13): 5 0.24 (s, 9H), 2.25 (s, 3H), 3.12 (apparent q, /= 4.8 Hz, 4H), 3.68 (t, /=
5.1 Hz, 2H), 3.74 (t, J= 5.1 Hz, 2H), 3.87 (s, 3H), 4.92 (s, 2H), 6.40 (dd, ./= 2.5 & 8.8 Hz,
1H), 6.46 (d, /= 2.5 Hz, 1H), 7.20 (d, J= 8.4 Hz, 1H).

[0800] To a solution of the TMS protected alkyne from above (480 m g, 1 mmol) in THF
(2mL) at 0°C under nitrogen atmosphere was added TBAF (1.4mL, 1.4 mmol). After two
hours, the reaction was quenched with saturated aq. NH4C1, and was extracted with Et20
(4X20 mL). The combined ethereal layer was dried (Na2SO4) and concentrated. The residue
was purified by chromatography to give the title compound: LC MS 407 (M*, 20-95 method,
RT = 4.42 min); 'H NMR (400 MHz, CDC13): 8 2.23 (s, 3H), 3.14-3.18 (m, 4H), 3.22 (s, 1H),
3.69 (t, J=4.8 Hz, 2H), 3.74 (t, J= 5.1 Hz, 2H), 3.87 (s, 3H), 4.93 (s, 2H), 6.40-6.43 (m,
1H), 6.46 (d, 7= 2.6 Hz, 1H), 7.20 (d, 7= 8.3 Hz, 1H).

PROTOCOL II: Preparation of Oxo-pvridine Species!
Synthesis of (4-Chloro-5-methyI-3-pyridin-3-yl-pyrazol-1-yl)-acetic acid ethyl ester:
>•

[0801] 1.92gm (9.95 mmol) of 3-(3-pyridyl)-4-chloro-5-methylpyrazole, 1.62gm (11.75
mmol) potassium carbonate, and 1.51gm (9.04 mmol) of ethyl bromoacetate were combined
in 25 mL of dry N,N-dimethylformamide, and the mixture was heated at 85°C for four hours.
The mixture was then allowed to cool to ambient temperature, partitioned between 1M pH =
7 phosphate buffer and ethyl acetate, and the phases were separated. The ethyl acetate phase
was washed twice with water, once with brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by chromatography to give the title compound.
Synthesis of [4-Chloro-5-methyl-3-(l-oxy-pyridin-3-yl)-pyrazol-1-yl]-acetic acid ethyl
ester:

[0802] 3 70mg (1.32 mmol) of (4-Chloro-5-methyl-3-pyridin-3 -yl-pyrazol-1 -yl)-acetic acid
ethyl ester was dissolved in 6 mL of dry dichloromethane, the solution was cooled to 0°C,
and 320mg (1.85 mmol) of approximately 77% meta-chloroperoxybenzoic acid was added.
After 30 minutes, the flask was removed from the ice-water bath, and was allowed to warm to
room temperature. After three hours, the reaction was partitioned between ethyl acetate and
saturated sodium bicarbonate, and the phases were separated. The ethyl acetate phase was
dried over Na2SO after trituration with ether to give the title compound.

Synthesis of Sodium [4-chloro-5-methyl-3-(l-oxy-pyridin-3-yI)-pyrazol-1-yl]-acetate:

[0803] 170mg (0.58 mmol) of t4-Chloro-5-methyl-3-(l-oxy-pyridin-3-yl)-pyrazol-1-yl]-
acetic acid ethyl ester and 46 mg (1.6 mmol) of sodium hydroxide were combined in 2.3 mL
of dry methanol at 50°C. After 30 minutes the reaction was complete, and the flask was
allowed to cool to room temperature. The slurry was diluted with ethyl acetate, and the solids
were isolated by filtration to give the title compound.
[4-ChIoro-5-methyi-3-(l-oxypyridin-4-yI)-pyrazol-1-yl]-acetic acid

[0804] The title compound was obtained by following Protocol II.
PROTOCOL JJ: Heteroaryl substituted pyrazoles via cvcloaddrtion and cvclization
reactions:
Synthesis of 2-(4-chIoro-3-tetrazol-5-yl-5-methyl-pyrazol-1-yl)-1- [4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0805] A mixture of 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (41m g, 0.1 mmol, 1 equiv), NaN3 (130m g, 2
equiv), and NH4C1 (110 m g, 2 equiv) in 1 mL of DMF were heated at 130oC for 3 hours,
and then cooled to room temperature. The crude product was purified by reverse phase
HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield the title compound: 1H NMR

(400 MHz, CDC13) 8 7.35 (d, 1H), 6.82 (d, 1H), 6.70 (dd, 1H), 5.12 (s, 2H), 3.90 (s, 3H),
3.88 (m, 4H), 3.50 (m, 2H), 3.34(m, 2H), 2.33 (s, 3H); LCMS observed for (M+H)+: 451.
y
Synthesis of 2-[4-chloro-5-methyl-3-[l,2,3]oxadiazol-3-yl-pyrazol-1-yl]-1-[4-(4-chIoro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0806] A mixture of 2-(3-cyano-4-cMoro-5-methyl-pvrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (41 m g, 0.1 mmol , 1 equiv), NH20H*HC1 (35
m g, 5 equiv) and EtaN (140 uL, 10 equiv) in 1 mL of ethanol were heated at 50 °C for 2
hours and then cooled to room temperature. The white solid was collected, treated with
trimethylformate (1 mL) and 1 crystal of PTSA at 50°C for 2 hours. Reverse phase HPLC
(acetonitrile-H20 with 0.1% TFA as eluent) gave the title compound: 'H NMR (400 MHz,
CDC13) 8 8.80 (s, 1H), 7.30 (d, 1H), 6.72 (d, 1H), 6.62 (dd, 1H), 5.18 (s, 2H), 3.90 (s, 3H),
3.92 (m3 2H), 3.80 (m, 2H), 3.38(m, 2H), 3.30 (m, 2H), 2.39 (s, 3H); LCMS observed for
(M+H)+:451.
PROTOCOL KK: Synthesis of compounds using Negishi coupling reactions
Synthesis of l-I4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-ylJ-2-[4-chloro-5-methyl-3-
(l-methyl-1H-imidazol-2-yl)-pyrazol-1-yl]-ethanone

[0807] 1-methylimidazole (48 m g, 1.5 equiv) in 10 mL of THF at -78 °C was treated with
BuLi (2.5 M in hexanes, 0.28 mL, 1.5 equiv) for lh. ZnCl2 (1M in ether (1.8 mL, 4.5 equiv)
was added and the mixture was stirred at 0 °C for lh. 2-(3-iodo-4-chloro-5-methyl-pyrazol-
l-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (204 m g, 0.4 mmol , 1
equiv) and Pd(PPh3)4 (46 m g, 0.1 equiv) were added sequentially. The resulting mixture
was refluxed overnight, cooled to room temperature, quenched with ater, extracted with

EtOAc. The organic layer was purified by reverse phase HPLC to yield the title compound:
LCMS Retention time: 3.3 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a
4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS
observed for (M+H)+: 463.
PROTOCOL LL: Mannich Additions to aromatic rings.
1-[4-(4-Chloro-5-methoxy-2-methylaminomethyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0808] 250mg of 1-[4-(4-Chloro-5-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-
3-trifluoromethyl-pyrazol-1-yl)-ethanone(0.55mmol, l.Oeq), 374mgmethylamineHCl(5.5
mmol, lO.Oeq), 414uL 37% formaldehyde in H20 (5.5 mmol, lO.Oeq), and 1 mL DME were
combined in a 4 mL vial. The mixture was heated in a 60°C oil bath overnight and purified
by preparative HPLC: LC/MS(ES) (M+H) 494.4; HPLC retention time = 5.71 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20%
B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile).

EXAMPLE 3
[0809] Protocols referred to within the following example are the protocols described
within Example 3, unless otherwise indicated.
PROTOCOL A: Metal catalysed arvlation reactions of secondary amines
Synthesis of 1-[4-(4-ChIoro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
piperazin-1-yl-pyrazol-1-yl)-ethanone

[0810] Following Protocol A from example 1, A mixture of 2-(3-iodo-4-chloro-5-methyl-
pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (204 mg, lequiv),
piperazine (430 mg, 10 equiv), Xantphos (40 mg, 0.3 equiv), Pd2(dba)3 (72 mg, 0.1 equiv)
and CS2CO3 (200 mg, 1.5 equiv) in 1 mL of THF were heated at 70 °C overnight and then
cooled to room temperature, taken up in EtOAc, washed with water. The organic layer was
purified by reverse phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield the title
compound: LCMS Retention time: 3.07 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 467.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yI]-2-(4-chloro-5-methyl-3-
pyrrolidin-1-yl-pyrazol-1-yl)-ethanone

[0811] The title compound was prepared following a variation on Protocol A. LCMS
retention time: 4.77 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5 p., 35°C) using a 4.5

minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:452.
Synthesis of 1-[4-(4-Chloro-3-methoxy-pheny!)-piperazin-1-yl]-2-(4-chloro-5-methyl-4-
piperidin-1-yl-pyrazol-1-yl)-ethanone

[0812] The title compound was prepared following a variation on Protocol A. LCMS
retention time: 5.07 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5\x, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 466.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyI)-piperazin-1-yI]-2-[4-chloro-5-methyl-3-
(4-methyl-piperazin-1-yl)-pyrazoI-1-yI]-ethanone

[0813] The title compound was prepared following a variation on Protocol A. LCMS
retention time: 3.24 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:481.

Synthesis of 2-[4-ChIoro-3-(l,l-dioxo-llambda*6*-thiomorpholin-4-yI)-S-methyI-
pyrazoI-1-yl]-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

[0814] The title compound was prepared following a variation on Protocol A. LCMS
retention time: 4.26 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:516.
Synthesis of 2-(4-Chloro-3-dimethylamino-5-methyI-pyrazol-1-yl)-1-[4-(4-chIoro-3-
methoxy-phenyl)-piperazin-1-yI]-ethanone

[0815] The title compound was prepared following a variation on Protocol A. LCMS
retention time: 5.29 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 426.

PROTOCOL I: General procedure for the synthesis of pyrazoles via condensation of
hydrazines with ff-diketones:
y
Synthesis of 3-Trifluorometyl -l,4,6,7-tetrhydro-pyrazolo[4,3-c]pyridine-5-carboxylic
acid tert-butyl ester:

[0S16] 5g l-Boc-4-piperidone (25mmol), 15 mg p-TSA, 25ml benzene and 2.2ml
morphiline (25mmol) were added in a 50 ml round bottle flask with Dean-Stark, headed to
reflux overnight. After removing most of benzene by rotor-evaporator, 15 ml DCM was
added, cold in ice-bath and added 0.35 ml TEA (25mmol), 0.35ml Trifluoroacetic anhydride
(25mmol) was added drop wise at 0C. After addition, remove the ice-bath. The reaction
mixture was stirred at room temperature overnight. The solvent was removed by rotor-
evaporator. Dissolved the residues in anhydride EtOH, and 3 equivalent of hydrazine was
added under ice-bam, then removed the ice-bath and stirred at room temperature overnight.
The solvent was removed by rotor-evaporator. The compounds were purified by normal
phase column (Column: 140g silica gel, Running Buffer: 50% EtOAc/Hexane) to gave above
title product, along with some Boc-deprotected product.
PROTOCOL L: chlorination or bromination of pyrazoles with N-chlorosuccinimide
(NCS) or N-bromosuccinimide (NBS)
4-ChIoro-3-trifluoromethyMH-pyrazole:

[0817] The above compound was prepared using same Protocol L from example 1.

4-Chloro-3-iodo-5-trifluoromethyIpyrazole:

[0818] The above compound was prepared using same protocol as in the synthesis of 4-
Chloro-3-Iodo-5-methylpyrazole.
3-Iodoindazole

[0819] Iodine (8 g, 32 mmol), potassium hydroxide (3.36 g, 60 mmol) were successively
added to a solution of indazole (1.88 g, 16 mmol) in DMF (30 mL) at room temperature
Stirring continued for 1.5 h. Then, the reaction mixture was diluted with ether (100 mL),
washed with saturated aqueous sodiumthio sulfite. The aqueous phase was back extracted
with ether, the ethereal layer was washed with water, brine, dried (MgSC^) and concentrated.
The iodoindazole obtained in 95% yield and was pure enough for further reactions.
PROTOCOL P: Couplings of arylpiperazines with pyrazolyl-acetic acid derivatives -
compounds prepared by HATU mediated coupling:
2-(4-ChIoro-5-(2-hydroxypropyl)-3-trifluoromethylpyrazoJ-1-yl)-1-(4-(4-chIoro-3-
methoxyphenyl)piperazin-1-yl)ethanone:

[0820] The above compound was synthesized using the same Protocol P in example 1, and
the crude product was purified by HPLC. LC MS: m/z 495 (M+H), retention time = 4.71
minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%

to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of l-(4-(4-chIoro-3-methoxyphenyl)-2(/?)-piperazfa-1-yl)-2-(4-Chloro-3-(l-
hydroxy-3-pyrimidin-2-yI-pyrazol-1-yl)ethanone:

[0821] The above compound was synthesized following Protocol P, and the crude product
was purified by PTLC using 70 ethyl acetate: 30% n-hexane as mobile phase. LC MS: m/z
491 (M+H), Rt = 3.59 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazin-1-yI]-2-
[4-chloro-5-methyl-3-(2-methyI-pyridin-4-yl)-pyrazol-1-yl]-ethanone:

[0822] Title compounds were prepared following Protocol P, wherein l-(3-methoxyphenyl-
4-chloro)-3-(fl)-hydroxymethyl piperazine and ([4-Chloro-5-methyl-3-(2-methyl-pyridin-4-
yl)-pyrazol-1-yl]-acetic acid were used as the coupling components. Purified by HPLC
(Column: Varian Dynamax 250x21.4mm Microsorb 100-8 C18, Buffer A: 0.1%TFA/H20,
Buffer B: 0.1%TFA/ACN, Gradient: B from 10% to 95% within 60 min, Flow: 20 ml/min) to
give the title products as a white powder: HPLC retention time = 4.94 minutes (Agilent
Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a

1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 504.1, found = 504.1.
Synthesis of 1-[4-(4-ChIoro-2-fluoro-5-methoxy-phenyI)-piperazin-1-yl]-2-(4-chloro-5-
methyI-3-pyrimidin-2-yl-pyrazol-1-yl)-ethanone

[0823] Title compound was prepared following Protocol P, wherein 1 -(4-Chloro-2-fluoro-
5-methoxy-phenyl) piperazine and [4-chloro-5-methyl-3-pyrimidin-2-yl-pyrazol-1-yl]-acetic
acid were used as the coupling components. Purified by TLC (5%MeOH in DCM) to give
the title compound as a white solid: HPLC retention time = 3.41 minutes (Agilent Zorbax SB-
CIS, 2.1X50mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute
wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic
acid / 99.9% acetonitrile); MS (ES) M+H expect = 479.1, found = 479.1.
Synthesis of 1-[4-(4-ChIoro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyI-piperazin-1-yl]-2-
[4-chIoro-3-(l-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yI]-ethanone:

[0824] Title compound were prepared following Protocol P, wherein l-(4-Chloro-2-fluoro-
5-methoxy-phenyl)-3-(S)-methyl piperazine and [4-chloro-3-(l-hydroxy-1-methyl-ethyl)-5-
methyl-pyrazol-1-yi]-acetic acid were used as the coupling components. Purified by HPLC
(Column: Varian Dynamax 250x21.4mm Microsorb 100-8 C18, Buffer A: 0.1%TFA/H2O,
Buffer B: 0.1%TFA/ACN, Gradient: B from 25% to 95% within 60 min, Flow: 20 ml/min) to

give the title compound: HPLC retention time = 4.48minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); MS (ES) M+H expect = 473.1, found = 455.1 and 473.1.
Synthesis of 2-(4-Chloro-3-iodo-5-methyl-pyrazol-1-yl)-1-[4-(4-chIoro-3-methoxy-
phenyl)-2(S)-methyl-piperazin-1-yl]-ethanone

[0825] Following Protocol P, l-(4-Chloro-3-methoxy-phenyl)-3-(S)-methyl-piperazine and
(4-Chloro-3-iodo-5-methyl-pyrazol-1-yl)-acetic acid were coupled to give the title
compound: LCMS Retention time: 5.20 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 523.
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yI]-2-(4-chloro-3-
iodo-5-methyl-pyrazol-1-yl)-ethanone

[0826] Following Protocol P, l-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazineand (4-
Chloro-3-iodo-5-methyl-pyrazol-1-yl)-acetic acid were coupled to give the title compound:
LCMS Retention time: 5.13 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS
observed for (M+H)+: 527.

Synthesis of 1-[4-(4-ChIoro-2-fluoro-5-methoxy-phenyI)-2(S)-methyl-piperazin-1-yl]-2-
(4-chloro-3-iodo-5-methyl-pyrazol-1-yl)-ethanone

[0827] Following Protocol P, 1 -(4-Chloro-2-fluoro-5-methoxy-phenyl)-3-(S)-methyl-
piperazine and (4-Chloro-3-iodo-5-methyl-pyrazol-1-yl)-acetic acid were coupled to give the
title compound: LCMS Retention time: 5.23 minutes (Agilent Zorbax SB-C18,2.1X50 mm,
5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A
= 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 541.
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyl)-2-(S)-methylpiperazin-1-yI]-2-(4-chloro-
5-methyI-3-oxazol-2-yl-pyrazoI-1-yI)ethanone:

[0828] The title compound was obtained according to peptide coupling Protocol P. LCMS
(ES) M+H 464.1; Rf 4.40 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a
4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 1-[4-(4-ChIoro-3-methoxyphenyl)-2-(R)-hydroxymethylpiperazin-1-yl]-2-(4-
chloro-5-methyI-3-oxazol-2-ylpyrazol-1-yl)ethanone:
y

[0829] The title compound was obtained according to peptide coupling Protocol P. LCMS
(ES) M+H 480.2; Rf 3.95 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a
4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-[4-Chloro-5-methyI-3-(2-methyl-pyridin-4-yl)-pyrazol-1-yl]-1-[4-(2,4-
difluoro-5-methoxy-phenyl)-piperazin-1-yI]-ethanone:

[0830] Title compound was prepared following Protocol P, wherein 2,4-difluoro-5-
methoxy-phenyl)-piperazine and [4-Chloro-5-methyl-3-(2-methyl-pyridin-4-yl)-pyrazol-1-
yl]-acetic acid were used as the coupling components. Purified by HPLC to give the title
compound: HPLC retention time = 3.3minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C)*using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); MS (ES) M+H expect = 476.1, found = 476.1.

Synthesis of 2-[4-chloro-3(l,2-dihydroxy-1-methyI-ethyl)-5-methyl-pyrazol-1-yl]-1-[4-(3-
methoxy-4-chIoro-phenyl)-piperazin-1-yL]-ethanone

[0831] Title compounds were prepared following Protocol P, wherein 1-[4-(3-methoxy-4-
chloro-phenyl)]-piperazin and 2-[4-chloro-3(l, 2-dihydroxy-1-methyl-ethyl)-5-methyl-
pyrazol-1-yl]-acetic acid were used as the coupling components. Purified by HPLC
(Column: Varian Dynamax 250x21.4mm Microsorb 100-8 C18, Buffer A: 0.1%TFA/H2O,
Buffer B: 0.1%TFA/ACN, Gradient: B from 10% to 60% within 40 min, Flow: 20 ml/min)
to give the title compound. HPLC retention time = 3.41 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); MS (ES) M+H expect = 457.1, found = 439.1(-H20), 457.1.
Synthesis of l-(4-(4-chIoro-3-methoxyphenyl)piperazin-1-yl)-2-(4-Chloro-5-pyrazol-1-
ylmethyl-3-trifluoromethylpyrazoI-1-yl)ethanone:

[0832] The above compound was synthesized using (4-Chloro-5-pyrazol-1-ylmethyl-3-
trifluoromethyl-pyrazol-1-yl)-acetic acid, following Protocol P. The crude product was
purified by PTLC using 70% ethyl acetate: 30% n-hexane as mobile phase: LC MS m/z 517
(M+H), Rt = 5.47 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /

5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); 1H NMR (400
MHz, CDC13): 8 3.17 (t, J= 5.1 Hz, 2H), 3.23 (t, J= 5.1 Hz, 2H) 3.64 (t, J= 5.2 Hz, 2H),
3.77^, J= 5.2 Hz, 2H), 3.89 (s, 3H), 5.32 (s, 2H), 5.38 (s, 2H), 6.28 (t, J= 2.2 Hz, 1H), 6.43
(apparent dd, J= 2.9 & 8.5 Hz, 1H), 6.49 (d, 7= 2.6 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.47
(t, .7=1.9 Hz, 1H).
PROTOCOL T: KiCOi mediated coupling reaction of chloroacetyl arylpiperazines
with pvrazoles
Synthesis of 2-(4-Chloro-5-(l-hydroxy-1-methyIethyI)-3-trifluoromethylpyrazoI-1-yI)-1-
(4-(4-chIoro-3-methoxyphenyl)piperazin-1-yI)ethanone:

[0833] The above compound was synthesized using 2-(4-Chloro-5-trifluoromethyl-2H-
pyrazol-3-yl)-propan-2-ol, following Protocol T from example 1, and the crude product was
purified by HPLC. LCMS: m/z495 (M+H), R, = 5.33 minutes (Agilent ZorbaxSB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).
2-(4-ChIoro-5-iodo-3-trifluorontethyI-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-
piperazin-1-yl]-ethanone

[0834] The above compound was prepared using 4-Chloro-5-iodo-3-trifluoromethyl-1-H-
pyrazole, following Protocol T.

Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-
(4-chloro-5-methyl-3-pyrimidin-2-yI-pyrazol-1-yl)-ethanoneand 1-[4-(4-Chloro-2-
flu pyrimidin-2-yl-pyrazol-1-yI)ethanone

[0835] Title compounds were prepared following Protocol T, wherein 2-Chloro-1-[4-(4-
chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanoneand4-chloro-5-
methyl-3-pyrimidin-2-yl-pyrazol were used as the coupling components. Purified by HPLC
(Column: Varian Dynamax 250x21.4mm Microsorb 100-8 C18, Buffer A: 0.1%TFA/ H20,
Buffer B: O.WoTFAIACN, Gradient: B from 10% to 95% within 60 min, Flow: 20 ml/min) to
give above tijtle products as white powders.
[0836J Isomer I: HPLC retention time = 4.31 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); MS (ES) M+H expect = 493.1, found = 493.4.
[0837] Isomer II: HPLC retention time = 4.66 minutes (same conditions as above); MS
(ES) M+H expect = 493.1, found = 493.4.
Synthesis of 1-[4-(4-Chloro-3-methoxyphenyI)piperazin-1-yl]-2-(4-chIoro-5-methyl-3-
oxazol-5-ylpyrazol-1-yl)ethanone


[0838] The title compound was synthesized according to Protocol T. LCMS (ES) M+H
450.1; Rf 4.15 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of2-(3-chloroindazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-
yl)ethanone

[0839] The above compound was synthesized following Protocol T: LCMS 419 (M+H), Rt
= 4.79 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient
of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of l-(4-(4-chlro-3-methoxyphenyl)piperzin-1-yl)-2-indazoI-1-yl-ethanone and
l-(4-(4-chlro-3-methoxyphenyI)piperzin-1-yl)-2-indazol-2-yl-ethanone:

[0840] The above compounds were obtained following Protocol T.
[0841] Nl-Isomer: LC MS 385 (M+H), Rt = 4.22 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).

[0842] N2-Isomer: LC MS 385 (M+H), Rt = 4.03 minutes (same method as above).
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-[4-chIoro-3-
y
(1-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-ethanone:

[0843] Title compound was prepared following Protocol T, wherein l-(4-Chloro-2-fluoro-
5-methoxy-phenyl)piperazin-4-chloromethyl-ketoneand4-chloro-3-(l-hydroxy-1-methyl-
ethyl)-5-methyl-pyrazol were used as the coupling components. Purified by HPLC (Column:
Varian Dynamax 250x21.4mm Microsorb 100-8 CI 8, Buffer A: 0.1%TFA/ H20, Buffer B:
0.1%TFA/ACN, Gradient: B from 25% to 70% within 40 min, Flow: 20 ml/min) to give the
title compound: HPLC retention time = 5.26 minutes (Agilent Zorbax SB-C18,2.1X50 mm,
5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A
= 0.1% formic acid / 5% acetomtrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); MS (ES) M+H expect = 459.1, found = 441.1 and 459.1.
Synthesis of l-{2-[4-(4-Chloro-3-hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-
trifluoromethyI-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacidtert-butyl
ester

[0844] Title compound was prepared following Protocol T, wherein l-(3-methoxyphenyl-
4-chloro) piperazin-4-chloromethyl-ketone and 3-trifiuoromethyl-l,4,6,7-tetrahydro-
pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester were used as the coupling
components. Purified by recrystallization with ACN/H2O. HPLC retention time =
5.17 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5(4., 35°C) using a 4.5 minute gradient of

20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 558.2,
four/d = 502.2; 'H NMR (CDC13,400MHz) 7.22 (d, 1H), 6.48(s, 1H), 6.43(d, 1H), 4.96
(s,2H), 4.50 (s, 2H), 3.83 (s, 3H), 3.65-3.80 (m, 6H), 3.12-3.22 (d, 4H), 2.73 (m, 2H), 1.48(s,
9H)ppm.
Synthesis of 1-[4-(2,4-difluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-3-(l-
hydroxy-1-methyl-ethyI)-5-methyi-pyrazol-1-yl]-ethanone

[0845] Title compound was prepared following Protocol T, wherein l-(2,4-difluoro-5-
methoxy-phenyl)piperazin-4-chloromethyl-ketoneand4-chloro-3-(l-hydroxy-1-methyl-
ethyl)-5-methyl-pyrazol were used as the coupling components. Purified by normal phase
column (Column: 40g silica gel, 20%-30% EtOAc/DCM), and recrystallization by
ACNAVater to give the title products as a white solid: HPLC retention time = 3.9 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 443.1, found = 425.1 (-
H20) and 443.1.
Synthesis of 1-[4-(4-ChIoro-3-methoxy-phenyI)-2-(S)-methyl-piperazin-1-yl]-2-(4-fluoro-
5-methyl-3-pyridin-2-yI-pyrazoH-yl)-ethanone:


[0846] Title compound was prepared following Protocol T, wherein l-(3-methoxyphenyl-
4-chloro-)-3-methyl-piperazin-4-chloromethyl-ketoneand4-fluoro-5-meuiyl-3-pyridin-2-yl-
pyrazol were used as the coupling components. Purified by HPLC to give the title
compound: HPLC retention time = 3.75 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u',
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); MS (ES) M+H expect = 458.2, found = 458.2.
Synthesis of 2-(3-lodoindazol-1-yI)-1-(4-(4-chloro-3-methoxyphenyl)piperazin-1-
yl)ethanone: ,

[0847] The above compound was synthesized following Protocol T: LC MS 511 (M+H); Rt
= 4.89 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a4.5 minute gradient
of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-[4-chIoro-3 (l-hydroxy-1-methyl-ethyl)-5-methyI-pyrazol-1-yI]-1-[4-(3-
methoxy-4-chloro-phenyI)- 2-methyI-piperazin-1-yl]-ethanone(Isomer I) and of 2-[4-
chloro-5(l-hydroxy-1-methyl-ethyl)-3-methyI-pyrazol-1-yl]-1-[4-(3-methoxy-4-chIoro-
phenyl)- 2-methyl-piperazin-1-yl]-ethanone (Isomer II):

[0848] Title compounds were prepared following Protocol T, wherein l-(3-methoxyphenyl-
4-chloro) 2-methyl-piperazine-4-chloromethyl-ketone and 4-chloro-3 (1-hydroxy-1-methyl-

ethyl)-5-methyl-pyrazol were used as the coupling components, purified by HPLC (Column:
Varian Dynamax 250x21.4mm Microsorb 100-8 C18, Buffer A: 0.1%TFA/ H20, Buffer B:
0.1%TFA/ACN, Gradient: B from 10% to 95% within 60 min, Flow: 20 ml/min) to give
above 2 isomer products as a white powder.
[0849] Isomer I: HPLC retention time = 4.28 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); MS (ES) M+H expect = 455.1, found = 437.1(-H20), 455.1.
[0850] Isomer II: HPLC retention time = 4.54 minutes (same method as with isomer I);
MS (ES) M+H expect = 455.1, found = 437.1(-H20), 455.1.
PROTOCOL V; Preparation of compounds via acid or base-mediated de-protections.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-trifluoromethyl-
4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-ethanone:

[0851] 0.23g of l-{2-[4-(4-Chloro-3-hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-
trifluoromethyl-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester
was stirred with 2 ml 4N HC1 / Dioxane at room temperature for 40 minutes. 20 ml Ethyl
ether was added, and the resulting solid was collected and washed with ether. The compound
was recrystallized with ACN / H20 to give 0.2 g of the title compound: HPLC retention time
= 3.03 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient
of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES) M+H expect = 458.15,
found = 458.1.

Synthesis of lithium 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-
yI)-acetyl]-piperazin-1-yl}-4-methoxy-benzoate

[0852] Following a variation of Protocol V, A 5 mL flask was charged with 5-chloro-2-{4-
[2-(4-chloro-5-methyl-3 -trifluoromethyl-pyrazol-1 -yl)-acetyl]-piperazin-1 -yl} -4-methoxy-
benzoic acid methyl ester (43 mg, 0.084 mmol), 0.4 mL MeOH, 0.9 mL THF, and LiOH
(0.42 mL, 0.25 M). After stirring 2 days, the solution was diluted with water and the volatile
solvents were removed in vacuo, during which the lithium carboxylate precipitated. The
solids were filtered and dried at reduced pressure to afford 36 mg (86%) of the target salt as a
white solid: 1H NMR (400 MHz, CD30D) 5 7.44 (s, 1H), 6.58 (s, 1H), 5.28 (s, 2H), 3.89 (s,
3H), 3.71-3.79 (m, 4H), 3.16-3.21 (m, 2H), 3.09-3.14 (m, 2H), 2.26 (s, 3H); MS (ES) M+H
expect 495.1, found495.1; HPLC (80:20-5:95 0.1% TFA/H2O:0.08% TFA/MeCN) R, = 4.87
min. u
PROTOCOL X; Preparation of compounds via Acvlation or sulfonvlation.
Synthesis of 1-[4-(4-ChIoro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-methanesulfonyl-3-
trifluoromethyI-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-ethanone:

(0853] To a stirred solution of 70 mg (0.13mmol) 1 -[4-(4-Chloro-3-methoxy-phenyl)-
piperazto-1-yl]-2-(3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-ethanone
in 2 ml DCM under ice-bath was added 0.046ml TEA (0.33 mmol), following by 0.012 ml
(0.15 mmol) Methanesulfonyl chloride. The reaction was stirred for 30 min in ice bath.
More DCM "was added after reaction, and the DCM layer was washed with Sat. NaHCO3,
Brine, dried over MgSO4, and concentrated to give the title compound as a white solid:

HPLC retention time = 4.78 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic
acid A 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES)
M+H expect = 536.1, found = 536.1.
N-(5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-
piperazin-1-yI}-4-methoxy-benzyl)-N-methyl-methanesulfonamide:

[0854] To 200mg of 1-[4-(4-Chloro-5-methoxy-2-methylaminomethyl-phenyl)-piperazin-
l-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.42mmol, l.Oeq) and
126uL triethylamine (0.90mmol, 2.1eq) in 1.4mL dichloromethane in a 4mL vial fitted was
added a stir bar. The solution was cooled in an ice water bath and 34uL
methanesulfonylchloride (0.43mmol, 1.05eq) was added. The ice bath was removed and the
solution was allowed to stir overnight. The crude product was purified by HPLC, and the
product was treated with 4M HC1 in p-dioxane to give the title compound: LC/MS(ES)
(M+H) = 572.1; retention time = 7.32minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of
20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazm-1-yI]-2-(4-chloro-5-
acetylaminomethyl-3-trifluoromethyl-pyrazol-1-yI)-ethanone


[0855] A mixture of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
aminomethyl-3-txifluoromethyl-pyrazol-1-yl)-ethanone (50 mg, 1 equiv), acetyl chloride (13
mg, 1.5 equiv), and TEA (50 mg, 3 equiv) in 2 mL of DCM was stirred at room temperature
for lh. Reverse phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title
compound: LCMS retention time: 4.60 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5\a,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 508.
Synthesis of 1-[4-(4-Chloro-3-merhoxy-phenyl)-piperaziii-1-yI]-2-(4-chloro-5-
methylsulfonylaminomethyl-3-trifluoromethyl-pyrazoI-1-yI)-ethanone

[0856] A mixture of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
aminomethyl-3-trifiuoromethyl-pyrazol-1-yl)-ethanone (50 mg, 1 equiv), MeSO2Cl (19 mg,
1.5 equiv), and TEA (50 mg, 3 equiv) in 2 mL of DCM was stirred at room temperature for
lh. Reverse phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title
compound: LCMS retention time: 4.78 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 544.
Synthesis of (4-Chloro-2-{2-[4-(4-chIoro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-
ethyI}-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-urea

[0857] A mixture of 1 -[4-(4-Chloro-3-methoxy-phenyl)-piperazin-l -yl]-2-(4-chloro-5-
aminomethyl-3-txifluoromethyl-pyrazol-1-yl)-ethanone (50 mg, 1 equiv), TMSNCO (30 mg,

2.5 equivin 2 mL of THF was stirred at room temperature for lh. Reverse phase HPLC
(acetonitrile-H20 with 0.1% TFA as eluent) gave the title compound: LCMS retention time:
4.26 mmutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35CC) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed for (M+H)+: 509.
PROTOCOL Y: Preparation of compounds via alleviation.
Synthesis of 2-(4-Chloro-5-methyl-1H-pyrazol-3-yI)-propan-2-ol

[0858] 4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.14g, 0.8 mmol)
was dissolved in 6 ml anhydrous THF, cooled to 0°C, and 3ml (9.0mmol) of 3M MeMgBr in
ethyl ether was added drop wise. The reaction was then removed from the ice-bath, and was
stirred at ambient temperature for one hour. The reaction mixture was poured into 1M
phosphate buffer (pH = 7), and the mixture was extracted with EtOAc. The phases were
separated, and the ethyl acetate layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated to afford the title compound: MS (ES) M-OH expect = 157.1, found
= 157.1; 1HNMR (CDCL3,400MHz) 5 2.25 (s, 3H), 1.64 (s, 6H) ppm.
2-(4-Chloro-5-trifluoromethyl-2H-pyrazol-3-yI)-propan-2-ol

[0859] The above compound was synthesized following the same protocol as above using
4-Chloro-5-trifiuoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester.

(4-Chloro-5-pyrazol-1-ylmethyl-3-trifluoromethyl-pyrazol-1-yl)-aceticacid

[0860] (5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid ethyl ester
was treated with an excess of pyrazole and potassium carbonate in DMF at 60°C, followed by
treatment of the product with lithium hydroxide to give the title compound.
l-{4-[4-ChIoro-2-(l-hydroxy-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0861] Prepared a slurry of lOg of 5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-
pyrazol-1-yl)-acetyl]-piperazin-1-yl}-4-methoxy-benzaldehyde (20.9mmol, l.Oeq) in 70mL
THF in a 250mL 3-necked flask fitted with a stir bar, thermometer, and addition funnel fitted
with an N2 inlet. The mixture was cooled in an ice water bath to 3°C, then 7.3mL of 3.0M
MeMgBr in Et20 (21.9mmol, 1.05eq) was added dropwise. LC/MS showed reaction was
only about 50% complete. Additional MeMgBr solution was added until the aldehyde was
consumed (approx. 5 mL were needed). The reaction was quenched with a small amount of
water, the solvents removed under vacuum, and the crude material purified by column
chromatography to give the title compound: LC/MS(ES) (M+H) 495.1; retention time
5.41minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5p., 35°C) using a 2.0 minute isocratic
period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).

Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-y!]-2-[4-chloro-5-methyl-3-
(2-methyI-2H-tetrazoI-5-yl)-pyrazol-1-yl]-ethanoneand1-[4-(4-Chloro-3-methoxy-
pheriyI)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(2-methyI-1H-tetrazoI-5-yI)-pyrazol-1-
yl]-ethauone

[0862] A mixture of 2-(4-chloro-3-tetrazol-5-yl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (9 mg, 1 equiv), Mel (3 /*L, 5 equiv), and K2CO3
(20 mg, excess) in 1 mL of DMF were heated at room temperature for 3 days. The crude
product was purified by reverse phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to
yield 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyl-3-(2-methyl-
2H-tetrazol-5-yl)-pyrazol-1-yl]-ethanone. LCMS Retention time: 4.06 min. LCMS observed
for (M+H)+: 465. From this reaction, 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-
[4-chloro-5-methyl-3-(2-methyl-1H-tetrazol-5-yl)-pyrazol-1-yl]-ethanone was also obtained.
The two products co-eluted from HPLC and TLC. LCMS Retention time: 4.06 minutes
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile) for both isomers. LCMS observed for (M+H)+:
465 for both isomers.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yI]-2-(4-chloro-5-morpholin-
4-ylmethyI-3-trifluoromethyl-pyrazol-1-yI)-ethanone


[0863] A mixture of (5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid
ethyl ester (350 mg, 1 equiv) and morpholine (0.5 mL, 5 equiv) in 1 mL of DMF was stirred
at room temperature overnight, diluted with ethyl acetate, washed with water. The organic
layer was evaporated, diluted with 3 mL of THF and treated with 3 mL of IN LiOH for 2
hours. Preparative reverse phase HPLC gave (4-Chloro-5-morpholin-4-ylmethyl-3-
trifluoromethyl-pyrazol- l-yl)-acetic acid.
[0864] A mixture of l-(4-Chloro-3-methoxy-phenyl)-piperazine (30 mg, 1 equiv), (4-
Chloro-5-morpholin-4-ylmethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (44 mg, 1 equiv),
HATU (42 mg, 1.1 equiv) and TEA(0.2 mL, 6 equiv) in 1 mL of DMF was stirred at room
temperature for 12 hours. Dilution with EtOAc, followed by washing with saturated aqueous
NaHCO3 and reverse phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title
compound: LCMS retention time: 4.69 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 536.
Synthesis of 1 -[4-(4-Chloro-3-methoxy-phenyI)-piperazin-1-yl]-2-(4-chloro-5-
dimethylaminomethyl-3-trifluorornethyI-pyrazol-1-yI)-ethanone

[0865] A mixture of (5-Bromomethyl-4-chloro-3 -trifluoromethyl-pyrazol-1 -yl)-acetic acid
ethyl ester (350 mg, 1 equiv) and NHMe2 (2 M in THF, 2.5 mL, 5 equiv) in 1 mL of DMF
was stirred at room temperature overnight, diluted with ethyl acetate, washed with water.
The organic layer was evaporated, diluted with 3 mL of THF and treated with 3 mL of IN
LiOH for 2 hours. Preparative reverse phase HPLC gave (4-Chloro-5-dimethylaminomethyl-
3-trifluoromethyl-pyrazol-l -yl)-acetic acid.
[0866] A mixture of l-(4-Chloro-3-methoxy-phenyl)-piperazine (30 mg, 1 equiv), (4-
Chloro-5-dimethylaminomethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (28 mg, 1 equiv),
HATU (42 mg, 1.1 equiv) and TEA(0.2 mL, 6 equiv) in 1 mL of DMF was stirred at room

temperature for 12 hours. Dilution with EtOAc, followed by washing with saturated aqueous
NaHCO3 and reverse phase HPLC (acetonitrile-H^O with 0.1% TFA as eluent) gave the title
compound: LCMS retention time: 3.42 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 494.
Synthesis of 1-[4-(4-ChIoro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methylsulfonyImethyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0867J A mixture of (5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid
ethyl ester (350 mg, 1 equiv) and NaSO2Me (510 mg, 5 equiv) in 1 mL of DMF was stirred
at room temperature overnight, diluted with ethyl acetate, washed with water. The organic
layer was evaporated, diluted with 3 mL of THF and treated with 3 mL of IN LiOH for 2
hours. Preparative reverse phase HPLC gave (4-Chloro-5-methylsulfonylmethyl-3-
trifluoromethyl-pyrazol-1 -yl)-acetic acid.
[0868] A mixture of l-(4-Chloro-3-methoxy-phenyl)-piperazine (30 mg, 1 equiv), (4-
Chloro-5-methylsulfonylmethyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (32 mg, lequiv),
HATU (42 mg, 1.1 equiv) and TEA(0.2 mL, 6 equiv) in 1 mL of DMF was stirred at room
temperature for 12 hours. Dilution with EtOAc, followed by washing with saturated aqueous
NaHCC>3 and reverse phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title
compound: LCMS retention time: 5.08 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); LCMS observed for (M+H)+: 529.

PROTOCOL Z: Preparation of compoimds via peroxvacid-mediated N-oxidation.
Synthesis of 1-[4-(4-ChIoro-3-methoxyphenyl)-4-oxypiperazin-1-yl]-2-(4-chloro-5-
methyI-3-oxazol-2-ylpyrazol-1-yI)ethanone

[0869] The title compound was synthesized according to Protocol Z, from example 1.
LCMS (ES) M+H 466.1, Rf 0.62 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C)
using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1%
formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
PROTOCOL DP: Preparation of compounds via Palladium and Copper mediated
Processes.
Synthesis of 2-(4-ChIoro-5-methanesuIfonyl-3-trifluoromethylpyrazol-1-yI)-1-(4-(4-
chloro-3-methoxyphenyl)piperazin-1-yl)ethanone and l-(4-(4-chloro-3-
methoxyphenyl)piperazin-1-yl)-2-(4-Chloro-3-trifluoromethylpyrazoI-1-yl)ethanone:

[0870] The above compounds were obtained following the copper-mediated processes in
Protocol DD from example 2, and the reaction mixture was purified by PTLC using 50%
ethyl acetate: 50% n-hexane as mobile phase.

[0871] 2-(4-Chloro-5-methanesulfonyl-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-chloro-3-
methoxyphenyl)piperazin-1-yl)ethanone: LC MS m/z 515 (M+H), Rt = 5.34 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5ji, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).
[0872] l-(4-(4-chloro-3-methoxyphenyl)piperazin-1-yl)-2-(4-Chloro-3-trifluoromethyl
pyrazol-1-yl)ethanone: LC MS m/z 437 (M+H), Rt = 5.22 minutes (same method as above);
1H NMR (400 MHz, CDC13): 8 3.15 (apparent quintet, J = 5.1 Hz, 4H), 3.68 (apparent t, J =
5.1 Hz, 2H), 3.78 (apparent t, J = 5.1 Hz, 2H), 3.89 s, 3H), 5.03 (s, 2H), 6.42 (apparent dd, J
= 2.5 & 8.4 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H).
Synthesis of 2-(3-phenylsuIfonyl-4-chloro-5-methyI-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyI)-piperazin-1-yI]-ethanone

[0873] A mixture of 2-(4-Chloro-3-iodo-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-2(S)-methyl-piperazin-1-yl]-ethanone (204 mg, 1 equiv), NaSO2Ph (200 mg, 3
equiv) and Cul (228 mg, 3 equiv) in 1 mL of DMSO were heated at 110°C overnight and
then cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield the title compound: LCMS
Retention time: 4.95 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5[i, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:523.

Synthesis of 2-(4-chloro-3-[l ,2,4]triazol-1-yl-5-methyl-pyrazoH-yI)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0874] The title compound was prepared following a variation on Protocol DD. LCMS
Retention time: 3.80 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 450.
1-[4-(4-Chloro-3-methoxy-phenyI)-2(S)-methyl-piperazin-1-yl]-2-(4-chloro-S-methyl-3-
[l,2,3]triazol-1-yl-pyrazol-1-yl)-ethanone

[0875] The title compound was prepared following a variation on Protocol DD. LCMS
Retention time: 4.28 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:464.
1-[4-(4-ChIoro-3-methoxy-pIienyl)-2(S)-methyl-piperazin-1-yI]-2-(4-chloro-5-methyl-3-
pyrazol-1-yl-pyrazol-1-yl)-ethanone


[0876] The title compound was prepared following a variation on Protocol DD. LCMS
Retention time: 4.56 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:463.
2-(4'-Chloro-3,5*-dimethy1-[l,3,]bipyrazolyl-l,-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-
2(S)-methyl-piperazin-1-yl]-ethanone

[0877] The title compound was prepared following a variation on Protocol DD. LCMS
Retention time: 4.59 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 477.
1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyI)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
[l,2,3]triazol-1-yI-pyrazol-1-yI)-ethanone

[0878] The title compound was prepared following a variation on Protocol DD. LCMS
Retention time: 5.75 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:468.

1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyI)-piperazin-1-ylJ-2-(4-chloro-5-methyl-3-
pyrazol-1-yl-pyrazol-1-yl)-ethanone

[0879] The title compound was prepared following a variation on Protocol DD. LCMS
Retention tinie: 5.96 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 467.
2-(4'-Chloro-3,S'-dimethy1-[l,3*]bipyrazolyl-l,-yl)-1-[4-(4-Chloro-2-fluoro-5-methoxy-
phenyl)- piperazin-1-ylj-ethanoue

[0880] The title compound was prepared following a variation on Protocol DD. LCMS
Retention time: 6.02 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:481.
Synthesis of 1-[4-(4-ChIoro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-3-
cyano-5-methyl-pyrazol-1-yI)-ethanone


[0881] A mixture of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-
chloro-3-iodo-5-methyl-pyrazol-1-yl)-ethanone (260 mg, 1 equiv) and CuCN (450 mg, 10
equiy) in 1 mL of DMF were heated at 175°C for 1 h and then cooled to room temperature,
taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin pad of celite and
concentrated. The crude product was purified by reverse phase HPLC (acetonitrile-H20 with
0.1% TFA as eluent) to yield the title compound: LCMS Retention time: 5.12 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5|i, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid/ 99.9% acetonitrile); LCMS observed for (M+H)+: 426.
Synthesis of 2-(3-benzenesulfonyl-4-chloro-5-methyl-pyrazol-1-yI)-1-[4-(4-chloro-3-
methoxy-phenyl)-2(S)-methyI-piperazin-1-yl]-ethanone

[0882] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-2-(S)-methylpiperazin-1-yl]-ethanone (204 mg, 1 equiv), NaSO2Ph (200 mg, 3
equiv) and Cul (228 mg, 3 equiv) in 1 mL of DMSO were heated at 110°C overnight and
then cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield the title compound: LCMS
Retention time: 5.40 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5(X, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid/
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:537. i
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yI]-2-(4-chIoro-3-
methauesuIfonyl-5-methyI-pyrazol-1-yl)-ethanone


[0883] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-Chloro-2-fluoro-5-
methoxy-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1 equiv), NaSO2Me (117 mg, 3 equiv)
and Cul (217 mg, 3 equiv) in 1 mL of DMSO were heated at 110°C overnight and then
cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered
through a thin pad of celite and concentrated. The crude product was purified by reverse
phase HPLC (acetonitrile-H20 with 0.1% TFA as eluent) to yield the title compound: LCMS
Retention time: 5.90 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u,, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A == 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 479.
Synthesis of 2-(3-cyano-4-chIoro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyl)-2(S)-methyl-piperazin-1-yl]-ethanone

[0884] A mixture of 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-
phenyI)-2-(S)-methylpiperazin-1-yl]-ethanone (260 mg, 1 equiv) and CuCN (450 mg, 10
equiv) in 1 mL of DMF were heated at 175°C for 1 h and then cooled to room temperature,
taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin pad of celite and
concentrated. The crude product was purified by reverse phase HPLC (acetonitrile-HjO with
0.1% TFA as eluent) to yield the title compound: LCMS Retention time: 5.96 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile); LCMS observed for (M+H)+: 422.
Synthesis of l-(4-(4-chlro-3-methoxyphenyl)piperzin-1-yl)-2-(3-pyrazol-1-yl-indazol-1-
yl)ethanone:


[0885] The above compound was synthesized following the copper-mediated amine
arylation protocol DD, using 2-(3-iodoindazol-1-yl)-1-(4-(4-chloro-3-
methoxyphenyl)piperazin-1-yl)ethanone and pyrazole. LC MS 451 (M+H); retention time =
5.89 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of
20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile /
94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of l-(4-(4-chIro-3-methoxyphenyl)piperzin-1-yl)-2-(3-methanesuIfonyl-
indazoI-1-yi)ethanone:

[0886J The above compound was synthesized using the copper-mediated varient of
Protocol DD used to make sulfones. LC MS 463 (M+H), retention time = 5.46 minutes
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).
PROTOCOL EE: General procedure for the synthesis of oxazole substitution on
pyrazol:
Synthesis of (5-Methyl-12£pyrazoI-3-yl)methanol

[0887] To a solution of the ester (308 mg) in CH2C12 (8 mL) and THF (10 mL) stirring at
0°C, a solution of lithium aluminum hydride (1 M in ether, 3.0 mL) was slowly added. The
reaction mixture was stirred for an additional 30 min and was quenched by the addition of
H20 (0.1 mL), aqueous NaOH solution (10%, 0.2 mL) andH20 (0.3 mL). The mixture was
filtered and evaporated in vacuo to give the title compound.

Synthesis of (4-Chloro-5-methyI-l/£-pyrazol-3-yl)methanol

[0888] To a solution of the alcohol (1.32 g) in CH2C12 (30 mL) was added N-
chlorosuccinimide (1.74 g). The reaction mixture was stirred at room temperature for
overnight and aqueous NaOH solution (30 mL) was added. The organic layer was separated
out and the aqueous layer was extracted with ethyl acetate (3x30 mL). The combined
organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give the title
compound.
Synthesis of 4-Chloro-5-methyl-l/?-pyrazole-3-carbaldehyde

[0889] To a solution of the alcohol (14.6 mg) in dimethoxyethane (1 mL) was added MnC>2
(51 mg) in one portion. The reaction mixture was heated up to 110°C for 3 h and cooled to
room temperature. The mixture was filtered and the remaining solid was washed with hot
ethanol (3 mL). The combined organic solution was evaporated in vacuo to give the title
aldehyde.
Synthesis of 5-(4-Chloro-5-methyl-l/f-pyrazol-3-yl)oxazole

[0890] To a solution of the aldehyde (14 mg) in ethanol (1 mL) was added NaOEt (14 mg)
and TosMic (20 mg). The reaction mixture was stirred at room temperature for 1 h and
evaporated in vacuo. The mixture was dissolved in saturated aqueous NaHCC>3 solution (1
mL) and extracted with ethyl acetate (3 x 1 mL). The combined organic solution was dried
and evaporated to give the title compound.

.PROTOCOL JJ: Heteroaryl substituted pyrazoles via cvcloaddition and cyclization
reactions!
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[4-chloro-5-methyI-3-
(5-methy1-[l,2,4]oxadiazol-3-yl)-pyrazol-1-yl]-ethaaone

[0891] A mixture of 2-(3-cyano-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone (41 mg, 1 equiv), NH2OH-HCl (35 mg, 5 equiv)
and Et3N (140 /xL, 10 equiv) in 1 mL of ethanol were heated at 50°C for 2 hours and then
cooled to room temperature. The white solid was collected, treated with
trimethylorthoacetate (1 mL) and 1 crystal of PTSA at 50°C for 2 hours. Reverse phase
HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title compound: LCMS
Retention time: 4.26 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 465.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-2(S)-methyI-piperazin-1-yl]-2-(4-chloro-
5-methyl-3-[l,2,4]oxadiazol-3-yl-pyrazol-1-yl)-ethanone

[0892] A mixture of 2-(3-cyano-4-chloro-5-methyl-p3a-azol-1-yl)-1-[4-(4-chloro-3-
methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanoae (160 mg, 1 equiv), NHbOH'HCl (79
mg, 3 equiv) and Et3N (264 pL, 5 equiv) in 1 mL of etrianol were heated at 50°C for 2 hours
and then cooled to room temperature. The white solid was collected, treated with
trimethylorthoformate (1 mL) and 1 crystal of CSA at 5 0°C for 2 hours. Reverse phase
HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title compound: LCMS

Retention time: 5.24 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5ju, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% aefctonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for(M+H)+:465.
Synthesis of 1-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chlorO-
5-methyl-3-[l,2,4]oxadiazoI-3-yI-pyrazoI-1-yl)-ethanone

[0893] A mixture of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1 -yl] -2-(4-
chloro-3-cyano-5-methyl-pyrazol-1-yl)-ethanone (165 mg, 1 equiv), NH2OH>HCl (79 mg, 3
equiv) and Et3N (264 jttL, 5 equiv) in 1 mL of ethanol were heated at 50°C for 2 hours and
then cooled to room temperature. The white solid was collected, treated with
trimethylortfypformate (1 mL) and 1 crystal of CSA at 50°C for 2 hours. Reverse phase
HPLC (acetonitrile-H20 with 0.1% TFA as eluent) gave the title compound: LCMS
Retention time: 5.30 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS observed
for (M+H)+: 469.
PROTOCOL KK: Synthesis of compounds using Negishi coupling reactions
Synthesis of l-(4-(4-chlro-3-methoxyphenyl)piperzin-1-yl)-2-(3-thiazol-2-yl-indazoI-1-
yl)ethanone:

[0894] The above compound was synthesized following Protocol KK from example 2,
using 1 -[4-(4-Chloro-3methoxy-phenyl)-piperazin-1 -yl]-2-(3-iodo-indazol-l -yl)-ethanone, to

give the title compound: LC MS 462 (M+H), Rt = 5.37 minutes (Agilent Zorbax SB-C18,
2.1X50 mm, 5\i, 35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile/ 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile); 1H NMR (400 MHz, CDC13): 5 3.07 (apparent quintet, J = 4.8 Hz, 4H),
3.75 (t, J = 5.2 Hz, 2H), 3.81 (t, J = 4.8Hz, 2H), 3.86 (s, 3H), 5.34 (s, 2H), 6.37 (dd, J = 2.6 &
8.4 Hz, 1H), 6.42 (d, J = 2.5 Hz,lH), 7.18 (d, J = 8.5 Hz, 1H), 7.30- 7.35 (m, 2H), 7.45- 7.53
(m, 2H), 7.96 (d, J = 3.0 Hz, 1H), 8.46-8.48 (m, 1H).
Synthesis of (4-Chloro-5-methyl-3-oxazol-2-ylpyrazol-1-yl)acetic acid tert-butyl ester

[0895] The title compound was obtained according to Nigishi Coupling Protocol KK.
Synthesis of (4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)acetic acid

[0896] To a solution of the ester (144 mg) in CH2C12 (3 mL) was added trifluoroacetic acid
(0.23 mL) and triethylsilane (1 mL). The reaction mixture was stirred at room temperature
for 3 h and evaporated in vacuo to give the title compound.
Synthesis of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
thiazol-2-yl-pyrazol-1-yI) ethanone


[08971 Following Protocol KK, A mixture of 2-(3 -iodo-4-chloro-5-methyl-pyrazol-1 -yl)-1 -
[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-eth.anone (204 mg, 0.4 mmol, 1 equiv), 2-
thiazonyl Zinc bromide (0.5 M in THF, 1.6 mL, 2 equiv) and Pd(PPh3)4 (46 mg, 0.1 equiv)
was refluxed overnight, cooled to room temperature, quenched with water, extracted with
EtOAc. The organic layer was purified by reverse phase HPLC to yield the title compound:
LCMS Retention time: 4.36 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); LCMS
observed for (M+H)+: 466.
PROTOCOL LL: Mannich Additions to aromatic rings.
Synthesis of 5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-
acetyI]-piperazin-1-yl}-4-methoxy-benzaldehyde:

[0898J Took 7.6g dry DMF (97.5mmol, 4.4eq) in a 250mL 3-necked flask fitted with a
stirring paddle, thermometer, and addition funnel fitted with an N2 inlet. The flask was
cooled in a salt water bath until t ~ -10C, then 2.3 mL POC13 (24.4mmol, 1.1 eq) was added in
a slow stream over a five minute period. The mixture was allowed to stir for 15min, then a
solution of 10.Og of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (22.2mmol, l.Oeq) in 35mL dry DMF was
added dropwise over a Vi hr period. The temperature was kept below 5°C during the
addition. The flask was then transferred to an oil bath and warmed to 35°C. After four
hours, the solution was poured into 200mL of vigorously stirring H2O which resulted in a
thick beige precipitate. The pH was adjusted to ~8 with 40% NaOH in H2O, and the solid
was collected by vacuum filtration, washed well with H2O, then, dried under vacuum to give
the title compound: LC/MS(ES) (M+H) 479.0; retention time 7.24minutes (Agilent Zorbax
SB-C18,2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a

5.0 minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
S
1-[4-(4-Chloro-2-hydroxymethyI-5-methoxy-phenyI)-piperazin-1-yll-2-(4-chIoro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0899] Took lOOmg 5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetyl]-piperazin-1-y]}-4-methoxy-benzaldehyde (0.20mmol, I .Oeq) and 15.3mgNaBH4
(0.40mmol, 2.Oeq) in 500uL THF in a 4 mL vial fitted with a stir bar. The vial was loosely
capped and the mixture allowed to stir for 3hours at room temperature. The reaction was
quenched with a small amount of aqueous HC1, the resulting white precipitate was collected
by vacuum filtration and dried under vacuum to give the title compound: LC/MS(ES) (M+H)
481.3, retention time = 4.51minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a
2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B
with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B =
0.08% formic acid / 99.9% acetonitrile).
PROTOCOL MM: Preparation of compounds bv transformation of C-C and C-N triple
bonds
Synthesis of 2-(3-acetyl-4-chloro-5-methyIpyrazoL-1-yl)-1-(4-(4-chloro-3-methoxy
phenyl)piperazin-1-yl)ethanone:


[0900] Mercuric sulfate (16 rag, 0.05 mmol) was added to a 0°C stirred solution of 2-(4-
Chloro-3-ethynyl-5-methyl-pyrazol-1-yl)-1-(4-chloro-3-methoxyphenyL)-piperazin-1-
yl)eth?none (90 mg, 0.22 mmol) and cone, sulfuric acid (0.2 mL) in a mixture of THF: H20
solvent (2 mL:l mL). Stirring continued at r.t for 1 h, neutralized with saturated aqueous
NaHCC>3, and extracted with ethyl acetate (3X 20 mL). The combined organic layer was
washed with water, brine, dried (Na2SC>4) and concentrated. The residue was purified by
HPLC using 20-80% method to get 2-(3-Acetyl-4-Chloro-5me%lpyrazol-1-yl)-1-(4-(4-
chloro-3-methoxyphenyl) piperazin-1-yl)ethanone in pure form in 60% yield: LC MS: m/z
425 M*", Rt = 4.33 min (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); JH NMR (400 MHz,
CDC13): 8 2.28 (s, 3H), 2.55 (s, 3H), 3.18 (apparent d, J= 15.4 Hz, 4H), 3.73 (apparent d, /=
15.6 Hz, 4H), 3.89 (s, 3H), 5.01 (s, 2H), 6.43 (apparent d, J= 8.7 Hz, 1H), 6.49 (s, 1H), 7.21
(d,J=8.3Hz, 1H).
Synthesis of 2-(4-Chloro-3-(l-hydroxyethyI)-5methylpyrazol-1-yl)-l -(4-(4-chloro-3-
methoxy phenyl) piperazin-1-yl)ethanone:

[0901] Sodium borohydride was added to a stirred solution of 2-(3-Acetyl-4-Chloro-
5methylpyrazol-1-yl)-1-(4-(4-chloro-3-methoxyphenyl) piperazin-1-yl)ethanone (100 mg,
0.23 mmol) in methanol at OoC. The reaction was pulled out of the ice/"water bath, and
stirring was continued for 2 hours. Then the reaction mixture was diluted with water and
extracted with ethyl acetate. The combined organic layer was washed with water, brine,
dried over Na2SO4 and concentrated. The residue was purified by HPLC using 20-80%
method to get 2-(4-Chloro3-(l-hydroxyethyl)-5methylpyrazol-1-yl)-1-(4-(4-chloro-3-
methoxy phenyl) piperazin-1-yl)ethanone: LC MS: m/z 427 M+H, Rt = 3.91 minutes
(Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).

Synthesis of 2-[3-(2-Aminomethylpyridin-4-yI)-4-chloro-5-methylpyrazol-1-yIJ-1-[4-(4-
chloro-3-methoxyphenyl)piperazin-1-yl]ethanone

[0902] To a solution of 4-(4-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-
2-oxo-ethyl}-5-memyl-1H-pyrazol-3-yl)-pyridine-2-carbonitrile (49 mg) in MeOH (1 mL) at
0°C was added CoC12-6H20 (71 mg) and NaBH4 (114 mg). The reaction mixture was stirred
at 0°C for an additional 30 min and quenched by the addition of water (1 mL). The mixture
was filtered and purified by preparative HPLC to give the title compound: LCMS (ES) M+H
489.1; Rf 3.13 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
PROTOCOL NN: Preparation of compounds using Nickel and Chromium-mediated
reactions.
2-{4-Chloro-5-(l-hydroxy-ethyl)-3-trifluoromethyl-pyrazol-1-yI]-1-[4-(4-chloro-3-
methoxy-phenyl)-piperazin-1-yl]-ethanone

[0903] 2-(4-Chloro-5-iodo-3-trifluoromethylpyrazol-l -yl)-l -(4-(4-chloro-3-
methoxyphenyl) piperazin-1-yl)ethanone (100 mg, 0.18 mmol) was added to a 0°C stirred
solution of acetaldehyde (156 mg, 3.56 mmol) and chromous chloride (218 mg, 1.78 mmol)
doped with 1% NiCl2 (2 mg) in dry DMSO. The reaction was removed from the bath, and
stirring continued for 2 hours. Then, the reaction mixture was diluted with saturated aqueous
ammonium chloride and extracted with ethyl acetate (3X 20 mL). The combined organic

layer was washed with water, brine, dried (Na2SO4) and concentrated. The residue was
purified by HPLC to get the title compound in 55% yield. LC MS: m/z 481 (M+-H),
Retention time = 4.68 minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5
minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of 2-(4-Chloro-5-(l-hydroxyphenyImethyl)-3-trifluoromethylpyrazol-1-yl)-1-
(4-(4-chloro-3-methoxy phenyl) piperazin-1-yl)ethanone:

[0904] The title compound was synthesized using same as the above protocol. LC MS:
m/z 543 (M+H), Rt = 5.20 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a
4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); *H NMR
(400 MHz, CDClj): 5 3.08-3.20 (m, 4H), 3.40-3.45 (m, 1H), 3.51-3.58 (m, IH), 3.75
(apparent t, J= 5.1Hz, 2H), 3.89 (s, 3H), 4.33 (d, J= 16.1 Hz, IH), 4.70 (d, J= 6.6 Hz, IH),
4.96 (d, J= 16.1 Hz, IH), 6.19 (apparent d, 7= 6.2 Hz, IH), 6.40 (apparent dd, J = 3.6 & 8.8
Hz, IH), 6.46 (apparent d, 7= 2.6 Hz, lH),7.20-7.40 (m, 5H).
Synthesis of2-(5-Benzoyl-4-Chloro-3-trifluoromethylpyrazol-1-yl)-1-(4-(4-cliloro-3-
methoxy phenyl) piperazin-1-yl)ethanone:

[0905] MNO2 (20 mg) was added to a stirred solution of 2-(4-Chloro-5-(l -
hydroxyphenylmethyl)-3 -trifluoromethylpyrazol-1 -yl)-1 -(4-(4-chloro-3-methoxy phenyl)
piperazin-1-yl)ethanone (20 mg) in dry dichloromethane (1 mL) at ambient temperature
under nitrogen. Stirring continued at same temperature for 24 hours. Then, the reaction
mixture was diluted with acetone, passed through a short plug of Si02 column to remove

inorganic impurities. The eluent was concentrated and the residue was purified by HPLC to
get the title compound in 85% yield. LC MS: m/z 541 (M+H), 20-95 method, R,t = 5.64
minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20%
to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9%
water, B - 0.08% formic acid / 99.9% acetonitrile); *H NMR (400 MHz, CDC13): 8 3.07 (t, J
= 5.1 Hz, 2H), 3.21 (t, /= 4.8 Hz, 2H), 3.60 (t, J= 5.1 Hz, 2H), 3.65 (t, 7= 5.1 Hz, 2H), 3.89
(s, 3H), 5.44 (s, 2H), 4.33 (d, J= 16.1 Hz, 1H), 4.70 (d, J= 6.6 Hz, 1H), 6.40 (apparent dd, J
= 2.6 & 8.3 Hz, 1H), 6.46 (apparent d,/= 3 Hz, lH),7.20-7.22 (m, 1H), 7.50-7.54 (m, 2H),
7.63-7.67 (m, 1H), 7.89-7.91 (m, 2H).
Synthesis of [4-ChIoro-5-(2-hydroxy-propyI)-3-trifluorometh.yI-pyrazol-1-yl] -acetic
acid:

[0906] The above compound was synthesized via a two-step procedure. The first step
follows the general chromous chloride-mediated Protocol NN, followed by basic hydrolysis
of the ester to give the title compound.
PROTOCOL OO: Reductive Animation on arvl aldehydes using Borohydride Reagents
1-[4.(4-Chloro-2-dimethylaminomethyl-5-methoxy-phenyl)-piperazm-1-yl]-2-(4-chloro-
5-methyI-3-trifluoromethyl-pyrazol-1-yi)ethanone:


[0907] Took 200mg of 5-Chloro-2- {4-[2-(4-chloro-5-methyl-3-rifluoromemyl-pyrazo]-l -
yl>acetyl]-piperazin-1-yl}-4-methoxy-benzaldehyde (0.42mmol, l.Oeq), 5uL AcOH
(~0.08jaimol, O.lOeq), 2.4eq of dimethylamine as a 1M solution in methanol (l.Ommol), and
1 .OmL of 1: l(v/v) THF:MeOH in 4mL vials fitted with stir bars; the mixture was allowed to
stir for Vi hr at room temperature, after which 79mg NaBH3CN (1.26mmol, 3.0eq) was
added. The vial was then loosely capped, and the stirring was allowed to continue overnight
at room temperature. The crude product was purified by preparative HPLC, followed by
treatment with 4M HC1 in p-dioxane to give the title compound: LC/MS(ES) (M+H) 508.2;
retention time 5.42minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5\i, 35°C) using a 2.0
minute isocratic period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a
2.5 minute wash at 95% B (A = 0.1 % formic acid / 5% acetonitrile / 94.9% water, B = 0.08%
formic acid / 99.9% acetonitrile).
l-{4-[4-Chloro-2-(isopropylamino-methyl)-5-methoxy-phenyl]-piperazin-1-yI}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0908] Following Protocol OO above, using isopropylamine, gave the title compound:
LC/MS(ES) (M+H) 522.2, retention time 5.73minutes using the same method as in the
protocol above.

l-{4-[4-ChIoro-2-(ethyIamino-methyl)-5-methoxy-plienyl]-piperazin-1-yl}-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0909] Following Protocol OO above, using ethylamine, gave the title compound:
LC/MS(ES) (M+H) 508.2, retention time 5.73minutes using the same method as in the
protocol above.
1-[4-(4-Chloro-2-cycIopentylaminomethyl-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-
chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-ethanone:

[0910] Following Protocol OO above, using aminocyclopentane, gave the title compound:
LC/MS(ES) (M+H) 548.2, retention time 5.90 minutes vising the same method as in the
protocol above.

1-[4-(4-ChIoro-5-methoxy-2-morphoIIn-4-yImethyI-phenyl)-piperazin-1-yI]-2-(4-chloro-
5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0911] Following Protocol OO above, using morpholine, gave the title compound:
LC/MS(ES) (M+H) 550.2, retention time 5.36 minutes using the same method as in the
protocol above.
1-[4-(2-Acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazoM-yl)-ethanone:

[0912] Took 8.0g l-{4-[4-Chloro-2-(l-hydroxy-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-
2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-]-yl)-ethanone (16.2mmol, l.Oeq) in70mL
pyridine in a 200mL round bottom flask fitted with a stir bar and N2 inlet. Added 9.1g PDC
(24.2mmol, 1.5eq) and stirred the mixture overnight at room temperature. The solvent was
then removed under vacuum and the crude product purified by column chromatography
(chloroform/hexane) to give the title compound: LC/MS(ES) (M+H) 493.1; retention time =
4.90minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 2.0 minute isocratic
period of 20% B, followed by a 5.0 minute gradient of 20% to 95% B with a 2.5 minute wash
at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid /
99.9% acetonitrile).

PROTOCOL PP; Reductive Amination on arvl ketones using Borohvdride Reagents
l.{4-[^_Chloro-5-methoxy-2-(l-methylamino-ethyl)-phenylJ-piperazin-1-yl}-2-(4-chloro-
5-methyl-3-trifluoromethyl-pyrazol-1-yI)-ethanone:

[0913] Took lOOmg 1-[4-(2-Acetyl-4-chloro-5-methoxy-phenyl)-piperazin-1-yl]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.20mmol, l.Oeq), 180 uL
Ti(OiPr)4 (0.60mmol, 3.0eq), and 2.5eq of methylamine (2M in THF) in 500uL of THF in a
4mL vial fitted with a stir bar. The mixture was stirred at room temperature for 3hours, then
38mg NaBH3CN (0.60mmole, 3.0eq) was added to the vial and the mixture was stirred
overnight. The reaction was quenched with a small amount of aqueous HC1, and the resulting
white precipitate was removed by vacuum filtration and discarded. The mother liquor was
purified by HPLC. The product were then re-dissolved in methylene chloride, and washed
with 0.5M aqueous EDTA. The organic phase was separated and dried under vacuum. The
residue was treated with 4M HC1 in p-dioxane to give the title product as a solid: LC/MS(ES)
(M+H) 508.1, retention time = 5.08minutes (Agilent Zorbax SB-C18,2.1X50 mm, 5ji, 35°C)
using a 2.0 minute isocratic period of 20% B, followed by a 5.0 minute gradient of 20% to
95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9%
water, B = 0.08% formic acid / 99.9% acetonitrile).

l-{4-[4-ChIoro-2-(l-dimethylamino-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0914] Following Protocol PP above, using dimethylamine, gave the title compound:
LC/MS(ES) (M+H) 522.1, retention time 5.02 minutes using the same method as in the
protocol above.
l-{4-[4-Chloro-5-methoxy-2-(l-ethylamino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-chloro-5-
methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0915] Following Protocol PP above, using ethylamine, gave the title compound:
LC/MS(ES) (M+H) 522.1, retention time 4.96 minutes using the same method as in the
protocol above.

l-{4-[4-Chloro-5-methoxy-2-(l-isopropylamino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-
chIoro-5-methyl-3-trifluoromethyI-pyrazol-1-yI)-ethanone:

J0916] Following Protocol PP above, using isopropylamine, gave the title compound:
LC/MS(ES) (M+H) 536.2, retention time 5.10 minutes using the same method as in the
protocol above.
l-{4-[4-Chloro-5-methoxy-2-(l-cyclopentyIamino-ethyI)-phenyI]-piperazin-1-yl}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0917J Following Protocol PP above, using cyclopentylamine, gave the title compound:
LCVMS(ES) (M+H) 562.2, retention time 5.19 minutes using the same method as in the
protocol above.

l-{4-[4-Chloro-5-methoxy-2-(l-pyrrolidin-1-yl-ethyl)-phenyl]-piperazin-1-yl}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazoI-1-yl)-etI».anone:

[0918] Following Protocol PP above, using cyclopentylamine, gave the title compound:
LC/MS(ES) (M+H) 548.2, retention time 5.12 minutes using the same method as in the
protocol above.
PROTOCOL OQ: General preparation of oxime derivatives from aryl aldehydes and
ketones.

[0919] Took lOOmg of the appropriate carbonyl compound (0.20mmol, l.Oeq), 90 uL
Ti(OiPr)4 (0.30mmol, 1.5eq), and 5.0eq of the appropriate hydroxylamine HC1 in 500uL
THF in 4mL vials fitted with stir bars: the mixtures were allowed to stir overnight at 60C.
The reactions were quenched with a small amount of coaic. HC1 and purified by preparative
HPLC. The free bases were prepared by dissolving the products in DCM and extraction with
aqueous K2CO3, after which the organic phases were separated and dried under vacuum.
The products were analyzed by LCMS using the following method: (Agilent Zorbax SB-C18,
2.1X50 mm, 5\i, 35°C) using a 2.0 minute isocratic period of 20% B, followed by a 5.0
minute gradient of 20% to 95% B with a 2.5 minute wash at 95% B (A = 0.1% formic acid /
5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).

5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazoH-yl)-acetyl]-piperazin-
l-yl}-4-metb.oxy-benzaldehydeoxime:
t
[0920] Following Protocol QQ, using 5-Chloro-2- {4-t2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1 -yl)-acetyl]-piperazin-1 -yl} -4-methoxy-benzaldehyde and
hydroxylamine, gave the title compound as a mixture of cis and trans isomers: LC/MS(ES)
(M+H) 494.1, retention time = 4.70minutes.
5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-
l-yl}-4-methoxy-benzaldehyde O-methyl-oxime:

[0921] Following Protocol QQ, using 5-Chloro-2-{4-[2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetyl]-pipera2in-1-yl}-4-methoxy-benzaldehydeand
O-methylhydroxylamine, gave the title compound as a mixture of cis and trans isomers:
LC/MS(ES) (M+H) 508.1, retention time = 4.67minutes.

l-{4-[4-Chloro-2-(l-(Z)-hydroxyimino-ethyl)-5-methoxy-phenyl]-piperazin-1-yl}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0922] Following Protocol QQ, using 1-[4-(2-Acetyl-4-chloro-5-methoxy-phenyl)-
piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanoneand
hydroxylamine, gave the title compound: LC/MS(ES) (M+H) 508.1, retention time = 4.73
minutes.
l-{4-[4-Chloro-2-(l-(E)-hydroxyimino-ethyl)-5-methoxy-pheuyII-piperazin-1-yI}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0923] Following Protocol QQ, using 1-[4-(2-Acetyl-4-chloro-5-methoxy-plienyl)-
piperazin-1 -yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-l -yl)-ethanone and
hydroxylamine, gave the title compound: LC/MS(ES) (M+H) 508.1, retention time = 4.67
minutes.

l-{4-[4-Chloro-5-methoxy-2-(l-(Z)-methoxyimino-ethyI)-phenyIJ-piperazin-1-yI}-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0924] Following Protocol QQ, using 1 -[4-(2-Acetyl-4~chloro-5-methoxy-phenyl)-
piperazin-1 -yl]-2-(4-chloro-5-methyl-34rifluoromethyl-pyrazol-l -yl)-ethanone and
O-Methylhydroxylamine, gave the title compound: LCVMS(ES) (M+H) 522.1, retention time
= 5.27 minutes.
l-{4-[4-Chloro-5-methoxy-2-(l-(E)-methoxyimino-ethyl)-phenyl]-piperazin-1-yl}-2-(4-
chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-ethaiione:

[09251 Following Protocol QQ, using 1-[4-(2-Acetyl-4-chloro-5-methoxy-phenyl)-
piperazin-1 -yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-l -yl)-ethanone and
O-Methylhydroxylamine, gave the title compound: LC/MS(ES) (M+H) 522.1, retention time
= 5.42 minutes.

PROTOCOL RR: General PROTOCOL for addition of organometallic reagents to
aldehydes, followed by deproprotection and Bop-mediated coupling
Synthesis of l-l4-(4-chloro-3-methoxy-phenyl)-2-(l-hydroxy-ethyI)-piperazui-1-yl]-2-(4-
chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone:

[0926] To a rapidly stirring solution of 4-(4-chloro-3-methoxy-phenyl)-2-formyl-
piperazine-lrcarboxylic acid tert-butyl ester (120 mg, 0.338 mmol) in 2.5 mL THF at-78°C
was added MeMgBr (0.17 mL, 3.0 M) dropwise. The homogeneous mixture was stirred 1 h
at -78°C, removed from the cold bath, and then quenched with saturated ammonium chloride.
The resultant solution was partitioned between ethyl acetate and saturated sodium
bicarbonate, the organic phase separated, and the aqueous phase extracted with ethyl acetate
(3 X 25 mL). The combined organics were dried with sodium sulfate and concentrated in
vacuo to afford 120 mg of the hydroxylethyl piperazine. The crude product (110 mg, 0.296
mmol) was dissolved in 2.3 mL methylene chloride, lowered to 0°C, and TFA (0.228 mL,
2.96 mmol) was added dropwise. The reaction was stirred 15 min at 0°C, removed from the
ice bath, and stirred a further 265 min at room temperature. The resultant solution was
concentrated under reduced pressure to afford the deprotected amine as a dark foam. A 10
mL flask was subsequently charged with the crude amine salt, (4-chloro-5-methyl-3-
trifluoromethyl-pyrazoI-1-yl)-acetic acid (86 mg, 0.355 mmol), diisopropylethyl amine
(0.226 mL, 1.30 mmol), and DMF (4 mL). The solution was lowered to 0°C and BOP (157
mg, 0.355 mmol) was added in one portion. The reaction was stirred 10 min at 0°C, raised to
room temperature, and stirred a further 3 h. The resultant solution was diluted with ether,
quenched with saturated ammonium chloride, partitioned with sodium bicarbonate and ethyl
acetate, and the aqueous layer extracted with ethyl acetate (4 X 35 mL). The combined

organics were diluted with 30 mL hexanes, washed with saturated sodium bicarbonate (2 X
30 mL), dried with sodium sulfate, and concentrated in vacuo. The crude product (168 mg)
was purified by column chromatography (30:70 EtOAc:hexanes) to afford 39 mg of the title
compound: MS (ES) M+H expect 495.1, found 495.0; HPLC Rt= 5.05 minutes, iLsing the
following method: (Agilent Zorbax SB-C18,2.1X50 mm, 5\i, 35°C) using a 4.5 minute
gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1 % formic aci d / 5%
acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile).
Synthesis of H4-(4-chIoro-3-methoxy-phenyI)-2-(l-hydroxy-2-methyI-propyt)-
piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethano».e

[0927] Following the sequence of steps in Protocol RR, using iso-Propylrnagnesium
chloride as the organometallic reagent, afforded the title compound; MS (ES) M+H expect
523.1, found 523.1; HPLC R,= 5.59 min.
Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(hydroxy-phenyl-methyl)-piperazin-1-
yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0928] Following the sequence of steps in Protocol RR, using phenylmagnesium. bromide
as the organometallic reagent, afforded the title compound: MS (ES) M+H expect 557.1,
found 557.1; HPLC R, = 5.59 min.

Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-2-(l-hydroxy-2-phenyl-ethyl)-piperazin-
l-yl]-2-(4-chloro-5-methyl-3-trifluoromethyI-pyrazol-1-yl)-ethanone

[0929J Following the sequence of steps in Protocol RR, using benzylmagnesium chloride
as the organometallic reagent, afforded the title compound: MS (ES) M+H expect 571.1,
found 571.1; HPLC Rt= 5.61 min.
Synthesis of (5-chIoro-2- {4- [2-(4-chloro-5-methyl-3-trifluoromethyI-pyrazoI-1-yI)-
acetyl]-piperazin-1-yl}-4-methoxy-pheayl)-hydroxy-acetonitrile:

[09301 Step 1: To a solution of ethanol (0.018 mL, 0.313 mmol) in 25 mL THF at 0°C was
added w-BuLi (0.125 mL, 0.313 mmol) dropwise. The solution was stirred 10 min, followed
by the addition of trimethylsilyl cyanide (0.625 mL, 4.70 mmol). The reaction was stirred a
further 10 min and 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetyl]-piperazin-1-yl}-4-ethoxy-benzaldehyde (1.50 g, 3.13 mmol) was added in one
portion. The resultant solution was removed from the ice bath, stirred 2.75 h, and then
quenched with saturated ammonium bicarbonate. The aqueous layer was subsequently
extracted with ethyl acetate (3 X 40 mL), the combined organics dried with sodium sulfate,
and the solvent removed in vacuo to afford 1.78 g (98%) of the crude TMS cyanohydrin
which was used directly in the next step.
[0931] Step 2: A 50 mL flask was charged with the crude TMS cyanohydrin, 3.1 mL 10%
HC1,10 mL water, and 10 mL THF. The resultant solution was stirred vigorously for 90 min,
followed by dilution with ethyl acetate and quenching with saturated sodium bicarbonate.
The mixture was stirred 5 min, the organic layer separated, and the aqueous layer extracted
with ethyl acetate (3X30 mL). The combined organics were dried with sodium sulfate and
concentrated in vacuo to generate 1.32 g of the crude cyanohydrin, contaminated with

approximately 10% of the corresponding 6-benzaldehyde. The crude product was
recrystallized (EtOAc/CH2Cl2/hexanes) to afford 780 mg (50%) of the desired cyanohydrin
containing 6.81 (s, 1H), 5.52 (s, 1H), 5.00 (s, 2H), 3.80 (s, 3H), 3.65-3.83 (m, 4H), 3.02-3.20 (m, 2H),
2.85-2.98 (m, 2H), 2.60 (s, 3H); MS (ES) M+H expect 506.1, found 506.1; HPLC Rt= 4.68
min.
Synthesis of (5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-
acetyl]-piperazin-1-yl}-4-methoxy-phenyl)-oxo-acetonitrile

[0932] (5-chloro-2- {4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-l -yl)-acetyl]-
piperazin-1-yl}-4-methoxy-phenyl)-hydroxy-acetonitrile (650 mg, 1.28 mmoi) was dissolved
in 1 mL MeCN, diluted with 8 mL methylene chloride, and the Dess-Martin Periodinane (5.7
mL, 0.25 M) was added dropwise (due to the poor solubility of the recrystallized starting
material in methylene chloride, the cyanohydrin was dissolved in THF and then the solvent
removed at reduced pressure to reveal a foam that was soluble in MeCN). Upon stirring 3 h,
me reaction was quenched with saturated sodium thiosulfate and stirred 10 min. The
resulting solution was partitioned between ethyl acetate and sodium bicarbonate, the organic
layer separated, and the aqueous layer extracted with ethyl acetate (3 X 40 mL). The
combined organics were dried over sodium sulfate and evaporated in vacuo to afford 550 mg
(85%) of the desired acyl cyanide, contaminated with approximately 10% of the 6-
benzaldehyde, which was used directly in the next step.

PROTOCOL SS: Formation of amide bonds via reaction of acykyanides with amines
Synthesis of 5-chloro-4-methoxy-2-{4-[2-(5-methyI-4-phenyI-3-trifluoromethyI-pyrazoI-
l-yl)-acetyl]-piperazin-1-yl}-benzamide:

[0933] A 4 mL scintillation vial was charged with (5-chloro-2-{4-[2-(4-chloro-5-methyl-3-
trifluoromethyl-pyrazol-1-yl)-acetyl]-pipera2in-1-yl}-4-methoxy-phenyl)-oxo-acetonitrile(82
mg, 0.163 mmol), a catalytic quantity of dimethylaminopyridine, ammonia (0.813 mL, 2.0 M
in MeOH), and methylene chloride (0.8 mL). The resultant solution was stirred 5 h,
concentrated in vacuo, and purified by reverse phase HPLC to afford the title compound: MS
(ES) M+H expect 494.1, found 494.1; HPLC R, = 4.26 minutes, using the following method:
(Agilent Zorbax SB-C18,2.1X50 mm, 5u, 35°C) using a 4.5 minute gradient of 20% to 95%
B with a l.l minute wash at 95% B (A = 0.1% formic acid / 5% acetonitrile / 94.9% water, B
= 0.08% formic acid / 99.9% acetonitrile).
Synthesis of S-chloro-2-{4-[2-(4-chIoro-5-methyl-3-trifluoromethyl-pyrazoi-1-yl)-aceryl]-
piperazin-1-yl}-4-methoxy-N-methyl-benzamide:

[0934] Following Protocol SS, using methylamine, gave the title compound: MS (ES) M+H
expect 508.1, found 508.1; HPLC Rt= 4.44 min.

Synthesis of 5-chloro-2-{4-[2-(4-chIoro-5-methyI-3-trifluoromethyl-pyrazol-1-yl)-acetyI]-
piperazin-1-yl}-4-methoxy-N^N-dimethyl-benzamide:

[0935] Following Protocol SS, using dimethylamine, gave the title compound; MS (ES)
M+H expect 522.1, found 522.1; HPLC Rt= 4.46 min.
Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetylI-
piperazin-1-yI}-N-ethyl-4-methoxy-benzamide

[0936] Following Protocol SS, using ethylamine, gave the title compound: MS (ES) M+H
expect 522.1, found 522.1; HPLC Rt= 4.66 min.
Synthesis of l-{4-[4-chIoro-5-methoxy-2-(pyrrolidine-1-carbonyI)-phenyl]-piperazm-1-
yl}-2-(5-methyl-4-phenyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0937] Following Protocol SS, using pyrrolidine, gave the title compound: MS (ES) M+H
expect 548.1, found 548.1; HPLC R, = 4.64 min.

Synthesis of l-{4-[4-chloro-5-methoxy-2-(morphoIine-4-carbonyl)-phenyl]-piperazin-1-
yl}-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yI)-ethanone

[0938] Following Protocol SS, using morpholine, gave the title compound: MS (ES) M+H
expect 564.15 found 564.1; HPLC R, = 4.42 min.
Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-
piperazin-1-yi}-4-methoxy-N-(2-methoxy-ethyl)-benzamide:

[09391 Following Protocol SS, using 2-methoxyIethylamine, gave the title compound: MS
(ES) M+H expect 552.1, found 552.1; HPLC Rt= 4.66 min.
Synthesis of 5-chloro-2-{4-[2-(4-chIoro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-
piperazin-1-yl}-4-methoxy-N-(2-morphoIin-4-yI-ethyI)-benzamide

[0940] Following Protocol SS, using 2-N-Morpholino-ethylamine, gave the title
compound: MS (ES) M+H expect 607.2, found 607.2; HPLC R, = 3.47 min.

Synthesis of l-{4-[4-chloro-5-methoxy-2-(4-pynmidin-2-yI-piperazine-1-carbonyl)-
pfaenyI]-piperazin-1-yI}-2-(4-chIoro-5-methyl-3-trifluoromethyI-pyrazoI-1-yI)-ethanone

[0941] Following Protocol SS, using l-(2-pyridyl)piperazine, gave the title compound: MS
(ES) M+H expect 641.2, found 641.1; HPLC R,= 4.77 mia
Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-
piperazin-1-yl}-4-methoxy-N-(2-pyridin-2-yl-ethyl)-benzamide

[0942] Following Protocol SS, using 2-(2-aminoethyl)pyridine, gave the title compound:
MS (ES) M+H expect 599.2, found 599.1; HPLC B«- 3.75 min.
Synthesis of l-{4-[4-chloro-5-raethoxy-2-(4-pyridin-4-yl-piperazine-1-carbonyl)-phenyl]-
piperazin-1-yI}-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

[0943] Following Protocol SS, using l-(4-pyridyl)piperazine, gave the title compound: MS
(ES) M+H expect 640.2, found 640.1; HPLC Rt= 3.61 min.

Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-y])-acetyIJ-
piperazin-1-yl}-N-(3-imidazol-1-yl-propyl)-4-methoxy-benzamide

[0944] Following Protocol SS, using 1 -(3-aminopropyl)imidazole, gave the title compound:
MS (ES) M+H expect 602.2, found 602.1; HPLC Rt= 3.41 min.
Synthesis of 5-chloro-2-{4-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-y])-acetyl]-
piperazin-1-yl}-4-methoxy-benzoic acid methyl ester:

[0945] Following a variant of Protocol P, a solution of 5-chloro-4-methoxy-2-piperazin-1 -
yl-benzoic acid methyl ester (183 mg, 0.642 mmol), (4-chloro-5-methyl-3-trifluoromethyl-
pyrazol-1 -yl)-acetic acid (218 mg, 0.899 mmol), and triethylamine (0.45 mL, 3.21 mmol) in
methylene chloride (5 mL) at 0°C was added BOP (397 mg, 0.899 mmol) in one portion.
After stirring 15 min at 0°C and then 165 min at room temperature, the solvent was removed
in vacuo. The resultant residue was partitioned between ether and saturated sodium
bicarbonate, and the aqueous layer extracted with ether (3 X 25 mL) and ethyl acetate (3 X 25
mL). The combined organics were dried with Na2SO4, concentrated in vacuo, and the
resultant crude product was purified via silica gel chromatography (30:70 EtOAc:hexanes) to
afford 188 mg (57% yield) of the target amide as a white solid.
Synthesis of 4-(4-chloro-3-methoxy-phenyl)-2-(R)-formyl-piperazine-1-carboxylic acid
tert-butyl ester


[0946] To a solution of 4-(4-chloro-3-methoxy-phenyl)-2-(R)-hydroxymethyl-piperazine-1 -
carboxylic acid tert-butyl ester (1.10 g, 2.08 mmol) in methylene chloride (30 mL) at 0°C
was added the Dess-Martin Periodinane (16 mL, 0.25 M) dropwise. The resultant solution
was stirred 1 h at 0°C, 1 h at room temperature, and then quenched with saturated sodium
thiosulfate and saturated sodium bicarbonate. The aqueous layer was subsequently extracted
with ethyl acetate (3 X 30 mL), the combined organics dried with sodium sulfate, and the
solvent removed in vacuo. The residue was purified via column chromatography to afford
498 mg (46%) of the desired aldehyde.
PROTOCOL TT; Synthesis of compounds via epoxide formation and ring-opening
reactons.
Synthesis of (4-Chloro-3-isopropenyl-5-methyl-pyrazol-1-yl)-acetic acid ethyl ester

[0947] 1.3 g [4-Chloro-3-(l-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]-acetic acid
ethyl ester and 15 ml Benzene with catalytic amount of p-TSA was reflux with a Dean-Stark
overnight. Washed with water, dry over MgSC>4 and removed the solvent. Purified by
normal phase column (Column: 25g silica gel, 0%-10% EtOAc/Hexane) to give 0.4g above
title product. HPLC retention time = 5.3 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u,
35°C) using a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A =
0.1% formic acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9%
acetonitrile); MS (ES) M+H expect = 243.1, found = 243.1. !H NMR (CDC13,400MHz)
5.80 (d, 1H), 5.25(m, 1H), 4.81 (s, 2H), 4.2 (q, 2H), 2.21 (s, 3H), 2.13(m, 3H)ppm, 1.57 (s,
2H), 1.29(t,3H)ppm.

Synthesis of [4-Chloro-3-(l,2-dihydroxy-1-methyI-ethyl)-5-methyl-pyrazol-1-yl]-acetic
acid

[0948] To 0.4g (4-Chloro-3-isopropenyI-5-methyI-pyrazol-1-yl)-acetic acid ethyl ester
dissolved in DCM, 1.3eq of 3-Chloro-peroxybenzoic acid was added at ambient temperature.
After 3 hours, 1.3 eq. of NaHCC>3 was added. After stirring 2 more hours, more DCM was
added, the mixture was washed with Sat. NaHCCb, Brine, and dried over MgSCv After
filtration, removed solvent in vacuo to give 0.5 g of the crude epoxide.
[0949] The crude epoxide, 3ml THF, 1 ml MeOH and 0.6 ml 1 N NaOH were combined,
and stirred overnight. The mixture was neutralized to PH 5-6, most of the solvent was
removed in vacuo, and the residue was partitioned between water and ethyl acetate, and the
phases were separated. The aqueous phase was lyophilized to give the title compound:
HPLC retention time = 0.35 minutes (Agilent Zorbax SB-C18, 2.1X50 mm, 5u, 35°C) using
a 4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B (A = 0.1% formic
acid / 5% acetonitrile / 94.9% water, B = 0.08% formic acid / 99.9% acetonitrile); MS (ES)
M-H expect = 247.1, found = 246.9.

EXAMPLE 4
[0950] This example illustrates the activity associated with representative compounds of
the invention.
MATERIALS AND METHODS
A. Cells
1. CCR1 expressing cells
a) THP-1 cells
[0951] THP-1 cells were obtained from ATCC (TIB-202) and cultured as a suspension in
RPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5
g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate, 0.05% 2-mercaptoethanol and 10%
FBS. Cells were grown under 5% CO2/95% air, 100% humidity at 37°C and subcultured
twice weekly at 1:5 (cells were cultured at a density range of 2 x 105 to 2 x 106 cells/mL) and
harvested at 1 x 106 cells/mL. THP-1 cells express CCR1 and can be used in CCR1 binding
and functional assays.
b) Isolated human monocytes
[0952] Monocytes were isolated from human buffy coats using the Miltenyi bead isolation
system (Miltenyi, Auburn, CA). Briefly, following a Ficoll gradient separation to isolate
peripheral blood mononuclear cells, cells were washed with PBS and the red blood cells
lysed using standard procedures. Remaining cells were labeled with anti-CD14 antibodies
coupled to magnetic beads (Miltenyi Biotech, Auburn, CA). Labeled cells were passed
through AutoMACS (Miltenyi, Auburn, CA) and positive fraction collected. Monocytes
express CCR1 and can be used in CCR1 binding and functional assays.

B. Assays
1. Inhibition of CCR1 ligand binding
[0953] CCR1 expressing cells were centrifuged and resuspended in assay buffer (20 mM
HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, and with 0.2% bovine serum
albumin) to a concentration of 5 x 106 cells/mL for THP-1 cells and 5 x 105 for monocytes.
Binding assays were set up as follows. 0.1 mL of cells (5 x 105 THP-1 cells/well or 5 x 104
monocytes) was added to the assay plates containing the compounds, giving a final
concentration of ~2-10 uM each compound for screening (or part of a dose response for
compound IC50 determinations). Then 0.1 mL of ,25I labeled MlP-la (obtained from Perkin
Elmer Life Sciences, Boston, MA) or 0.1 mL of 125I labeled CCL15/leukotactin (obtained as
a custom radiolabeling by Perkin Elmer Life Sciences, Boston, MA) diluted in assay buffer to
a final concentration of ~50 pM, yielding ~30,000 cpm per well, was added (using 125I
labeled MlP-la with THP-1 cells and 125I labeled CCL15/leukotactin with monocytes), the
plates sealed and incubated for approximately 3 hours at 4°C on a shaker platform. Reactions
were aspirated onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution,
on a vacuum cell harvester (Packard Instruments; Meriden, CT). Scintillation fluid (40 ul;
Microscint 20, Packard Instruments) was added to each well, the plates were sealed and
radioactivity measured in a Topcount scintillation counter (Packard Instruments). Control
wells containing either diluent only (for total counts) or excess MlP-la or MIP-lp (1 ng/mL,
for non-specific binding) were used to calculate the percent of total inhibition for compound.
The computer program Prism from GraphPad, Inc. (San Diego, Ca) was used to calculate
IC50 values. IQo values are those concentrations required to reduce the binding of labeled
MlP-la to the receptor by 50%. . (For further descriptions of ligand binding and other
functional assays, see Dairaghi, et al., J. Biol. Chem. 274:21569-21574 (1999), Penfold, et
al., Proc. Natl. Acad. Sci. USA. 96:9839-9844 (1999), and Dairaghi, et al,. J. Biol. Chem.
272:28206-28209 (1997)).
2. Calcium mobilization
[0954] To detect the release of intracellular stores of calcium, cells (THP-1 or monocytes)
were incubated with 3 uM of INDO-1 AM dye (Molecular Probes; Eugene, OR) in cell media
for 45 minutes at room temperature and washed with phosphate buffered saline (PBS). After

INDO-1 AM loading, the cells were resuspended in flux buffer (Hank's balanced salt solution
(HBSS) and 1% FBS). Calcium mobilization was measured using a Photon Technology
International spectrophotometer (Photon Technology International; New Jersey) with
excitation at 350 nm and dual simultaneous recording of fluorescence emission at 400 nm and
490 nm. Relative intracellular calcium levels were expressed as the 400 nm/490 nm emission
ratio. Experiments were performed at 37°C with constant mixing in cuvettes each containing
106 cells in 2 mL of flux buffer. The chemokine ligands may be used over a range from 1 to
100 nM. The emission ratio was plotted over time (typically 2-3 minutes). Candidate ligand
blocking compounds (up to 10 µM) were added at 10 seconds, followed by chemokines at 60
seconds (i.e., MIP-1α; R&D Systems; Minneapolis, MN) and control chemokine (i.e., SDF-
1α; R&D Systems; Minneapolis, MN) at 150 seconds.
3. Chemotaxis assays
[0955] Chemotaxis assays were performed using 5 m pore polycarbonate,
polyvinylpyrrolidone-coated filters in 96-well chemotaxis chambers (Neuroprobe;
Gaithersburg, MD) using chemotaxis buffer (Hank's balanced salt solution (HBSS) and 1%
FBS). CCR1 chemokine ligands (i.e., MlP-1α, CCL15/Leukotactin; R&D Systems;
Minneapolis, MN) are use to evaluate compound mediated inhibition of CCR1 mediated
migration. Other chemokines (i.e., SDF-1α; R&D Systems; Minneapolis, MN) are used as
specificity controls. The lower chamber was loaded with 29 µl of chemokine (i.e., 0.1 nM
CCL15/Leukotactin) and varying amounts of compound; the top chamber contained 100,000
THP-1 or monocyte cells in 20 ul. The chambers were incubated 1-2 hours at 37°C, and the
number of cells in the lower chamber quantified either by direct cell counts in five high
powered fields per well or by the CyQuant assay (Molecular Probes), a fluorescent dye
method that measures nucleic acid content and microscopic observation.
IDENTIFICATION OF INHIBITORS OF CCR1
A. Assay
[0956] To evaluate small organic molecules that prevent the receptor CCR1 from binding
ligand, an assay was employed that detected radioactive ligand (i.e, MIP-1α or
CCL15/Leukotactin) binding to cells expressing CCR1 on the cell surface (for example,

THP-1 cells or isolated human monocytes). For compounds that inhibited binding, whether
competitive or not, fewer radioactive counts are observed when compared to uninhibited
controls.
[0957] THP-1 cells and monocytes lack other chemokine receptors that bind the same set of
chemokine ligands as CCR1 (i.e., MIP-1α, MPIF-1, Leukotactin, etc.). Equal numbers of
cells were added to each well in the plate. The cells were then incubated with radiolabeled
MlP-1α. Unbound ligand was removed by washing the cells, and bound ligand was
determined by quantifying radioactive counts. Cells that were incubated without any organic
compound gave total counts; non-specific binding was determined by incubating the cells
with unlabeled ligand and labeled ligand. Percent inhibition was determined by the equation:

B. Inhibitors from a compound library identified using CCR1 expressing
cells
[0958] In a screen of a set of compounds, the normalized standard deviation was 17%,
indicating that inhibitory activity of 34% or more was significant; again, a 40% threshold was
used. These pooled compound plates yielded 39 wells that exhibited greater than 40%
inhibition of MIP-1α binding. When screened a second time as pooled compound plates, 14
of these wells decreased ligand by greater than 40%. To determine which of the compounds
in each well inhibited CCR1 ligation of MIP-la, the pools were deconvoluted by testing each
of the compounds individually for inhibitory activity in the assay. Because some compounds
may act together to inhibit binding and deconvolution assays only tested compounds
individually, compounds that were effective in combination but not singly were not found in
this experiment. Testing the compounds singly identified inhibitory candidates:
C. Inhibitor from compound library identified using CCRl-expressing cells
[0959] CCX-105 was identified from the compound screening effort.


1. Dose Response Curves
[0960] To ascertain a candidate compound's affinity for CCR1 as well as confirm its ability
to inhibit ligand binding, inhibitory activity was titered over a 1 x 10-10 to 1 x 10-4 M range of
compound concentrations. In the assay, the amount of compound was varied; while cell
number and ligand concentration were held constant. Compound CCX-105 was titered and
found to be a potent inhibitor of CCR1 specific chemokine binding (see Table, for compound
1.001).
2. CCR1 functional assays
[0961] CCR1 is a seven transmembrane, G-protein linked receptor. A hallmark of
signaling cascades induced by the ligation of some such receptors is the pulse-like release of
calcium ions from intracellular stores. Calcium mobilization assays were performed to
determine if the candidate CCR1 inhibitory compounds were able to also block aspects of
CCR1 signaling. Candidate compounds able to inhibit ligand binding and signaling with an
enhanced specificity over other chemokine and non-chemokine receptors were desired.
[0962] Calcium ion release in response to CCR1 chemokine ligands (i.e., MIP-1α, MPIF-1,
Leukotactin, etc.) was measured using the calcium indicator INDO-1. THP-1 cells or
monocytes were loaded with INDO-1/AM and assayed for calcium release in response to
CCR1 chemokine ligand (i.e., MIP-1α) addition. To control for specificity, non-CCRl
ligands, specifically bradykinin, was added, which also signals via a seven transmembrane
receptor. Without compound, a pulse of fluorescent signal will be seen upon MIP-1α
addition. If a compound specifically inhibits CCR1-MIP-1α signaling, then little or no signal
pulse will be seen upon MIP-1α addition, but a pulse will be observed upon bradykinin

addition. However, if a compound non-specifically inhibits signaling, then no pulse will be
seen upon both MIP-1α and bradykinin addition.
[0963] As shown below, CCX-105 was able to significantly and specifically inhibit
signaling from CCR1.

[0964] One of the primary functions of chemokines is their ability to mediate the migration
of chemokine receptor-expressing cells, such as white blood cells. To confirm that CCX-105
inhibited not only CCR1 specific binding and signaling (at least as determined by calcium
mobilization assays), but also CCR1 mediated migration, a chemotaxis assay was employed.
THP-1 myelomonocytic leukemia cells, which resemble monocytes, as wells as freshly
isolated monocytes, were used as targets for chemoattraction by CCR1 chemokine ligands
(i.e., MIP-1α, CCL15/Ieukotactin). Cells were place in the top compartment of a microwell
migration chamber, while MEP-1α (or other potent CCR1 chemokine ligand) and increasing
concentrations of CCX-105 or other candidate compound was loaded in the lower chamber.
In the absence of inhibitor, cells will migrate to the lower chamber in response to the
chemokine agonist; if a compound inhibited CCR1 function, then the majority of cells will
remain in the upper chamber. To ascertain a candidate compound's affinity for CCR1 as well
as to confirm its ability to inhibit CCR1 mediated cell migration, inhibitory activity was
titered over a 1 x 10-10 to 1 x 10-4 M range of compound concentrations in this chemotaxis
assay. In this assay, the amount of compound was varied; while cell number and chemokine
agonist concentrations were held constant. After the chemotaxis chambers were incubated 1-
2 hours at 37°C, the responding cells in the lower chamber were quantified by labeling with
the CyQuant assay (Molecular Probes), a fluorescent dye method that measures nucleic acid
content, and by measuring with a Spectrafluor Plus (Tecan). The computer program Prism
from GraphPad, Inc. (San Diego, Ca) was used to calculate IC50 values. IC50 values are
those compound concentrations required to inhibit the number of cells responding to a CCR1
agonist by 50%.

3. In Vivo Efficacy
rabbit model of destructive joint inflammation
[0965] A study was conducted to evaluate the effects of CCX-105 on inhibiting the
inflammatory response of rabbits to an intra-articular injection of the bacterial membrane
component lipopolysaccharide (LPS). This study design mimics the destructive joint
inflammation seen in arthritis. Intra-articular injection of LPS causes an acute inflammatory
response characterized by the release of cytokines and chemokines, many of which have been
identified in rheumatoid arthritic joints. Marked increases in leukocytes occur in synovial
fluid and in synovium in response to elevation of these chemotactic mediators. Selective
antagonists of chernokine receptors have shown efficacy in this model (see Podolin, et al., J.
Immunol. 169(ll):6435-6444 (2002)).
[0966] In a rabbit LPS study conducted essentially as described in Podolin, et al. ibid.,
female New Zealand rabbits (approximately 2 kilograms) were treated intra-articularly in one
knee with LPS (10 ng) together with either vehicle only (phosphate buffered saline with 1 %
DMSO) or with addition of CCX-105 (dose 1 = 50 uM or dose 2 = 100 uM) in a total volume
of 1.0 mL. Sixteen hours after the LPS injection, knees were lavaged and cells counts
performed. Beneficial effects of treatment were determined by histopathologic evaluation of
synovial inflammation. The following inflammation scores were used for the histopathologic
evaluation: 1 - minimal, 2 - mild, 3 - moderate, 4 - moderate-marked. As shown below,
CCX-105 was able to significantly and specifically inhibit the inflammatory response in this
in vivo assay.

Evaluation of compound 1.028 in a rat model of collagen induced arthritis
[0967] A 17 day developing type II collagen arthritis study was conducted to evaluate the
effects of compound 1.028 on arthritis induced clinical ankle swelling. Rat collagen arthritis
is an experimental model of polyarthritis that has been widely used for preclinical testing of
numerous anti-arthritic agents (see Trentham, et al., J. Exp. Med. 146(3):857-868 (1977),


Bendele, et al., Toxicologic Pathol. 27:134-142 (1999), Bendele, et al., Arthritis Rheum.
42:498-506 (1999)). The hallmarks of this model are reliable onset and progression of
robust, easily measurable polyarticular inflammation, marked cartilage destruction in
association with pannus formation and mild to moderate bone resorption and periosteal bone
proliferation.
[0968] Female Lewis rats (approximately 0.2 kilograms) were anesthetized with isoflurane
and injected with Freund's Incomplete Adjuvant containing 2 mg/mL bovine type II collagen
at the base of the tail and two sites on the back on days 0 and 6 of this 17 day study.
Compound 1,028 was dosed daily in a sub-cutaneous manner from day 0 till day 17 at a dose
of 25 mg/kg and a volume of 1 mL/kg in the following vehicle (20% N,N-dimethylacetamide,
75% corn oil, 5% Tween-80). Caliper measurements of the ankle joint diameter were taken,
and reducing joint swelling was taken as a measure of efficacy. As shown below, compound
1.028 was able to significantly and specifically inhibit the arthritis induced ankle swelling in
this in vivo assay.

[0969] In the table below, structures and activity are provided for representative
compounds described herein. Activity is provided as follows for either or both of the
cherooraxis assay and/or binding assay, described above: +, IC50 > 12.5 µM; ++, 2500 nM IC50

















































































































[0970] It is understood that the examples and embodiments described herein are for
illustrative purposes only and that various modifications or changes in light thereof will be
suggested to persons skilled in the art and are to be included within the spirit and purview of
this application and scope of the appended claims. All publications, patents, and patent
applications cited herein are hereby incorporated by reference for all purposes.

WE CLAIM :
1. A compound selected from the group consisting of:












2. A compound selected from the group consisting of:




and

3. A compound selected from the group consisting of:








4. A compound selected from the group consisting of:



5. The compound as claimed in claim 1 having the formula :


6. The compound as claimed in claim 4 having the formula :

7. The compound as claimed in claim 4 having the formula :


The present invention provides compounds having formula (I) :

wherein the variables are as defined in the specification. The compounds act as potent antagonists
of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are useful in
pharmaceutical compositions, methods for the treatment of CCR1 - mediated diseases, and as
controls in assays for the identification of competitive CCR1 antagonists. The present invention
provides alternative solutions in the treatment of diseases mediated by CCR1 signaling.

Documents:

01882-kolnp-2006 abstract.pdf

01882-kolnp-2006 claims.pdf

01882-kolnp-2006 correspondence others.pdf

01882-kolnp-2006 description(complete).pdf

01882-kolnp-2006 drawings.pdf

01882-kolnp-2006 form-1.pdf

01882-kolnp-2006 form-3.pdf

01882-kolnp-2006 form-5.pdf

01882-kolnp-2006 international publication.pdf

01882-kolnp-2006 international search authority report.pdf

01882-kolnp-2006 priority document.pdf

01882-kolnp-2006-correspondence others-1.1.pdf

01882-kolnp-2006-correspondence1.2.pdf

01882-kolnp-2006-form-18.pdf

01882-kolnp-2006-form-3-1.1.pdf

01882-kolnp-2006-priority document-1.1.pdf

01882-kolnp-2006-priority document.pdf

1882-KOLNP-2006-ABSTRACT.pdf

1882-kolnp-2006-assignment.pdf

1882-KOLNP-2006-CANCELLED PAGES.pdf

1882-KOLNP-2006-CLAIMS.pdf

1882-kolnp-2006-correspondence.pdf

1882-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

1882-KOLNP-2006-DRAWINGS.pdf

1882-kolnp-2006-examination report.pdf

1882-kolnp-2006-form 13-1.1.pdf

1882-KOLNP-2006-FORM 13.pdf

1882-kolnp-2006-form 18.pdf

1882-KOLNP-2006-FORM 2.pdf

1882-kolnp-2006-form 3-1.1.pdf

1882-KOLNP-2006-FORM 3.pdf

1882-kolnp-2006-form 5.pdf

1882-KOLNP-2006-FORM-27.pdf

1882-kolnp-2006-gpa.pdf

1882-kolnp-2006-granted-abstract.pdf

1882-kolnp-2006-granted-claims.pdf

1882-kolnp-2006-granted-description (complete).pdf

1882-kolnp-2006-granted-drawings.pdf

1882-kolnp-2006-granted-form 1.pdf

1882-kolnp-2006-granted-form 2.pdf

1882-kolnp-2006-granted-specification.pdf

1882-kolnp-2006-others-1.1.pdf

1882-KOLNP-2006-OTHERS.pdf

1882-KOLNP-2006-PA.pdf

1882-KOLNP-2006-PETITION UNDER RULE 137.pdf

1882-kolnp-2006-reply to examination report-1.1.pdf

1882-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 247403
Indian Patent Application Number 1882/KOLNP/2006
PG Journal Number 14/2011
Publication Date 08-Apr-2011
Grant Date 05-Apr-2011
Date of Filing 06-Jul-2006
Name of Patentee CHEMOCENTRYX, INC.
Applicant Address 850 MAUDE AVENUE, MOUNTAIN VIEW CALIFORNIA
Inventors:
# Inventor's Name Inventor's Address
1 CHEN, WEI 37200 PASEO PADRE PKWY., APT.262, FREMONT, CALIFORNIA 94536
2 PENNELL, ANDREW, M.,, K. 148 HANCOCK STREET, SAN FRANCISCO CA 94114
3 WRIGHT, J., J., KIM 720 BAIR ROAD APT. 107, REDWOOD CITY CALIFORNIA 94063
4 SEN, SUBHABRATA 655 S. FAIROAKS AVENUE, #P-204, SUNNYVALE, CALIFORNIA 94086
5 MCMASTER, BRIAN, E. 120 WALKER DRIVE, MOUNTAIN VIEW CALIFORNIA 94043
6 DAIRAGHI, DANIEL, JOSEPH 178 EL DORADO AVENUE, PALO ALTO CALIFORNIA 94306
7 ZHANG, PENGLIE 251 WINCHESTER COURT, FOSTER CITY CALIFORNIA 94404
8 AGGEN, JAMES B. 1311 CALIFORNIA DRIVE, BURLINGAME CALIFORNIA 94010
PCT International Classification Number C07D231/12
PCT International Application Number PCT/US2004/041509
PCT International Filing date 2004-12-08
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/979,882 2004-11-01 U.S.A.
2 10/732,897 2003-12-09 U.S.A.