U.S. patent application number 10/989764 was filed with the patent office on 2005-10-20 for modulators of chemokine receptor activity.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Colon-Cruz, Roberto, Didiuk, Mary T., Duffy, Erin M., Garigipati, Ravi, Lau, Wan F., McDonald, Wayne S..
Application Number | 20050234090 10/989764 |
Document ID | / |
Family ID | 23046277 |
Filed Date | 2005-10-20 |
United States Patent
Application |
20050234090 |
Kind Code |
A1 |
Colon-Cruz, Roberto ; et
al. |
October 20, 2005 |
Modulators of chemokine receptor activity
Abstract
Chemokine receptor antagonists, in particular, bicyclic diamine
compounds of Formula (I) that act as antagonists of chemokine CCR2
and CCR3 receptors including pharmaceutical compositions and uses
thereof to treat or prevent diseases associated with monocyte
accumulation, lymphocyte accumulation or leucocyte accumulation are
described herein. 1
Inventors: |
Colon-Cruz, Roberto;
(Groton, CT) ; Didiuk, Mary T.; (Groton, CT)
; Duffy, Erin M.; (Deep River, CT) ; Garigipati,
Ravi; (South Glastonbury, CT) ; Lau, Wan F.;
(Noank, CT) ; McDonald, Wayne S.; (East Lyme,
CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
23046277 |
Appl. No.: |
10/989764 |
Filed: |
November 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10989764 |
Nov 15, 2004 |
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10093273 |
Mar 6, 2002 |
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6821964 |
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60273984 |
Mar 7, 2001 |
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Current U.S.
Class: |
514/300 ;
514/412; 546/113; 548/453 |
Current CPC
Class: |
A61P 17/04 20180101;
A61P 17/06 20180101; A61P 19/02 20180101; A61P 17/02 20180101; A61P
11/02 20180101; A61P 9/00 20180101; A61P 9/10 20180101; A61P 37/02
20180101; A61P 13/12 20180101; A61P 43/00 20180101; A61P 29/00
20180101; A61P 1/02 20180101; A61P 17/00 20180101; A61P 25/00
20180101; C07D 487/04 20130101 |
Class at
Publication: |
514/300 ;
514/412; 546/113; 548/453 |
International
Class: |
C07D 471/02; A61K
031/407; A61K 031/4745 |
Claims
1. A compound having the formula (I) 49wherein A is a substituted
or unsubstituted (C.sub.1-C.sub.6)alkyl, substituted or
unsubstituted (C.sub.2-C.sub.6)alkenyl, substituted or
unsubstituted partially saturated or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, substituted or unsubstituted partially
saturated or fully saturated 5 to 6 membered heterocyclic ring,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl group; a is 0, 1, 2 or 3; w, x, y and z are each
independently 0, 1, 2, 3 or 4, with the proviso that (i) w is not 0
when x is 0; (ii) y is not 0 when z is 0; (iii) x is not 0 when w
is 1, y is 0 and z is 1; (iv) x is not 0 when w is 1, z is 0 and y
is 1; (v) x is not 0 when y is 0; (vi) w is not 0 when z is 0;
(vii) w+x is less than 8; and (viii) y+z is less than 8; p is 0 or
1; L is a linking group selected from the group consisting of
--(CH.sub.2).sub.q--X--, where X is NH, O, or oxo and q is an
integer from 1 to 4 , --S(O).sub.r--(CH.sub.2).sub.t--- NH--, where
r is 0, 1 or 2 and t is integer from 1 to 4, -(aryl)-NH--,
-(heteroaryl)-NH--, and an amino acid residue where the amino
nitrogen of said amino acid residue is attached to B and the
carbonyl of said amino acid residue is attached to the ring
nitrogen; and B is a substituted or unsubstituted
(C.sub.1-C.sub.6)alkylcarbonyl, substituted or unsubstituted
arylcarbonyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkoxy-carbonyl, substituted or unsubstituted
aryloxycarbonyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkylsulfo- nyl, substituted or unsubstituted
arylsulfonyl, substituted or unsubstituted (C.sub.1-C.sub.6)
alkylthiocarbonyl, substituted or unsubstituted arylthiocarbonyl,
substituted or unsubstituted (C.sub.1-C.sub.6)alkyl-carbamoyl,
substituted or unsubstituted arylcarbamoyl, substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl-C(.dbd- .NH)--, substituted or
unsubstituted aryl-C(.dbd.NH)--, or a protecting group; a prodrug
thereof, or a pharmaceutically acceptable salt, hydrate, or solvate
of the compound or the prodrug.
2-28. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/273984 filed Mar. 7, 2001, which is
incorporated in its entirety herein by reference
FIELD OF THE INVENTION
[0002] The present invention relates to chemokine receptor
antagonists, in particular, bicyclic diamine compounds that act as
antagonists of chemokine CCR2 and CCR3 receptors including
pharmaceutical compositions and uses thereof to treat or prevent
diseases associated with monocyte accumulation, lymphocyte
accumulation or leucocyte accumulation.
BACKGROUND
[0003] The local production and secretion of a family of 8-10KD
chemotactic cytokines (called chemokines) mediate the local
accumulation of inflammatory cells in many pathological
inflammatory and autoimmune disease states. Chemokines have been
found to be highly expressed in a variety of pathological states,
including atherosclerosis, pulmonary fibrosis, asthma, psoriasis
and rheumatoid arthritis, coinciding with the chronic macrophage
accumulation of inflamed tissue (see, e.g., Barker, J. N., et al.,
J. Immunol, 146,1192 (1991); Koch, A. E. J. Clin. Invest, 90, 772
(1996); Nelken, N. A., et al., J. Clin. Invest, 88, 1121 (1991);
Gong, J. H., J. Exp. Med., 186, 131 (1997); Yla-Herttuala, S., et
al., Proc. Natl., Acad. Sci., 88, 5252 (1991); Rovin, B. H., et
al., Am. J. Kidney Dis., 31, 1065 (1998); and Gong, J. H. et al.,
J. Exp. Med, 186, 131 (1997)). Continuous local release of
chemokines at sites of inflammation mediates the excessive
migration of effector cells in chronic inflammation. Thus, blocking
leukocyte recruitment to target tissues by inhibiting chemokine
activity in inflammatory and autoimmune disease would be an
effective therapeutic intervention.
[0004] The chemoattractant chemokines belong to a super family of
pro-inflammatory mediators that promote the recruitment of multiple
lineages of leukocytes and lymphocytes. The human chemokine
polypeptides are 70-80 residues in length that share substantial
sequence homology. These polypeptides share a common structural
motif: a conserved set of four cysteine residues. Based on the
position of the first two or four cysteine residues and the
chromosomal location of the corresponding genes, two main chemokine
families, CC and CXC, have been identified. Members of the CXC
subfamily attract mainly neutrophils, except for platelet factor 4
(PF4) and gamma interferon inducible protein (IP10). The CC
chemokines attract mainly monocytes, eosinophils, and lymphocytes
but may also attract T lymphocytes. Monocyte chemoattractant
protein-1 (MCP-1) is a member of the CC chemokine family that is a
potent chemotactic and activating factor for monocytes and memory T
cells. The other members of the of the CC chemokine family, MCP-2,
MCP-3, MCP-4, MCP-5, macrophage inflammatory protein
(MIP)-1.alpha., MIP-1.beta., RANTES (regulated on activation,
normal T cell expressed and secreted) and eotaxin also mediate
chemotaxis in distinct but overlapping leukocyte subsets.
[0005] The molecular targets for chemokines are their cell surface
receptors that belong to the seven-transmembrane helix (STH),
G-protein coupled receptors. This type of receptor consists of a
single polypeptide chain with an extracellular amino-terminal
domain and a cytoplasmic-terminal domain. The amino terminal and
the third extracellular domain are important for receptor ligand
interaction. The third intracellular loop (50-75 amino acids long)
interacts directly with G-proteins. At least five CC chemokine
receptors have been identified (CCR1-CCR5) and all five CC
receptors belong to the STH G-coupled protein receptor family. Each
of these receptors mediates the binding and signaling of more than
one chemokine. For example, the CCR1 receptor is specific for MIP-1
.alpha., RANTES, and MCP-3. CCR2B recognizes both MCP-1 and MCP-3;
CCR3 is expressed on eosinophils and recognizes eotaxin; and CCR4
is found on basophils and responds to MIP1-.alpha., RANTES and
MCP-1. The MCP-1 receptor CCR2b signals through multiple G-proteins
including G.alpha.l, G.alpha.q, and G.alpha.16. See, e.g.,
Monteclaro, F. S., J. Biol. Chem., 37, 23186 (1997). Thus, in
addition to promoting the transmigration and emigration of
circulating monocytes into tissues, MCP-1 interaction with the CCR2
receptor increases histamine release, calcium influx, cAMP
activation, increases integrin expression and acts as a chemotactic
factor for monocytes/macrophages. For further discussions, see
Rollins, B. J., Blood, 78, 112 (1991); Neote, K., et al., Cell, 72,
415 (1993); Charo, I. F., et al., Proc Natl., Acad. Sci. USA, 91,
2752 (1994).
[0006] Various cell types including endothelial cells, smooth
muscle cells, macrophages and fibroblasts produce MCP-1 and its
murine homolog JE that was identified initially as a
platelet-derived growth factor inducible gene. Although MCP-1
expression has been documented in a variety of human diseases that
have inflammatory components, including atherosclerosis, multiple
sclerosis, asthma and rheumatoid arthritis among many others, a
direct cause and effect relationship has been difficult to prove.
MCP-1 along with many other chemokines is expressed in many
inflammatory lesions. Direct injection of MCP-1 into rodent's skin
provides only a mild infiltrate or no infiltrate at all. See,
Zachariae, C. O., J. Exp. Med., 171, 2177 (1990). However, MCP-1
has been demonstrated to play a role in atherosclerosis.
Overexpression of MCP-1 by macrophages in apolipoprotein E
deficient mice increases monocytic infiltration and
atherosclerosis. See, Aiello, R. J., et al., Arteriosclero Thromb
Vasc Biol, 19, 1518 (1999). Several studies using MCP-1 transgenic
mice have suggested that the ability of MCP-1 to elicit monocyte
infiltration depends on MCP-1 being expressed at specific sites.
See, Fuentes, M. E., J. Immunology, 155, 5769 (1995). Recently
MCP-1 deficient mice and MCP-1 receptor (CCR2) deficient mice were
shown to have decreased atherosclerotic lesion formation. See,
Boring, L. Nature, 394, 894 (1998).
[0007] Leukocyte entry into tissue involves a cascade of molecular
events including chemotactic signaling to circulating cells,
interaction with endothelial cells and transmigration through
tissues. Significant advances have been made in the identification
of leukocyte adhesion molecules and their cellular and
extracellular matrix legends. Leukocyte-endothelial interactions
occur in several phases which include rolling, firm adhesion and
transmigration. See, Traffic Signals for Lymphocyte Recirculation
and Leukocyte Emigration: The Multistep Paradigm; Springer, Cell,
76,301 (1994). Primarily a specific class of adhesion molecules
mediates each of the phases of adhesion. Integrins are one of the
specific classes and exist as heteromeric-cell surface proteins.
Recent cell culture studies have shown that the expression of
monocyte chemokines MCP-1, MIP-1 .alpha., and RANTES increases the
expression of the .alpha. chain of 2 members of the .beta.2 family
of integrins, CD11a and CD11b. CD11b (one of two subunits of the
CD11b/CD18 (Mac-1, CR3 receptor) .beta.2 integrin) is highly
regulated and is expressed maximally in terminally differentiated
myeloid cells. See, Corbi, A. J., Biol. Chem, 263, 12403 (1988).
Additionally MCP-1 has been reported to selectively activate the
.beta.1 integrin family of leukocyte molecules, suggesting a role
in leukocyte adhesion. See, Woldemar, et al., Immunity, 4, 179
(1996). Thus, in addition to acting as a chemoattractant, MCP-1 may
further potentiate the inflammatory response by promoting integrin
expression and cellular adhesion.
[0008] Chemoattractants appear to be required for the
transendothelial migration both in vivo and in vitro and can induce
many of the steps required for transmigration in vivo. MCP-1 is
also abundantly expressed at the sites of inflammation, antigen
challenge and autoimmune diseases and is an excellent candidate to
inhibit tissue trafficking of monocytes during inflammation and
autoimmune diseases. Therefore, compounds which inhibit the binding
of MCP-1 to the chemokine CCR2 receptor (MCP-1 receptor
antagonists) provide useful leads for drugs that will inhibit the
action of MCP-1 on target cells.
[0009] PCT publications WO 97/44329; WO 99/25686; WO 00/07678; WO
99/07351; WO 99/09984; WO 00/31032; WO 00/35452; WO 99/32468; WO
00/69820; WO 00/69815; and WO 00/69848; WO 00/46195; WO 00/46196;
WO 00/46197; WO 00/46198 and WO 00/46199 describe classes of cyclic
amines and cyclic diamines which reportedly modulate chemokine
receptor activity.
[0010] Homing and activation of eosinophils, basophils, and memory
CD4.sup.+ Th2.sup.+ lymphocytes in lung tissues are considered
important to the etiology of chronic airway inflammatory diseases.
These cells most likely orchestrate asthmatic and allergic
responses by secreting leukotrienes, histamine, and
pro-inflammatory Th2 cytokines such as GM-CSF, IL-3, IL-4, IL-5 and
IL-13. Further evidence for the role of Th2 cytokines comes from
studies with atopic asthmatics where bronchial cytokine expression
correlates with the patient's baseline FEV1, histamine PC.sub.20,
serum IgE levels, and disease severity. Studies in animal asthma
models also support a causative role of eosinophils, basophils and
Th2 cells in disease induction (see, Rothenberg, M. E., Am. J.
Respir., Cell Mol. Biol., 21, 291 (1999)).
[0011] Many chemokines have been shown to mediate the recruitment
and activation of eosinophils, basophils and Th2+ cells, which
express several chemokine receptors during different stages of cell
differentiation and/or activation. For example, eotaxin, eotaxin 2,
MCP-3, MCP-4, and RANTES, which are produced from human lung mast
cells, epithelial cells and macrophages as well as circulating
leukocytes, activate eosinophils, basophils and Th-2 cells through
binding to the cell surface receptor CCR3. See, Kitaura, M., et
al., J. Biol. Chem., 271, 7725 (1996) and Corrigan, C., Current
Opinion Invest. Drugs, 1, 321 (2000). Although they differ in
potency, they have a very similar range of biological actions. See,
Griffiths, J. D. et al., Biochem. Biophys. Res. Commun., 197, 1167
(1993); Jose, P. J. et al., J. Exp. Med., 179, 881 (1994); and
Rothenberg, M. E., New England J. Med., 338. 1592 (1998). Eotaxin
levels are elevated in induced sputum of atopic asthmatics compared
with normal controls. See, Yamada, H. et al., Allergy, 54, 730
(1999). Nasal challenge of eotaxin causes airway eosinophil
infiltration and activation, and produces clinically symptomatic
inflammatory responses in humans. See, Hanazawa, T. et al., J.
Allergy Clin. Immunol., 105, 58 (1999). Animal model studies also
demonstrate that the biological activity of eotaxin is involved in
selective infitration of eosinophils into lungs. In addition, the
antibody against eotaxin and CCR3 partially reduces antigen-induced
pulmonary eosinophilia in a guinea pig model of allergic asthma.
See, Sabroe, I., et al., J. Immunol., 161, 6139 (1998). Similar to
the anti-eotaxin treatment, knockout of CCR3 shows reduced
pulmonary infiltration of eosinophils in allergic mice. Hence,
antagonists of CCR3 provide useful compound leads for the treatment
of chronic inflammatory diseases such as allergy and asthma.
SUMMARY
[0012] The present invention provides a novel class of bicyclic
amine compounds that act as antagonists of chemokine receptors, in
particular CCR2 and CCR3 receptors. The bicyclic amine compounds of
the present invention include the following compounds of Formula
(I): 2
[0013] wherein
[0014] A is a substituted or unsubstituted (C.sub.1-C.sub.6)alkyl,
substituted or unsubstituted (C.sub.2-C.sub.6)alkenyl, substituted
or unsubstituted partially saturated or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, substituted or unsubstituted partially
saturated or fully saturated 5 to 6 membered heterocyclic ring,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl group;
[0015] a is 0, 1, 2 or 3;
[0016] w, x, y and z are each independently 0, 1, 2, 3 or 4, with
the proviso that (i) x is not 0 when w is 0; (ii) y is not 0 when z
is 0; (iii) x is not 0 when w is 1, y is 0 and z is 1; (iv) x is
not 0 when w is 1, z is 0 and y is 1; (v) x is not 0 when y is 0;
(vi) w is not 0 when z is 0; (vii) w+x is less than 8; and (viii)
y+z is less than 8;
[0017] p is 0 or 1;
[0018] L is a linking group selected from the group consisting of
--(CH.sub.2).sub.q--X--, where X is NH, O, or oxo (i.e., keto) and
q is an integer from 1 to 4, --S(O).sub.r--(CH.sub.2).sub.t--NH--,
where r is 0, 1 or 2 and t is an integer from 1 to 4, -(aryl)-NH--
(i.e., The aryl group is attached to the nitrogen of the bicyclic
diamine and the --NH-- group is attached to B. The aryl group may
also contain additional substituents on the aromatic ring.),
-(heteroaryl)-NH-- (i.e., The heteroaryl group is attached to the
nitrogen of the bicyclic diamine and the --NH-- group is attached
to B. The heteroaryl group may also contain additional substituents
on the heteroaromatic ring), and an amino acid residue where the
amino nitrogen of the amino acid residue is attached to B and the
carbonyl of said amino acid residue is attached to the ring
nitrogen; and
[0019] B is a substituted or unsubstituted
(C.sub.1-C.sub.6)alkylcarbonyl, substituted or unsubstituted
arylcarbonyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkoxy-carbonyl, substituted or unsubstituted
aryloxycarbonyl, substituted or unsubstituted
(C.sub.1-C.sub.6)alkylsulfo- nyl, substituted or unsubstituted
arylsulfonyl, substituted or unsubstituted (C.sub.1-C.sub.6)
alkylthiocarbonyl, substituted or unsubstituted arylthiocarbonyl,
substituted or unsubstituted (C.sub.1-C.sub.6)alkyl-carbamoyl,
substituted or unsubstituted arylcarbamoyl, substituted or
unsubstituted (C.sub.1-C.sub.6)alkyl-C(.dbd- .NH)--, substituted or
unsubstituted aryl-C(.dbd.NH)--, or a protecting group (Pg);
[0020] a prodrug thereof, or a pharmaceutically acceptable salt,
hydrate, or solvate of the compound or the prodrug.
[0021] An example of an amino acid residue is a unit having the
following formula 3
[0022] where the .alpha.-amino nitrogen of said amino acid residue
is attached to B;
[0023] R.sup.1 and R.sup.2 are each independently hydrogen,
substituted or unsubstituted (C.sub.1-C.sub.6)alkyl, substituted or
unsubstituted (C.sub.2-C.sub.6)alkenyl, substituted or
unsubstituted partially saturated or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, substituted or unsubstituted partially
saturated or fully saturated 5 to 6 membered heterocyclic ring,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl group; or R.sup.1 or R.sup.2 is taken together with
R.sup.3 to form a 5 to 6 membered ring; or R.sup.1 and R.sup.2 is
taken together to form a 3 to 6 membered ring; and
[0024] R.sup.3 is hydrogen, taken together with a substituent of B
forms a substituted or unsubstituted five or six membered partially
saturated or fully saturated heterocyclic ring (e.g., pyrrolidine,
pyrazole, imidazole, imidazoline, imidazolidine, morpholine,
butyrolactam, valerolactam, piperidine, piperazine,
imidazolidinone, phthalimide, and hydantoin), or taken together
with R.sup.1 or R.sup.2 forms a 5 to 6 membered ring.
[0025] Preferred compounds of formula (I) are those where A is
selected from (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
partially saturated or fully saturated (C.sub.3-C.sub.6)cycloalkyl,
partially saturated or fully saturated 5 to 6 membered heterocyclic
ring, aryl, or heteroaryl group, wherein each of these groups are s
unsubstituted or substituted with one or more groups (preferably 1,
2 or 3 groups) each independently selected from
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, aryl, heteroaryl,
halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy,
(C.sub.1-C.sub.6)alkoxy, aryloxy, sulfhydryl (mercapto),
(C.sub.1-C.sub.6)alkylthio, arylthio, mono- and
di-(C.sub.1-C.sub.6)alkyl amino, quaternary ammonium salts,
amino(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkylthio, cyanoamino, nitro, carbamyl, keto
(oxy), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl,
sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy, and
combinations thereof; a is 1; w and x are 0, 1 or 2; z and y are 0
or 1; p is 1; and L is 4
[0026] where R.sup.3 is hydrogen and R.sup.1 and R.sup.2 are each
independently selected from hydrogen and C.sub.1-C.sub.6 alkyl; and
B is selected from (C.sub.1-C.sub.6)-alkylcarbonyl, arylcarbonyl,
(C.sub.1-C.sub.6)alkoxy-carbonyl, aryloxycarbonyl,
(C.sub.1-C.sub.6)alkylsulfonyl, arylsulfonyl, (C.sub.1-C.sub.6)
alkylthiocarbonyl, arylthiocarbonyl,
(C.sub.1-C.sub.6)alkyl-carbamoyl, arylcarbamoyl,
(C.sub.1-C.sub.6)alkyl-C(.dbd.NH)--, and aryl-C(.dbd.NH)--, wherein
each of these groups are unsubstituted or substituted with one or
more groups (preferably 1, 2, or 3 groups) each independently
selected from (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
aryl, heteroaryl, halo (e.g., chloro, bromo, iodo and fluoro),
cyano, hydroxy, (C.sub.1-C.sub.6)alkoxy, aryloxy, sulfhydryl
(mercapto), (C.sub.1-C.sub.6)alkylthio, arylthio, mono- and
di-(C.sub.1-C.sub.6)alkyl amino, quaternary ammonium salts,
amino(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkylthio, cyanoamino, nitro, carbamyl, keto
(oxy), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl,
sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy, and
combinations thereof.
[0027] More preferred compounds of formula (I) are those where A is
selected from (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
partially saturated or fully saturated (C.sub.3-C.sub.6)cycloalkyl,
partially saturated or fully saturated 5 to 6 membered heterocyclic
ring, aryl, or heteroaryl group, wherein each of these groups are
unsubstituted or substituted with one or more R.sup.1a groups
(preferably 1, 2, or 3 R.sup.1a groups) each independently selected
from hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy
and aryl(C.sub.1-C.sub.6)al- koxy (e.g., benzyloxy); a is 1; (i) w,
x, z and y are 1, (ii) w is 2, x is 0, and z and y are 1,(iii) w is
0, x is 2, and z and y are 1, (iv) w, x and y are 1, and z is 0; or
(v) w, x, and z are 1, and y is 0; p is 1; L is
--(CH.sub.2).sub.q--C(.dbd.O)--, where q is an integer from 1 to 4;
and B is selected from (C.sub.1-C.sub.6)alkylcarbonyl,
arylcarbonyl, (C.sub.1-C.sub.6)alkoxy-carbonyl, aryloxycarbonyl,
(C.sub.1-C.sub.6)alkylsulfonyl, arylsulfonyl, (C.sub.1-C.sub.6)
alkylthiocarbonyl, arylthiocarbonyl,
(C.sub.1-C.sub.6)alkyl-carbamoyl, arylcarbamoyl,
(C.sub.1-C.sub.6)alkyl-C(.dbd.NH)-- and aryl-C(.dbd.NH)--, wherein
each of these groups are unsubstituted or substituted with one or
more R.sup.1b groups (preferably 1, 2, or 3 R.sup.1b groups) each
independently selected from halo, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6)alkyl (e.g., trifluoromethyl), C.sub.1-C.sub.6
alkoxy, halo(C.sub.1-.sub.6)alkoxy (e.g., trifluoromethoxy,
difluoromethoxy and the like), amino, amido (e.g., acetamido),
nitro, aryloxy (e.g., phenoxy) and C.sub.1-C.sub.6 alkylthio (e.g.,
methylthio, ethylthio and the like).
[0028] Even more preferred are those compounds of formula (I) where
A is aryl or heteroaryl, unsubstituted or substituted with one or
more R.sup.1a groups (preferably, 1, 2, or 3 R.sup.1a groups) each
independently selected from hydrogen, halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy and aryl(C.sub.1-C.sub.6)alkoxy (e.g.,
benzyloxy); and B is selected from (C.sub.1-C.sub.6)alkylcarbonyl
and arylcarbonyl, wherein each of these groups are unsubstituted or
substituted with 1, 2, or 3 R.sup.1b groups each independently
selected from halo, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6)alkyl (e.g., trifluoromethyl), C.sub.1-C.sub.6
alkoxy, halo(C.sub.1-C.sub.6)alkoxy (e.g., trifluoromethoxy,
difluoromethoxy and the like), amino, amido (e.g., acetamido),
nitro, aryloxy (e.g., phenoxy) and C.sub.1-C.sub.6 alkylthio (e.g.,
methylthio, ethylthio, and the like).
[0029] Most preferred compounds of formula (I) are those compounds
where A is phenyl, unsubstituted or substituted with 1, 2, or 3
R.sup.1a groups each independently selected from hydrogen, halo,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy.
[0030] In a preferred embodiment of the present invention,
compounds of Formula (IA) below are provided: 5
[0031] wherein
[0032] R.sup.1a for each occurance is independently hydrogen, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
aryl(C.sub.1-C.sub.6)alkox- y (e.g., benzyloxy), or two adjacent
R.sup.1a groups taken together form a substituted or unsubstitued
carbocyclic, heterocyclic, aromatic or heteroaromatic 5 to 6
membered fused ring;
[0033] m is 0, 1, 2, 3, 4, or 5 (preferably 3 or less);
[0034] R.sup.1 and R.sup.2 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, aryl(C.sub.1-C.sub.6)-alkyl (e.g., benzyl),
or R.sup.1 and R.sup.2 is taken together to form a 3 to 6 membered
ring, or R.sup.1 or R.sup.2 is taken together with R.sup.3 to form
a five- or six-membered ring;
[0035] R.sup.3 is hydrogen, taken together with R.sup.1b forms a
substituted or unsubstituted five or six membered partially
saturated or fully saturated heterocyclic ring, or taken together
with R.sup.1 or R.sup.2 form a five- or six-membered ring;
[0036] R.sup.1b for each occurance is independently hydrogen, halo,
C.sub.1-C.sub.6 alkyl, halo(C.sub.1-C.sub.6)alkyl (e.g.,
trifluoromethyl), C.sub.1-C.sub.6 alkoxy,
halo(C.sub.1-C.sub.6)alkoxy (e.g., trifluoromethoxy,
difluoromethoxy and the like), amino, amido (e.g., acetamido),
nitro, aryloxy (e.g., phenoxy), C.sub.1-C.sub.6 alkylthio (e.g.,
methylthio, ethylthio and the like), taken together with R.sup.3
forms a substituted or unsubstituted five or six membered partially
saturated or fully saturated heterocyclic ring, or two adjacent
R.sup.1b substituents taken together form a substituted or
unsubstitued carbocyclic, heterocyclic, aromatic or heteroaromatic
5 to 6 membered fused ring; and
[0037] n is 0, 1, 2, 3, 4 or 5 (preferably 3 or less);
[0038] a prodrug thereof, or a pharmaceutically acceptable salt,
hydrate, or solvate of the compound or the prodrug.
[0039] Preferred compounds are those where R.sup.1a is methyl or
chloro; m is 2; R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3
is hydrogen, R.sup.1b is methyl, trifluoromethyl, amino, iodo,
bromo, chloro or nitro; and n is 1 or 2; a prodrug thereof, or a
pharmaceutically acceptable salt, hydrate, or solvate of the
compound or the prodrug.
[0040] Also preferred are the following compounds:
[0041]
N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]--
2-oxo-ethyl}-3-trifluoromethyl-benzamide;
[0042]
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl]-2-oxo-ethyl}-5-nitro-benzamide;
[0043]
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl]-2-oxo-ethyl}-5-iodo-benzamide;
[0044]
2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0045]
3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,-
4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0046]
3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0047]
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide;
[0048]
3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0049]
3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,-
4-c]pyrrol-2-yl]-2-oxo-ethyl{-benzamide;
[0050]
3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl]-2-oxo-ethyl}-benzamide; and
[0051]
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]-2-oxo-ethyl}-benzamide;
[0052] a prodrug thereof, or a pharmaceutically acceptable salt,
hydrate or solvate of the compound or the prodrug.
[0053] Each of the compounds described herein contain at least one
chiral center; consequently, those skilled in the art will
appreciate that all enantiomers and/or diasteroisomers of the
compounds disclosed and discussed herein are within the scope of
the present invention. However, when the bicyclic rings are 4- or
5-membered rings, then the fused rings are preferably in the cis
configuration.
[0054] Compounds of Formula I above are useful chemokine receptor
antagonists; therefore, another embodiment of the present invention
is a pharmaceutical composition containing a therapeutically
effective amount of a compound of Formula I (including prodrugs
thereof, and pharmaceutically acceptable salts, hydrates, and/or
solvates of the compounds or the prodrugs) and a pharmaceutically
acceptable excipient, diluent or carrier.
[0055] In yet another embodiment of the present invention, a method
for treating or preventing diseases associated with monocyte and/or
lymphocyte accumulation is provided which comprises administering a
therapeutically effective amount of a compound of the present
invention (or a pharmaceutical composition containing a
therapeutically effective amount of a compound of the present
invention) to an animal in need thereof. The method is useful for
treating or preventing diseases such as atherosclerosis,
restenosis, gingivitis, psoriasis, rheumatoid arthritis,
glomerulonephritis, wound healing, Crohn's disease,
encephalomyelitis and transplant rejection in animals, in
particular mammals including humans. Accordingly, the compounds of
the present invention may be used in the manufacture of a
medicament for the treatment or prevention of diseases associated
with monocyte and/or lymphocyte accumulation.
[0056] In a preferred embodiment, a compound of Formula (1B) 6
[0057] where x, y, z, w, L, p and B have the same meaning as
described above for compounds of Formula (I) (including prodrugs
thereof and pharmaceutically acceptable salts, hydrates and
solvates of the compounds and the prodrugs) is administered to an
animal in need of treatment.
[0058] Preferred compounds for inhibition of binding to CCR2
receptors include the following:
[0059]
N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]--
2-oxo-ethyl}-3-trifluoromethyl-benzamide;
[0060]
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl]-2-oxo-ethyl}-5-nitro-benzamide
[0061]
2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl]-2-oxo-ethyl}-5-iodo-benzamide;
[0062]
2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0063]
3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and
[0064]
3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,-
4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0065] a prodrug thereof, or, a pharmaceutically acceptable salt,
hydrate or solvate of the compound or the prodrug.
[0066] In yet another aspect of the present invention, a
pharmaceutical kit for use by a consumer having or at risk of
having a disease or condition such as atherosclerosis, restenosis,
gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis,
wound healing, Crohn's disease; encephalomyelitis and transplant
rejection in animals, is provided. The kit comprises a) a suitable
dosage form comprising a compound of Formula I, a prodrug thereof,
or a pharmaceutically acceptable salt, hydrate or solvate of the
compound or the prodrug; and b) instructions describing a method of
using the dosage form to treat or prevent diseases associated with
monocyte and/or lymphocyte accumulation
[0067] Compounds of the present invention are also useful as
antagonists of eotaxin 2, MCP-3, MCP-4, and RANTES binding to the
CCR3 receptor; therefore, another embodiment of the present
invention is a method for treating or preventing diseases
associated with leucocyte accumulation is provided which entails
administering a therapeutically effective amount of a compound of
the present invention (or a pharmaceutical composition described
above) to an animal in need thereof. The method is useful for
treating or preventing chronic inflammatory diseases such as
allergy and asthma, including but not limited to allergic rhinitis,
eczema and atopic dermatitis in animals (preferably humans).
Accordingly, the compounds of the present invention may be used in
the manufacture of a medicament for the treatment or prevention of
diseases associated with leucocyte accumulation.
[0068] In a preferred embodiment, a compound of Formula (1C) 7
[0069] where x, y, z, w, L, p and B have the same meaning as
described above for compounds of Formula (I) (including prodrugs
thereof and pharmaceutically acceptable salts, hydrates and
solvates of the compounds and the prodrugs) is administered to an
animal in need of such treatment.
[0070] Preferred compounds for inhibition of binding to CCR3
receptors include the following:
[0071]
3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0072]
3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)hexahydro-pyrrolo[3,4-
-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;
[0073]
3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl]-2-oxo-ethyl}-benzamide;
[0074]
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]-2-oxo-ethyl}-benzamide; and
[0075]
3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide; a prodrug thereof, or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound or prodrug.
[0076] In yet another aspect of the present invention, a
pharmaceutical kit for use by a consumer having or at risk of
having a disease or condition resulting from a chronic inflammatory
diseases such as allergy and asthma is provided.
[0077] The kit comprises a) a suitable dosage form comprising a
compound of Formula I, a prodrug thereof, or a pharmaceutically
acceptable salt, hydrate or solvate of the compound or the prodrug;
and b) instructions describing a method of using the dosage form to
treat or prevent diseases associated with leucocyte
accumulation.
[0078] The compounds of the present invention may also be used in
conjunction with at least one other pharmaceutical agent for the
treatment or prevention of diseases/conditions described herein.
Suitable pharmaceutical agents that may be used in combination with
the compounds of the present invention include nutraceuticals,
cholesterol absorption inhibitors, HMG-CoA reductase inhibitors,
MTP/Apo B secretion inhibitors, HMG-CoA synthase inhibitors,
HMG-CoA reductase transcription inhibitors, HMG-CoA reductase
translation inhibitors, CETP inhibitors, squalene synthetase
inhibitors, squalene epoxidase inhibitors, squalene cyclase
inhibitors, combined squalene epoxidase/squalene cyclase
inhibitors, ACAT inhibitors, lipase inhibitors (including
pancreatic lipase inhibitors and gastric lipase inhibitors),
peroxisome proliferator-activated receptor (PPAR) agonists,
nonsteroidal anti-inflammatory drugs (NSAIDS) and cyclooxygenase
enzyme inhibitors (COX-2 inhibitors). Therefore, a method is
provided for treating or preventing a disease associated with
monocyte accumulation, lymphocyte accumulation or leucocyte
accumulation which comprising administering to a mammal in need of
such treatment a compound of the present invention and at least one
of the pharmaceutical agents described above.
[0079] The combination therapy may be administered as (a) a single
pharmaceutical composition which comprises a compound of the
present invention, at least one of the pharmaceutical agents
described above and a pharmaceutically acceptable excipient,
diluent, carrier or mixtures thereof; or (b) two separate
pharmaceutical compositions comprising (i) a first composition
comprising a compound of the present invention and a
pharmaceutically acceptable excipient, diluent, carrier or mixtures
thereof, and (ii) a second composition comprising at least one of
the pharmaceutical agents described above and a pharmaceutically
acceptable excipient, diluent, carrier or mixtures thereof. The
pharmaceutical compositions may be administered simultaneously or
sequentially and in any order.
[0080] In yet another embodiment of the present invention is a
pharmaceutical kit comprising: a) a compound of the present
invention, and a pharmaceutically acceptable carrier, excipient or
diluent in a first unit dosage form; b) a pharmaceutical agent
selected from the group consisting of a nutraceutical, a
cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a
MTP/Apo B secretion inhibitor, a HMG-CoA synthase inhibitor, a
HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase
translation inhibitor, a CETP inhibitor, a squalene synthetase
inhibitor, a squalene epoxidase inhibitor, a squalene cyclase
inhibitor, an ACAT inhibitor, a lipase inhibitor a peroxisome
proliferator-activated receptor agonist, a nonsteroidal
anti-inflammatory drug and a COX-2 inhibitor, and a
pharmaceutically acceptable carrier, excipient or diluent in a
second unit dosage form; and c) a container.
Definitions
[0081] As used herein, the term "alkyl" refers to a hydrocarbon
radical of the general formula C.sub.nH.sub.2n+1. The alkane
radical may be straight or branched. For example, the term
"(C.sub.1-C.sub.6)alkyl" refers to a monovalent, straight,
branched, or cyclic aliphatic group containing 1 to 6 carbon atoms
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl,
2-methylpentyl, and the like). The alkane radical may be
unsubstituted or substituted with one or more substituents defined
below. For example, a "haloalkyl" refers to an alkyl group
substituted with one or more halogen atoms (e.g., fluoromethyl,
difluoromethyl, trifluoromethyl, perfluoroethyl, and the like).
Similarly, the alkyl portion of an alkoxy, alkylamino,
dialkylamino, or alkylthio group have the same definition as
above.
[0082] The term "partially saturated or fully saturated cycloalkyl"
or "partially saturated or fully saturated heterocyclic ring"
refers to nonaromatic rings that are either partially or fully
hydrogenated. For example, partially or fully saturated cycloalkyl
includes groups such as cyclopropyl, cyclopropenyl, cyclobutyl,
cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl,
cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Partially
saturated or fully saturated heterocyclic rings include groups such
as dihydropyridinyl, pyrrolidinyl, (2-, 3- or
4)-N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidyl,
imidazolyl, imidazolidyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl,
morpholino, thiomorpholino, tetrahydrothienyl, and the like.
[0083] The term "alkenyl" refers to a hydrocarbon containing at
least one carbon-carbon double bond. As described above for alkyl,
the alkene radical may be straight or branched and the alkene
radical may be unsubstituted or substituted with one or more
substituents defined below.
[0084] The term "aryl" refers to aromatic moieties having single
(e.g., phenyl) or fused ring system containing 6 to 14 carbon atoms
(e.g., naphthalene, anthracene, phenanthrene, etc.). The aryl
groups may be unsubstituted or substituted with one or more
substituents (preferably no more than three substituents) defined
below. Substituted aryl groups include a chain of aromatic moieties
(e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.)
[0085] The term "heteroaryl" refers to aromatic moieties containing
at least one heteroatom (preferably, 1, 2, 3 or 4 heteratoms, more
preferably 1 or 2 heteroatoms) within the aromatic ring system
which may be the same or different (e.g., pyrrole, pyridine,
indole, thiophene, furan, benzofuran, imidazole, pyrimidine,
purine, benzimidazole, quinoline, etc.). The heteroatoms in the
ring system are generally selected from oxygen, sulfur, nitrogen or
combinations thereof. The aromatic moiety may consist of a single
or fused ring system containing 5 to 14 members. The heteroaryl
groups may be unsubstituted or substituted with one or more
substituents (preferably no more than three substituents) defined
below.
[0086] The term "amino acid residue" refers to a structural unit of
a natural, modified or unusual amino acid (as defined herein)
remaining after the loss of a hydroxy group from the carboxylic
acid group and the loss of a hydrogen from the amino group. For
example, a residue of valine would have the following structure;
8
[0087] The term "substituted" specifically envisions and allows for
substitutions which are common in the art. However, it is generally
understood by those skilled in the art that the substituents should
be selected so as to not adversely affect the pharmacological
characteristics of the compound or adversely interfere with the use
of the medicament. Suitable substituents for any of the groups
defined above include alkyl, alkenyl, aryl, heteroaryl, halo (e.g.,
chloro, bromo, iodo and fluoro), cyano, hydroxy, alkoxy, aryloxy,
sulfhydryl (mercapto), alkylthio, arylthio, mono- and di-alkyl
amino, quaternary ammonium salts, aminoalkoxy, hydroxyalkylamino,
aminoalkylthio, cyanoamino, nitro, carbamyl, keto (oxy), carbonyl,
carboxy, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl,
sulfinyl, thiocarbonyl, thiocarboxy, and combinations thereof.
[0088] The term "protecting group" or "Pg" refers to a substitutent
that is commonly employed to block or protect a particular
functionality while reacting other functional groups on the
compound. For example, an "amino-protecting group" is a substituent
attached to an amino group that blocks or protects the amino
functionality in the compound. Suitable amino-protecting groups
include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
Similarly, a "hydroxy-protecting group" refers to a substituent of
a hydroxy group that blocks or protects the hydroxy functionality.
Suitable hydroxy-protecting groups include acetyl and silyl. A
"carboxy-protecting group" refers to a substituent of the carboxy
group that blocks or protects the carboxy functionality. Common
carboxy-protecting groups include --CH.sub.2CH.sub.2SO.sub.2Ph,
cyanoethyl, 2-(trimethylsilyl)ethyl- ,
2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)ethyl,
nitroethyl and the like. For a general description of protecting
groups and their use, see T. W. Greene, Protective Groups in
Organic Synthesis, John Wiley & Sons, New York, 1991.
[0089] The term "solvate" refers to a molecular complex of a
compound represented by Formula I (including prodrugs and
pharmaceutically acceptable salts thereof) with one or more solvent
molecules. Such solvent molecules are those commonly used in the
pharmaceutical art, which are known to be innocuous to the
recipient, e.g., water, ethanol, and the like. The term "hydrate"
refers to the complex where the solvent molecule is water.
[0090] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that attenuates,
ameliorates, or eliminates one or more symptoms of a particular
disease, condition, or disorder, or prevents or delays the onset of
one or more symptoms of a particular disease, condition, or
disorder.
[0091] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the animal being treated therewith.
[0092] The term "animal" refers to humans, companion animals (e.g.,
dogs, cats and horses), food-source animals (e.g., cows, pigs,
sheep and poultry), zoo animals, marine animals, birds and other
similar animal species.
[0093] The term "compounds of the present invention" refers to
compounds of Formula (I), prodrugs thereof, and pharmaceutically
acceptable salts, hydrates and/or solvates of the compounds and/or
prodrugs, as well as, all stereoisomers (including diastereomers
(except trans configurations of four and five members fused rings
that are unstable) and enantiomers), tautomers and isotopically
labelled compounds.
DETAILED DESCRIPTION
[0094] In general, the compounds of the present invention can be
made by synthetic routes that include processes analogous to those
known in the chemical arts, particularly in light of the
description contained herein.
[0095] For illustrative purposes, the reaction schemes depicted
below provide potential routes for synthesizing the inventive
compounds. Although Scheme I illustrates attaching the "A" group
first and then the "B" group, those skilled in the art will
appreciate that "A" and "B" can be attached in reverse order using
the same general chemical procedures described herein. For a more
detailed description of the individual reaction steps, see the
Examples section. Those skilled in the art will appreciate that
other synthetic routes may be used to synthesize the inventive
compounds. Although specific starting materials are depicted in the
schemes below, other starting materials can be easily substituted.
For example, bicyclic diamine compounds having different ring
sizes, configurations, and combination of ring sizes may be used
instead of the mono amino-protected hexahydropyrrolo[3,4-c]pyrrole
I(a) shown in Schemes I and II. Preparations of bicyclic diamines
having different ring configurations is illustrated in the
Examples.
[0096] Scheme I illustrates the preparation of compounds of Formula
I where "A" is attached to the bicyclic diamine by means of a
reductive alkylation process and "B" is attached directly to the
bicyclic diamine system (i.e., p=0) by means of an amine coupling
reaction. 9
[0097] In the preparation of compounds of Formula I, protection of
remote functionality (e.g., primary amine, secondary amine) of
intermediates may be necessary. The need for such protection will
vary depending on the nature of the remote functionality and the
conditions of the preparation methods. Suitable amino-protecting
groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBz) and 9-fluorenylmethylen-oxycarbonyl (Fmoc).
The need for such protection is readily determined by one skilled
in the art. For a general description of protecting groups and
their use, see T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1991.
[0098] Intermediate I(b) is prepared by reacting the mono
amino-protected hexahydropyrrolo[3,4-c]pyrrole I(a) with the
desired aldehyde or ketone containing the functional group "A." For
example, when "A" is a 2,4-dimethyl phenyl group, then one would
react I(a) with 2,4-dimethyl benzaldehdye. Suitable aldehydes that
may be used include unsubstituted or substituted aryl-aldehydes
(e.g., benzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde,
4-methylbenzaldehyde, 2,4-difluorobenzaldehyde,
2,3-difluorobenzaldehyde, 3,5-difluorobenzaldehyde,
2,5-difluorobenzaldehyde, 2-chloro-benzaldehdye,
3-chloro-benzaldehyde, 4-chloro-benzaldehyde,
2-chloro-6-fluorobenzaldehyde, 3,4-dichlorobenzaldehyde,
2,4-dichlorobenzaldehyde 2-chloro-6-fluorobenzaldehyde,
2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde,
2,3-dimethylbenzaldehyde, 2,6-dimethoxybenzaldehyde,
2,4-dimethylbenzaldehyde, 2,5-dimethyl-4-methoxybenzaldehyde,
2-chloro-3,4-dimethoxybenzaldehyde, 2-benzyloxybenzaldehyde,
2-trifluoromethylbenzaldehyde, 4-trifluoromethylbenzaldehyde,
2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde,
4-hydroxybenzaldehyde, 2-aminobenzaldehyde, 3-aminobenzaldehyde,
4-aminobenzaldehyde), 2-naphthalenecarboxyaldehyde, and
6-methoxy-2-naphthalene-carboxyaldehyde), unsubstituted or
substituted alkyl-aldehydes (e.g., .alpha.-phenyl-acetaldehyde,
2-phenylpropionaldehyde, and 3-phenylbutyraldehyde,), unsubstituted
or substituted alkenyl-aldehydes (e.g., cinnamaldehyde,
.alpha.-methyl-trans-cinnamaldehyde, and 2,2-dimethyl-4-pentenal),
substituted or unsubstituted partially saturated or fully saturated
cycloalkyl-aldehydes (e.g., cyclopropane-carboxaldehyde,
cyclobutane-carboxaldehyde, cyclopentane-carboxaldehyde, and
cyclohexane-carboxaldehyde), substituted or unsubstituted partially
saturated or fully saturated 5 to 6 membered heterocyclic
aldehydes, and substituted or unsubstituted heteroaryl-aldehydes
(e.g., indole-5-carboxaldehyde, pyrrole-2-carbox-aldehyde,
2-pyridinecarbox-aldehyde, 3-pyridinecarbox-aldehyde,
4-pyridinecarbox-aldehyde, 2-furaldehyde, 3-furaldehyde,
2-thiophenecarbox-aldehyde, 3-thiophenecarbox-aldehyde,
2-quinolinecarbox-aldehyde, 3-quinolinecarbox-aldehyde, and
4-quinolinecarbox-aldehyde). Generally, reductive amination
reactions convert an aldehyde or ketone into a Schiff base by
reaction with amine intermediate I(a) in a polar solvent at a
temperature from about 10.degree. C. to about 40.degree. C. for
about 2 to about 24 hours. Typically, an equivalent or a slight
excess (i.e., 1.1 equivalents) amount of the aldehyde or ketone is
added to the amine. Suitable polar solvents include methylene
chloride, 1,2-dichloroethane, dimethylsulfoxide, dimethylformamide,
alcohols (e.g., methanol or ethanol), or mixtures thereof. A
preferred solvent is methanol. In the same reaction vessel, the
imine is then reduced to the tertiary amine in the presence of a
reducing agent at a temperature from about 0.degree. C. to about
10.degree. C. and then warmed to a temperature from about
20.degree. C. to about 40.degree. C. for about 30 minutes to about
2 hours. Suitable reducing agents include pyridine.borane complex
and metal borohydrides, such as sodium borohydride, sodium
triacetoxy borohydride and sodium cyanoborohydride.
[0099] In general, intermediate I(b) is deprotected by treating
with an anhydrous acid (e.g., trifluoroactetic acid) in an aprotic
solvent (e.g., methylene chloride) at a temperature from about
10.degree. C. to about 40.degree. C. for about 20 minutes to about
12 hours. Compound IA is then produced by combining the appropriate
coupling agent (e.g., carboxylic acid, acid chloride, acid
anhydride, sulfonyl chloride, isocyanates, etc.) containing "B"
with the deprotected amine I(c). When a carboxylic acid is used as
the coupler, the reaction is generally accomplished in the presence
of o-benzotriazol-1-yl-N,N,N',N'-tetramethyl-uronium-hexaflu-
orophosphate (HBTU) at a temperature of about 60.degree. C. For a
more detailed description of the reaction conditions see Example 1
in the Examples section. Suitable carboxylic acids include
unsubstituted and substituted aromatic or alkanoic acids, such as
benzoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid,
4-fluorobenzoic acid, 2-trifluoromethylbenzoic acid,
3-trifluoromethylbenzoic acid, 4-trifluoromethylbenzoic acid,
2-fluoro-3-trifluoromethylbenzoic acid,
2-fluoro-4-trifluoromethylbenzoic acid,
2-fluoro-5-trifluoromethylbenoic acid,
2-fluoro-6-trifluoromethylbenzoic acid,
3-fluoro-4-trifluoromethylb- enzoic acid,
3-fluoro-5-trifluoromethylbenzoic acid,
4-fluoro-2-trifluoromethylbenzoic acid, 5-fluoro-2-methylbenzoic
acid, 2,4-bis-trifluoromethylbenzoic acid,
2,5-bis-trifluoromethylbenzoic acid, 3,5-bis-trifluoromethylbenzoic
acid, 2,3-difluorobenzoic acid, 2,4-difluorobenzoic acid,
2,5-difluorobenzoic acid, 2,6-difluorobenzoic acid,
3,4-difluorobenzoic acid, 3,5-difluorobenzoic acid,
2,3,4-trifluorobenzoic acid, 2,3,6-trifluorobenzoic acid,
2,4,5-trifluorobenzoic acid, 2,4,6-trifluorobenzoic acid,
3,4,5-trifluorobenzoic acid, 2-difluoromethoxybenzoic acid,
2-trifluoromethyoxybenzoic acid, 4-trifluoromethoxybenzoic acid,
3-fluoro-4-methylbenzoic acid, 2-chloro-4-fluorobenzoic acid,
2-chloro-6-fluorobenzoic acid, 3-chloro-2-fluorobenzoic acid,
3-chloro-4-fluorobenzoic acid, 4-chloro-2-fluorobenzoic acid,
2-chloro-4,5-difluorobenzoic acid,
2-chloro-3-trifluoromethylbenzoic acid,
3-chloro-2,6-dimethoxybenzoic acid, 2-chiorobenzoic acid,
3-chlorobenzoic acid, 4-chlorobenzoic acid, 2,3-dichlorobenzoic
acid, 2,4-dichlorobenzoic acid, 2,5-dichlorobenzoic acid,
2,6-dichlorobenzoic acid, 3,4-dichlorobenzoic acid,
3-chloro-2,6-dimethoxybenzoic acid, 2-chloro-3,4-dimethoxybenzoic
acid, 5-chloro-2-methylbenzoic acid, 2-bromobenzoic acid,
3-bromobenzoic acid, 4-bromobenzoic acid, 2-bromo-4-chlorobenzoic
acid, 2-bromo-5-chlorobenzoic acid, 3-bromo-4-chlorobenzoic acid,
3-bromo-2-fluorobenzoic acid, 4-bromo-2-chlorobenzoic acid,
5-bromo-2-chlorobenzoic acid, 3-bromo-4-methylbenzoic acid,
2-bromo-5-methoxybenzoic acid, 2-bromo-3-methylbenzoic acid,
2-bromo-5-methylbenzoic acid, 3-bromo-2-methylbenzoic acid,
3-bromo-4-methylbenzoic acid, 4-bromo-2-methylbenzoic acid,
4-bromo-3-methylbenzoicacid, 2-methylbenzoic acid, 3-methylbenzoic
acid, 4-methylbenzoic acid, 4-isopropylbenzoic acid,
4-n-butylbenzoic acid, 4-tert-butylbenzoic acid,
2,5-dimethylbenzoic acid, 2,6-dimethylbenzoic acid,
3,4-dimethylbenzoic acid, 2-methoxybenzoic acid, 2-methoxybenzoic
acid, 4-propoxybenzoic acid, 2,4-dimethoxybenzoic acid,
2,6-dimethoxybenzoic acid, 2,3,6-trimethoxybenzoic acid,
2-amino-5-iodobenzoic acid, 2-amino-5-bromobenzoic acid,
2-amino-5-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid,
2-amino-5-nitrobenzoic acid, 2-amino-3-trifluoromethylbenzoic acid,
2-amino-3,5-dibromobenzoic acid, 2-acetoamino-5-bromobenzoic acid,
2-methyl-5-nitrobenzoic acid, 2-nitrobenzoic acid, 3-nitrobenzoic
acid, 5-chloro-2-nitrobenzoic acid,
3-nitro-5-trifluoromethylbenzoic acid, 2-phenoxybenzoic acid,
naphthalene-2-carboxylic acid, 3-methylsulfanylbenzoic acid,
4-ethylsulfanylbenzoic acid, 1H-pyrrole-2-carboxylic acid,
1H-3-pyrrole-carboxylic acid, furan-2-carboxylic acid,
furan-3-carboxylic acid, thiophene-2-carboxylic acid, thiophene
3-carboxylic acid, pyridine-2-carboxylic acid,
pyridine-3-carboxylic acid, pyridine-4-carboxylic acid, acetic
acid, propionic acid, butanoic acid, isobutyric acid,
3-methyl-butyric acid, pentanoic, hexanoic acid, and phenyl acetic
acid. Suitable acid anhydrides include phthalic anhydride.
[0100] Alternatively, the intermediate compound (Ic) may be
acylated with the appropriate acyl chloride or the appropriate
sulfonyl chloride in a reaction-inert solvent such as methylene
chloride in the presence of an amine base such as triethylamine at
a temperature of about 10.degree. C. to about 50.degree. C.,
typically ambient for about 6 to about 18 hours. Another
alternative method for attaching B is by reacting intermediate (Ic)
with the appropriate isocyanate in a reaction-inert solvent such as
toluene in the presence of a tertiary amine base such as Hunig's
base at a temperature of about 10.degree. C. to about 150.degree.
C., typically ambient for about 6 to about 18 hours; or with the
appropriate carboxylic acid in a reaction-inert solvent such as
methylene chloride in the presence of a carbodiimide (e.g.,
1-(3-dimethylaminopropyl)-3-ethylcarbod- iimide hydrochloride) at a
temperature of about 10.degree. C. to about 50.degree. C.,
typically ambient for about 6 to about 24 hours. Suitable sulfonyl
chlorides include benzenesulfonyl chloride,
4-methyl-benzenesulfonyl chloride, methanesulfonyl chloride,
ethanesulfonyl chloride, and propanesulfonyl chloride. Suitable
acid chlorides include the-acid-chloride derivatives of the
carboxylic acids listed earlier. Conversion of a carboxylic acid to
its corresponding acid chloride is well know to those skilled in
the art. Generally, the carboxylic acid may be converted by
reacting with a suitable chlorinating agent such as thionyl
chloride or oxalyl chloride. Suitable isocyanates include phenyl
isocyanate, 2-naphthyl isocyanate, o-tolyl isocyanate,
2-ethoxyphenyl isocyanate, m-tolyl isocyanate, p-tolyl isocyanate,
4-biphenyl isocyanate, o-nitrophenyl isocyanate, 4-nitrophenyl
isocyanate, m-chlorophenyl isocyanate, m-nitrophenyl isocyanate,
p-bromophenyl isocyanate, 3,4-dichlorophenyl isocyanate,
3-bromophenylisocyanate, 2,5-dichlorophenyl isocyanate,
p-ethoxyphenyl isocyanate, 1-naphthyl isocyanate, p-chlorophenyl
isocyanate, o-chlorophenyl isocyanate, o-methoxyphenyl isocyanate,
4-methoxyphenyl isocyanate, 2,4-dimethoxyphenyl isocyanate,
5-chloro-2,4-dimethoxyphenyl isocyanate, o-fluorophenyl isocyanate,
p-fluorophenyl isocyanate, 3-(trifluoromethyl)phenyl isocyanate,
4-iodophenyl isocyanate, 4-n-butylphenyl isocyanate,
4-chloro-2-methoxyphenyl isocyanate, 2-isopropylphenyl isocyanate,
2-methoxycarbonylphenyl isocyanate, 4-phenoxyphenyl isocyanate,
2-ethyl-6-methylphenyl isocyanate, 2,6-diethylphenyl isocyanate,
3,5-dimethoxyphenyl isocyanate, 3,4,5-trimethoxyphenyl isocyanate,
2,4-dichlorophenyl isocyanate, 2,4-difluorophenyl isocynanate,
4-butoxyphenyl isocyanate, 3-fluorophenyl isocyanate, 4-ethylphenyl
isocyanate, 3,4-dimethylphenyl isocyanate, 2,4dimethylphenyl
isocyanate, 2,3 dichlorophenyl isocyanate, 2,4,5-trimethylphenyl
isocyanate, 2,6-difluoro-2-nitrophenyl isocyanate,
2,5-difluorophenyl isocyanate, alpha, alpha,
alpha-trifluoro-o-tolyl-isoc- yanate, and
3,5-bis(trifluoromethyl)phenyl isocyanate.
[0101] Group B may also be attached by means of a linking group
(L). Scheme II illustrates the preparation of compounds of Formula
I where B is attached to the bicyclic diamine by means of an amino
acid linking group (L). 10
[0102] The same procedures as described above in Scheme I may be
used to produce intermediate I(c). The deprotected amine I(c) is
then coupled with the desired amino-protected amino acid linking
group to obtain intermediate I(d). The coupling reaction is
generally accomplished by reacting the deprotected amine with the
amino acid in the presence of a carbodiimide (e.g.,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in an
inert solvent (e.g., methylene chloride) at a temperature from
about 10.degree. C. to about 40.degree. C. for about 2 to about 24
hours. Any natural, modified or unusual amino acid may be used as
the linking group (L). Suitable natural amino acids include L-amino
acids commonly found in naturally occurring proteins and are listed
in WIPO Standard ST.25 (1998), Appendix 2, Table 3 (alanine,
cysteine, aspartic acid, glutamic acid, phenylalanine, glycine,
histidine, isoleucine, lysine, leucine, methionine, asparagine,
proline, glutamine, arginine, serine, threonine, valine, tryptophan
and tyrosine). Suitable modified or unusual amino acids include
those listed in WIPO Standard ST.25 (1998), Appendix 2, Table 4
(2-aminoadipic acid, 3-aminoadipic acid, beta-alanine
(beta-aminopropionic acid), 2-aminobutyric acid, 4-aminobutyric
acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid,
2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic
acid, 2,4-diaminobutyric acid, desmosine, 2,2'-diaminopimelic acid,
2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine,
hydroxylysine, allo-hydroxylysine, 3-hydroxyproline,
4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine
(sarcosine), N-methylisoleucine, 6-N-methyllysine, N-methylvaline,
norvaline, norleucine, and ornithine). The amino acids listed above
may be modified to provide additional amino acids for coupling by
chemical means well known to those skilled in the art (e.g.,
esterfication, alkylation, amidation, etc.).
[0103] The intermediate I(d) is then deprotected to produce the
free amino compound I(e) using the same general procedures used to
deprotect I(b). Compound IB is then produced by combining the
appropriate coupling agent (e.g., carboxylic acid, acyl chloride,
sulfonyl chloride, isocyanate, etc.) containing "B" with the
deprotected amine I(e) in the presence of a carbodiimide (e.g.,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in a
reaction inert solvent (e.g., methylene chloride) at a temperature
from about 10.degree. C. to about 40.degree. C. for about 2 to
about 24 hours. Suitable coupling agents containing B include those
described above.
[0104] Although Scheme II illustrates the use of an amino acid as a
linking group, other linking groups may be used as a means for
attaching group B to the bicyclic diamine (e.g., intermediate I(c)
in Scheme II, intermediate 3(a) in Scheme III or intermediate 4(a)
in Scheme IV). For example, Scheme III below illustrates the use of
a sulfonylalkylamino linking group. 11
[0105] Compounds of the present invention where L is a sulfonamide
linker with a nitrogen functional group can be prepared by reacting
the bicyclic amine (3(a)) with the desired amino-protected amino
methyl sulfonyl chloride in an inert solvent such as methylene
chloride or chloroform containing a suitable base such as
triethylamine or diisopropylethylamine at a temperature between
about 0.degree. C. and about 50.degree. C. for about 10 minutes to
about 3 hours. The reaction mixture can be quenched with water and
organic layers collected to provide the desired material (3(b)). No
further purification is necessary. The amino-protecting group can
be removed using conventional chemistry described earlier to
provide 3(c). Group B may be attached to the deprotected amino
group using any of the procedures described herein.
[0106] Scheme IV below illustrates the use of an alkylamino linker
(L) to attach B to the bicyclic diamine. 12
[0107] Compounds of the present invention where L is a
(C.sub.1-C.sub.3)alkylamino linker can be prepared by reacting the
bicyclic amine 4(a) with a commercially available aldehyde (or
ketone), or aldehyde (or ketone) prepared from the literature by
one skilled in the art in a solvent (e.g., methanol or ethanol) at
room temperature for about 3 hours to about 24 hours. A reducing
agent (e.g., sodium borohydride or sodium cyanoborohydride) is then
added to the mixture at about 0.degree. C. The reaction temperature
is allowed to warm to room temperature and allowed to stir for
another 1 to about 10 hours. The solvent is removed under vacuum
and the material washed with 1 M NaOH and extracted with a polar
solvent such as ethyl acetate or methylene chloride. The organic
layer is collected and concentrated to provide the desired product
(4(b)). The protecting group is then removed and the free amine can
be coupled to B using any of the procedures described earlier
(e.g., reaction with an acid chloride, sulfonyl chloride,
etc.).
[0108] Compounds of the present invention where L is an aryl or
heteroaryl amino linker can be prepared by the palladium-catalyzed
amination of an aryl or a heterocycle to the bicyclic diamine as
illustrated in Scheme V. 13
[0109] Intermediates 5(b) and 5(c) can be prepared by the
palladium-catalyzed amination of an amino-protected aryl or
heterocycle (heteroatom such as N, representated by Y) substituted
with a halide or a triflate (--OTf) as depicted in the Scheme V
above. Pd(dibenzylideneacetone).sub.2 or PdCl.sub.2 may be used.
Ligands such as triphenyl phosphine and
1,1-bis(diphenyphosphino)ferrocene (available from Strem Chemicals
Inc., Newburyport, Mass.) maybe also be used. A variety of amines
and amino-substituted aryl or heteroaryl halides or triflates
(e.g., p-aminophenylchloride, p-aminophenylbromide, or
p-aminophenyltriflate) having no additional substituents or
substituted with one or more R.sup.1a groups may be used. The
reaction conditions also tolerate the presence of functional
groups. In general, the bicyclic amine (1.2 equiv) is mixed with
the aryl halide or triflate (1.0 equiv) followed by the addition of
sodium t-butoxide (1.4 equiv) and Pd (0.5 mol %) and ligand (1.5
mol %) in an inert solvent such as toluene or ethylene glycol
dimethyl ether and heated to about 80.degree. C. to about
100.degree. C. for about 1 to about 27 hours. The reaction mixture
is then cooled to room temperature, diluted with ether, filtered
through a filter aid (e.g., Celite.TM. diatomaceous earth filter
aid available from World Minerals Corporation, Santa Barbara,
Calif.) and concentrated in vacuo to obtain the desired material.
For more detailed information, see Guram, A. S., Buchwald, S. L. J.
Am. Chem. Soc., 116, 7901 (1994); Boger, D. L, et al., J Org Chem,
50, 5790 (1965); and Kosugi, M, et al., Chem. Lett, 927 (1983). The
protecting group is then removed using conventional chemistry
described earlier and the deprotected amino group coupled to B
using any of the procedures described earlier.
[0110] Scheme VI below illustrates the use of a hydroxy- or
carboxy-alkyl linker (L) for attaching B to the bicyclic diamine.
14
[0111] Compounds of the present invention where L is a hydroxyalkyl
or a carboxyalkyl can be prepared by reacting the secondary amine
with sodium hydride or alkyl lithium (e.g., butyl lithium) and
adding it to a commercially available ethylene oxide in a solvent
such tetrahydrofuran or diethyl ether at about -78.degree. C. to
about 0.degree. C. for about 1 hour to about 24 hours. Group B may
be attached directly to the intermediate 6(a) containing the free
alcohol to produce compound 6(b). Group B may be attached using
conventional chemistry well known to those skilled in the art for
the formation of ethers (e.g., formation of the oxygen anion
followed by alkylation with the desired alkylating agent such as an
alkyl halide). Alternatively, the hydroxy group can be oxidized to
the carboxylic acid 6(c) using oxidizing agents such as NaOCl or
CrO.sub.3-pyr-HCl (PCC). The acid 6(c) can then be coupled to B to
provide compound 6(d).
[0112] Compounds of the present invention where "a" is zero may be
prepared using the general synthetic route depicted in Scheme VII.
15
[0113] Intermediates 7(a) and 7(b) can be prepared by the
palladium-catalyzed amination of aryl or heterocyclic (heteroatom
such as N, representated by Y) halides or triflates as described in
the Scheme V above. Group B is then attached using any of the
general procedures described above with or without a linking group
(L).
[0114] Conventional methods and/or techniques of separation, and
purification known to one of ordinary skill in the art can be used
to isolate the compounds of Formula (I), as well as the various
intermediates related thereto. Such techniques will be well-known
to one of ordinary skill in the art and may include, for example,
all types of chromatography (high pressure liquid chromatography
(HPLC), column chromatography using common adsorbents such as
silica gel (SPE column) or SCX Column, and thin-layer
chromatography), recrystallization, and differential (i.e.,
liquid-liquid) extraction techniques.
[0115] The Formula I compounds may be isolated and used per se or
in the form of a pharmaceutically acceptable salt, solvate and/or
hydrate. The term "pharmaceutically acceptable salt" refers to
non-toxic acid addition salts derived from inorganic and organic
acids. Suitable salt derivatives include halides, thiocyanates,
sulfates, bisulfates, sulfites, bisulfites, arylsulfonates,
alkylsulfates, phosphonates, monohydrogenphosphates,
dihydrogenphosphates, metaphosphates, pyrophosphonates, alkanoates,
cycloalkylalkanoates, arylalkonates, adipates, alginates,
aspartates, benzoates, fumarates, glucoheptanoates,
glycerophosphates, lactates, maleates, nicotinates, oxalates,
palmitates, pectinates, picrates, pivalates, succinates,
tartarates, citrates, camphorates, camphorsulfonates, digluconates,
trifluoroacetates, and the like. The salts also include cations
based on the alkali and alkaline earth metals, such as sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. See, for example, Berge,
et al., J. Pharm. Sci., 66, 1-19 (1977).
[0116] The term "prodrug" means a compound that is transformed in
vivo to yield a compound of Formula (I) or a pharmaceutically
acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. A discussion of the use of prodrugs is
provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[0117] For example, if a compound of Formula (I) or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0118] Similarly, if a compound of Formula (I) contains an alcohol
functional group, a prodrug can be formed by the replacement of the
hydrogen atom of the alcohol group with a group such as
(C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl- ,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl
(C.sub.1-C.sub.6)alkoxyca- rbonyloxymethyl,
N-(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each a-aminoacyl group
is independently selected from the naturally occurring L-amino
acids, P(O)(OH).sub.2, --P(O)(O(C.sub.1-C.sub.6)alkyl).- sub.2 or
glycosyl (the radical resulting from the removal of a hydroxyl
group of the hemiacetal form of a carbohydrate).
[0119] If a compound of Formula (I) incorporates an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY.sup.1
wherein Y.sup.1 is H, (C.sub.1-C.sub.6)alkyl or benzyl,
--C(OY.sup.2)Y.sup.3 wherein Y.sup.2 is (C.sub.1-C.sub.4) alkyl and
Y.sup.3 is (C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkyl- aminoalkyl, --C(Y.sup.4)Y.sup.5
wherein Y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino, morpholino, piperidin-1-yl or
pyrrolidin-1-yl.
[0120] The compounds of Formula (I) may contain asymmetric or
chiral centers, and, therefore, exist in different stereoisomeric
forms. It is intended that all stereoisomeric forms of the
compounds of Formula (I) as well as mixtures thereof, including
racemic mixtures, form part of the present invention. In addition,
the present invention embraces all geometric and positional
isomers. For example, if a compound of Formula (I) incorporates a
double bond or a fused ring, both the dis- and trans-forms, as well
as mixtures, are embraced within the scope of the invention.
[0121] Diasteromeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography and/or fractional crystallization. Enantiomers
can be separated by converting the enantiomeric mixture into a
diasteromeric mixture by reaction with an appropriate optically
active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's acid chloride), separating the diastereomers and
converting (e.g., hydrolyzing) the individual diastereomers to the
corresponding pure enantiomers. Also, some of the compounds of
Formula (I) may be atropisomers (e.g., substituted biaryls) and are
considered as part of this invention. Enantiomers can also be
separated by use of a chiral HPLC column.
[0122] The compounds of Formula (I) may exist in unsolvated as well
as solvated forms with pharmaceutically acceptable solvents such as
water, ethanol, and the like, and it is intended that the invention
embrace both solvated and unsolvated forms.
[0123] It is also possible that the compounds of Formula (I) may
exist in different tautomeric forms, and all such forms are
embraced within the scope of the invention. For example, all of the
tautomeric forms of the imidazole moiety are included in the
invention. Also, for example, all keto-enol and imine-enamine forms
of the compounds are included in the invention.
[0124] The present invention also embraces isotopically-labelled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine and chlorine, such as .sup.2H, .sup.3H,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
[0125] Certain isotopically-labelled compounds of Formula (I)
(e.g., those labeled with .sup.3H and .sup.14C) are useful in
compound and/or substrate tissue distribution assays. Tritiated
(i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Isotopically labelled compounds of
Formula (I) can generally be prepared by following procedures
analogous to those disclosed in the Schemes and/or in the Examples
hereinbelow, by substituting an isotopically labelled reagent for a
non-isotopically labelled reagent.
[0126] Compounds of the present invention are useful MCP-1
antagonists; therefore, another embodiment of the present invention
is pharmaceutical compositions comprising a compound of the present
invention and a pharmaceutically acceptable excipient, diluent or
carrier.
[0127] A typical pharmaceutical composition is prepared by mixing a
compound of the present invention with a carrier, diluent,
excipient or mixtures thereof. Suitable carriers, diluents and
excipients are well known to those skilled in the art and include
materials such as carbohydrates, waxes, water soluble and/or
swellable polymers, hydrophilic or hydrophobic materials,
gelatin,oils, solvents,water, and the like. The particular carrier,
diluent or excipient used will depend upon the means and purpose
for which the active ingredient is being applied. Solvents are
generally selected based on solvents recognized by persons skilled
in the art as safe (GRAS) to be administered to a mammal. In
general, safe solvents are non-toxic aqueous solvents such as,
water and other non-toxic solvents that are soluble or miscible in
water. Suitable solvents include water, ethanol, propylene glycol,
polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures
thereof. The formulations may also include one or more buffers,
stabilizing agents, surfactants, wetting agents, lubricating
agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents and other
known additives to provide an elegant presentation of the drug or
aid in the manufacturing of the pharmaceutical product (i.e.,
medicament).
[0128] The pharmaceutical compositions may be prepared using
conventional dissolution and mixing procedures. For example, the
bulk drug substance (e.g., a compound of the present invention in
bulk form) is dissolved in a suitable solvent in the presence of
one or more of the excipients described above. The compound is
typically formulated into pharmaceutical dosage forms to provide an
easily controllable dosage of the drug and to give the patient an
elegant and easily handleable product.
[0129] Another aspect of the present invention is methods for
treating or preventing diseases associated with monocyte and/or
lymphocyte accumulation which comprises administering a
therapeutically effective amount of a compound of the present
invention to an animal in need thereof. CCR2 receptor antagonists
have been shown to inhibit the binding of MCP-1 to its receptor.
The compounds of the present invention block the migration of
monocytes in vitro and inhibit integrin expression induced by MCP-1
and are therefore useful as agents for the treatment of
inflammatory diseases, especially those associated with monocyte
accumulation, including but not limited to, atherosclerosis,
restenosis, gingivitis, glomerulonephritis, psoriasis, colitis,
multiple sclerosis, pulmonary fibrosis, Crohn's disease,
encephalomyelitis, sepsis, nephritis, asthma, rheumatoid arthritis,
wound healing and tissue transplant rejection in animals
(preferably humans). Accordingly, the compounds of the present
invention (including the pharmaceutical compositions and processes
used therein) may be used in the manufacture of a medicament for
the therapeutic applications described herein (e.g., treatment or
prevention of diseases/conditions associated with monocyte and/or
lymphocyte accumulation).
[0130] The compounds of the present invention can be administered
to a patient at dosage levels in the range of from about 0.01 to
about 100 mg per day. As used herein, the term "unit dose" or "unit
dosage" refers to physically discrete units that contain a
predetermined quantity of a compound of the present invention
calculated to produce a desired therapeutic effect. The dosage to
be administered may vary depending upon the physical
characteristics of the patient, the severity of the patient's
symptoms, and the means used to administer the drug. The specific
dose for a given patient is usually set by the judgment of the
attending physician. It is also noted that the compounds of the
present invention can be used in sustained release, controlled
release, and delayed release formulations, which forms are also
well known to one of ordinary skill in the art.
[0131] The pharmaceutical composition for application may be
packaged in a variety of ways depending upon the method used for
administering the drug. Generally, an article for distribution
includes a container which contains the pharmaceutical composition
in an appropriate form. Suitable containers are well-known to those
skilled in the art and include materials such as bottles (plastic
and glass), sachets, ampoules, plastic bags, metal cylinders, and
the like. The container may also include a tamper-proof assemblage
to prevent indiscreet access to the contents of the package. In
addition, the container has deposited thereon (or made a part of
the container) a label which describes the contents of the
container. The label may also include appropriate warnings.
[0132] The compounds of this invention may also be used in
conjunction with other pharmaceutical agents for the treatment of
the diseases/conditions described herein. Suitable pharmaceutical
agents that may be used in combination with the compounds of the
present invention include nutraceuticals, cholesterol absorption
inhibitors, HMG-CoA reductase inhibitors, MTP/Apo B secretion
inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase
transcription inhibitors, HMG-CoA reductase translation inhibitors,
CETP inhibitors, squalene synthetase inhibitors, squalene epoxidase
inhibitors, squalene cyclase inhibitors, combined squalene
epoxidase/squalene cyclase inhibitors, ACAT inhibitors, lipase
inhibitors (including pancreatic lipase inhibitors and gastric
lipase inhibitors) and peroxisome proliferator-activated receptor
(PPAR) agonists (preferably PPAR.alpha. agonists).
[0133] Any naturally occurring compound that acts to lower plasma
cholesterol levels may be administered in combination with the
compounds of the present invention. These naturally occurring
compounds are referred to herein as "nutraceuticals" and include,
for example, garlic extract and niacin.
[0134] Any cholesterol absorption inhibitor may be used as the
second compound in the combination aspect of this invention. The
term "cholesterol absorption inhibition" refers to the ability of a
compound to prevent cholesterol contained within the lumen of the
intestine from entering into the intestinal cells and/or passing
from within the intestinal cells into the blood stream. Such
cholesterol absorption inhibition activity is readily determined by
those skilled in the art according to standard assays (e.g., J.
Lipid Res. 34, 377-395 (1993)). Suitable cholesterol absorption
inhibitors are well known to those skilled in the art and include
compounds such as steroidal glycosides which are described in WO
94/00480.
[0135] Any HMG-CoA reductase inhibitor may be used as the second
compound in the combination aspect of this invention. The term
"HMG-CoA reductase inhibitor" refers to compounds which inhibit the
bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid
catalyzed by the enzyme HMG-CoA reductase. Such inhibition is
readily determined by those skilled in the art according to
standard assays (e.g., Meth. Enzymol., 71,455-509 (1981) and
references cited therein). A variety of these compounds are
described and referenced below however other HMG-CoA reductase
inhibitors will be known to those skilled in the art. For example,
U.S. Pat. No. 4,231,938 discloses certain compounds isolated after
cultivation of a microorganism belonging to the genus Aspergillus,
such as lovastatin. U.S. Pat. No. 4,444,784 discloses synthetic
derivatives of the aforementioned compounds, such as simvastatin.
U.S. Pat. No. 4,739,073. discloses certain substituted indoles,
such as fluvastatin. U.S. Pat. No. 4,346,227 discloses ML-236B
derivatives, such as pravastatin. EP-491226A discloses certain
pyridyidihydroxyheptenoic acids, such as rivastatin. U.S. Pat. Nos.
4,681,893 and 5,273,995 disclose certain
6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as
atorvastatin and the hemicalcium salt thereof (Lipitor.RTM.).
Additional HMG-CoA reductase inhibitors include itavostatin (aka
nisvastatin, pitavastatin, NK-104) and rosuvastatin (ZD-4522).
[0136] Any MTP/Apo B secretion (microsomal triglyceride transfer
protein and/or apolipoprotein B secretion) inhibitor may be used as
the second compound in the combination aspect of this invention.
The term "MTP/Apo B secretion inhibitor" refers to compounds which
inhibit the secretion of triglycerides, cholesteryl ester, and
phospholipids. Such inhibition is readily determined by those
skilled in the art according to standard assays (e.g., Wetterau, J.
R., Science, 258, 999 (1992)). A variety of these compounds are
known to those skilled in the art. Suitable MTP/Apo B secretion
inhibitors include biphenyl-2-carboxylic
acid-tetrahydro-isoquinolin-6-yl amide derivatives as described in
U.S. Pat. Nos. 5,919,795 and 6,121,283.
[0137] Any HMG-CoA synthase inhibitor may be used as the second
compound in the combination aspect of this invention. The term
"HMG-CoA synthase inhibitor" refers to compounds which inhibit the
biosynthesis of hydroxymethylglutaryl-coenzyme A from
acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the
enzyme HMG-CoA synthase. Such inhibition is readily determined by
those skilled in the art according to standard assays (e.g., Meth
Enzymol., 35,155-160 (1975): Meth. Enzymol. 110,19-26 (1985) and
references cited therein). A variety of these compounds are
described and referenced below, however other HMG-CoA synthase
inhibitors will be known to those skilled in the art. U.S. Pat. No.
5,120,729 discloses certain beta-lactam derivatives. U.S. Pat. No.
5,064,856 discloses certain spiro-lactone derivatives prepared by
culturing a microorganism (MF5253). U.S. Pat. No. 4,847,271
discloses certain oxetane compounds such as
11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,-
5,7-trimethyl-2,4-undeca-dienoic acid derivatives.
[0138] Any compound that decreases HMG-CoA reductase gene
expression may be used as the second compound in the combination
aspect of this invention. These agents may be HMG-CoA reductase
transcription inhibitors that block or decrease the transcription
of DNA or translation inhibitors that prevent or decrease
translation of mRNA coding for HMG-CoA reductase into protein. Such
compounds may either affect transcription or translation directly,
or may be biotransformed to compounds that have the aforementioned
activities by one or more enzymes in the cholesterol biosynthetic
cascade or may lead to the accumulation of an isoprene metabolite
that has the aforementioned activities. Such regulation is readily
determined by those skilled in the art according to standard assays
(e.g., Meth. Enzymol., 110, 9-19 (1985)). Inhibitors of HMG-CoA
reductase gene expression are well known to those skilled in the
art. For example, U.S. Pat. No. 5,041,432 discloses certain
15-substituted lanosterol derivatives. Other oxygenated sterols
that suppress synthesis of HMG-CoA reductase are discussed by E. I.
Mercer (Prog.Lip. Res., 32, 357-416 (1993)).
[0139] Any compound having activity as a CETP inhibitor can serve
as the second compound in the combination therapy aspect of the
instant invention. The term "CETP inhibitor" refers to compounds
that inhibit the cholesteryl ester transfer protein (CETP) mediated
transport of various cholesteryl esters and triglycerides from HDL
to LDL and VLDL. Such CETP inhibition activity is readily
determined by those skilled in the art according to standard assays
(e.g., U.S. Pat. No. 6,140,343). A variety of CETP inhibitors will
be known to those skilled in the art. For example, 4-amino
substituted-2-substituted-1,2,3,4-tetrahydroquinolines disclosed in
U.S. Pat. No. 6,140,343. U.S. Pat. No. 5,512,548 discloses certain
polypeptide derivatives having activity as CETP inhibitors, while
certain CETP-inhibitory rosenonolactone derivatives and
phosphate-containing analogs of cholesteryl ester are disclosed in
J. Antibiot., 49(8), 815-816 (1996), and Bioorg. Med. Chem. Lett.,
6, 1951-1954 (1996), respectively.
[0140] Any squalene synthetase inhibitor may be used as the second
compound of this invention. The term "squalene synthetase
inhibitor" refers to compounds which inhibit the condensation of 2
molecules of farnesylpyrophosphate to form squalene, catalyzed by
the enzyme squalene synthetase. Such inhibition is readily
determined by those skilled in the art according to standard assays
(e.g., Meth. Enzymol, 15, 393-454 (1969) and Meth. Enzymol, 110,
359-373 (1985) and references contained therein). A variety of
these compounds are known to those skilled in the art. For example,
U.S. Pat. No. 5,026,554 discloses fermentation products of the
microorganism MF5465 (ATCC 74011) including zaragozic acid. A
summary of other squalene synthetase inhibitors has been compiled
(Curr.Op.Ther. Patents, 3, 861-4 (1993)).
[0141] Any squalene epoxidase inhibitor may be used as the second
compound in the combination aspect of this invention. The term
"squalene epoxidase inhibitor" refers to compounds which inhibit
the bioconversion of squalene and molecular oxygen into
squalene-2,3-epoxide, catalyzed by the enzyme squalene epoxidase.
Such inhibition is readily determined by those skilled in the art
according to standard assays (e.g., Biochim Biophys Acta, 794,
466-471 (1984)). A variety of these compounds are well known to
those skilled in the art. For example, U.S. Pat. Nos. 5,011,859 and
5,064,864 disclose certain fluoro analogs of squalene; EP
publication 395,768 A discloses certain substituted allylamine
derivatives; PCT publication WO 9312069 discloses certain amino
alcohol derivatives; and U.S. Pat. No. 5,051,534 discloses certain
cyclopropyloxy-squalene derivatives.
[0142] Any squalene cyclase inhibitor may be used as the second
component in the combination aspect of this invention. The term
"squalene cyclase inhibitor" refers to compounds which inhibit
the,bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed
by the enzyme squalene cyclase. Such inhibition is readily
determined by those skilled in the art according to standard assays
(e.g., FEBS Lett., 244, 347-350 (1989)). Squalene cyclase
inhibitors are well known to those skilled in the art. For example,
U.S. Pat. No. 5,580,881 discloses the use of
1,2,3,5,6,7,8,8a-octahydro-5,5,8a-trimethyl-(8a.beta.)-6-isoquinolineamin-
e derivatives as squalene cyclase inhibitors.
[0143] Any combined squalene epoxidase/squalene cyclase inhibitor
may be used as the second component in the combination aspect of
this invention. The term "combined squalene epoxidase/squalene
cyclase inhibitor" refers to compounds that inhibit the
bioconversion of squalene to lanosterol via a squalene-2,3-epoxide
intermediate. In some assays it is not possible to distinguish
between squalene epoxidase inhibitors and squalene cyclase
inhibitors. However, these assays are recognized by those skilled
in the art. Thus, inhibition by combined squalene
epoxidase/squalene cyclase inhibitors is readily determined by
those skilled in art according to the aforementioned standard
assays for squalene cyclase or squalene epoxidase inhibitors. A
variety of squalene epoxidase/squalene cyclase inhibitors are well
known to those skilled in the art. For example, U.S. Pat. Nos.
5,084,461 and 5,278,171 disclose certain azadecalin derivatives; EP
publication 468,434 discloses certain piperidyl ether and
thio-ether derivatives such as 2-(1-piperidyl)pentyl isopentyl
sulfoxide and 2-(1-piperidyl)ethyl ethyl sulfide; PCT publication
WO 94/01404 discloses certain acyl-piperidines such as
1-(1-oxopentyl-5-phenylthio)-4-(2-hydrox-
y-1-methyl)-ethyl)piperidine; and U.S. Pat. No. 5,102,915 discloses
certain cyclopropyloxy-squalene derivatives.
[0144] Any ACAT inhibitor can serve as the second compound in the
combination therapy aspect of this invention. The term "ACAT
inhibitor" refers to compounds that inhibit the intracellular
esterification of dietary cholesterol by the enzyme acyl CoA:
cholesterol acyltransferase. Such inhibition may be determined
readily by one of skill in the art according to standard assays,
such as the method described in Heider et al., Journal of Lipid
Research., 24,1127 (1983). A variety of these compounds are well
known to those skilled in the art. For example, U.S. Pat. No.
5,510,379 discloses certain carboxysulfonates, while WO 96/26948
and WO 96/10559 both disclose urea derivatives having ACAT
inhibitory activity.
[0145] Examples of ACAT inhibitors include DL-melinamide disclosed
in British Pat. No. 1,123,004 and Japan. J. Pharmacol., 42, 517-523
(1986); 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide
disclosed in U.S. Pat. No. 4,716,175;
N-[2,6-bis(1-methylethyl)phenyl]-N'-[[1-(4-dimethylam-
inophenyl)cyclopentyl]-methyl]urea disclosed in U.S. Pat. No.
5,015,644;
2,6-bis(1-methylethyl)-phenyl[[2,4,6-tris(1-methylethyl)phenyl]-acetyl]su-
lfamate disclosed in copending U.S. patent application Ser. No.
08/233,932 filed Apr. 13, 1994; and the like.
[0146] Any lipase inhibitor may be used in combination with the
compounds of the present invention. The term "lipase inhibitor"
refers to a compound that inhibits the metabolic cleavage of
dietary triglycerides into free fatty acids and monoglycerides.
Under normal physiological conditions, lipolysis occurs via a
two-step process that involves acylation of an activated serine
moiety of the lipase enzyme. This leads to the production of a
fatty acid-lipase hemiacetal intermediate, which is then cleaved to
release a diglyceride. Following further deacylation, the
lipase-fatty acid intermediate is cleaved, resulting in free
lipase, a monoglyceride and a fatty acid. The resultant free fatty
acids and monoglycerides are incorporated into bile
acid-phospholipid micelles, which are subsequently absorbed at the
level of the brush border of the small intestine. The midelles
eventually enter the peripheral circulation as chylomicrons. Such
lipase inhibition activity is readily determined by those skilled
in the art according to standard assays (e.g., Methods Enzymol,
286, 190-231 (1997)).
[0147] Pancreatic lipase mediates the metabolic cleavage of fatty
acids from triglycerides at the 1- and 3-carbon positions. The
primary site of the metabolism of ingested fats is in the duodenum
and proximal jejunum by pancreatic lipase, which is usually
secreted in vast excess of the amounts necessary for the breakdown
of fats in the upper small intestine. Because pancreatic lipase is
the primary enzyme required for the absorption of dietary
triglycerides, inhibitors have utility in the treatment of obesity
and the other related conditions. Such pancreatic lipase inhibition
activity is readily determined by those skilled in the art
according to standard assays (e.g., Methods Enzymol, 286, 190-231
(1997)).
[0148] Gastric lipase is an,immunologically distinct lipase that is
responsible for approximately 10 to 40% of the digestion of dietary
fats. Gastric lipase is secreted in response to mechanical
stimulation, ingestion of food, the presence of a fatty meal or by
sympathetic agents. Gastric lipolysis of ingested fats is of
physiological importance in the provision of fatty acids needed to
trigger pancreatic lipase activity in the intestine and is also of
importance for fat absorption in a variety of physiological and
pathological conditions associated with pancreatic insufficiency.
See, for example, C. K. Abrams, et al., Gastroenterology, 92, 125
(1987). Such gastric lipase inhibition activity is readily
determined by those skilled in the art according to standard assays
(e.g., Methods Enzymol, 286, 190-231 (1997)).
[0149] A variety of gastric and/or pancreatic lipase inhibitors are
well known to one of ordinary skill in the art. Preferred lipase
inhibitors are those inhibitors selected from the group consisting
of lipstatin, tetrahydrolipstatin (orlistat), valilactone,
esterastin, ebelactone A, and ebelactone B. The compound
tetrahydrolipstatin is especially preferred. The lipase inhibitor,
N-3-trifluoromethylphenyl-N'-3-chloro-4'-
-trifluoromethylphenylurea, and the various urea derivatives
related thereto, are disclosed in U.S. Pat. No. 4,405,644. The
lipase inhibitor, esteracin, is disclosed in U.S. Pat. Nos.
4,189,438 and 4,242,453. The lipase inhibitor,
cyclo-O,O'-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxim- e, and the
various bis(iminocarbonyl)dioximes related thereto may be prepared
as described in Petersen et al., Liebig's Annalen, 562, 205-229
(1949).
[0150] A variety of pancreatic lipase inhibitors are well known to
those skilled in the art. For example, the pancreatic lipase
inhibitors lipstatin, (2S, 3S, 5S, 7Z,
10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]--
2-hexyl-3-hydroxy-7,10-hexadecanoic acid lactone, and
tetrahydrolipstatin (orlistat), (2S, 3S,
5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl--
3-hydroxy-hexadecanoic 1,3 acid lactone, and the variously
substituted N-formylleucine derivatives and stereoisomers thereof,
are disclosed in U.S. Pat. No. 4,598,089. Tetrabydrolipstatin is
prepared as described in, e.g., U.S. Pat. Nos. 5,274,143;
5,420,305; 5,540,917; and 5,643,874. The pancreatic lipase
inhibitor, FL-386, 1-[4-(2-methylpropyl)cyclohexyl]-2-[-
(phenylsulfonyl)oxy]-ethanone, and the variously substituted
sulfonate derivatives related thereto, are disclosed in U.S. Pat.
No. 4,452,813. The pancreatic lipase inhibitor, WAY-121898,
4-phenoxyphenyl-4-methylpipe- ridin-1-yl-carboxylate, and the
various carbamate esters and pharmaceutically acceptable salts
related thereto, are disclosed in U.S. Pat. Nos. 5,512,565;
5,391,571 and 5,602,151. The pancreatic lipase inhibitor,
valilactone, and a process for the preparation thereof by the
microbial cultivation of Actinomycetes strain MG147-CF2, are
disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650
(1987). The pancreatic lipase inhibitors, ebelactone A and
ebelactone B, and a process for the preparation thereof by the
microbial cultivation of Actinomycetes strain MG7-G1, are disclosed
in Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980). The use
of ebelactones A and B in the suppression of monoglyceride
formation is disclosed in Japanese Kokai 08-143457, published Jun.
4, 1996.
[0151] Other compounds that are marketed for hyperlipidemia may
also be used in combination with compounds of the present
invention, including those compounds marketed for
hypercholesterolemia which are intended to help prevent or treat
atherosclerosis, for example, bile acid sequestrants, such as
Welchol.RTM., Colestid.RTM., LoCholest.RTM. and Questran.RTM.; and
fibric acid derivatives, such as Atromid.RTM., Lopid.RTM. and
Tricor.RTM.. Examples of bile acid sequestrants are also discussed
in U.S. Pat. Nos. 3,692,895 and 3,803,237 (colestipol); U.S. Pat.
No. 3,383,281 (cholestyramine) and Casdorph R. in Lipid
Pharmacology, 1976;2:222-256, Paoletti C., Glueck J., eds. Academic
Press, N.Y.
[0152] Any peroxisome proliferator-activated receptor (PPAR)
agonists (preferably PPAR.alpha. agonists) can be used in
combination with compounds of the present invention. Suitable PPAR
agonists include fibrates (e.g., bezafibrate, ciprofibrate,
clofibrate, fenofibrate, and gemfibrozil, which are all
commercially available) and glitazones (e.g., pioglitazone, and
rosiglitazone, which are both commercially available). Gemfibrozil
is described in U.S. Pat. No. 3,674,836; bezafibrate is described
in U.S. Pat. No. 3,781,328; clofibrate is described in U.S. Pat.
No. 3,262,850; and fenofibrate is described in U.S. Pat. No.
4,058,552.
[0153] Other compounds that may be used in combination with the
compounds of the present invention include NSAIDs, COX-2
inhibitors, and antiallergics. Suitable nonsteroidal
anti-inflammatory drugs (NSAIDS) include compounds such as
ibuprofen (Motrin.TM., Advil.TM.), naproxen (Naprosyn.TM.),
sulindac (Clinori.TM.), diclofenac (Voltare.TM.), piroxicam
(Feldene.TM.), ketoprofen (Orudis.TM.), diflunisal (Dolobid.TM.),
nabumetone (Relafen.TM.), etodolac (Lodine.TM.), oxaprozin
(Daypr.TM.), and indomethacin (Indocin.TM.). Suitable COX-2
inhibitors (cyclooxygenase enzyme inhibitors) include compounds
such as celecoxib (Celebrex.TM.) and rofecoxib (Vioxx.TM.).
[0154] All of the references cited above relating to pharmaceutical
agents that may be used in combination with the compounds of the
present invention are incorporated herein by reference.
[0155] According to the methods of the invention, a compound of the
present invention or a combination therapy is administered to a
subject in need of such treatment, preferably in the form of a
pharmaceutical composition. In the combination aspect of the
invention, the compound of the present invention and the second
pharmaceutical agent may be administered either separately or in a
pharmaceutical composition comprising both. It is generally
preferred that such administration be oral. However, if the subject
being treated is unable to swallow, or oral administration is
otherwise impaired or undesirable, parenteral or transdermal
administration may be appropriate. In combination therapy
treatment, both the compounds of this invention and the other drug
therapies are administered to mammals (e.g., humans) by
conventional methods well known to those skilled in the art.
[0156] According to the methods of the invention, when a
combination of a compound of the present invention and a second
pharmaceutical agent are administered together, such administration
can be sequential in time or simultaneous with the simultaneous
method being generally preferred. For sequential administration, a
compound of the present invention and the second pharmaceutical
agent can be administered in any order. It is generally preferred
that such administration be oral. It is especially preferred that
such administration be oral and simultaneous. When a compound of
the present invention and the second pharmaceutical agent are
administered sequentially, the administration of each can be by the
same or by different methods.
[0157] According to the methods of the invention, a compound of the
present invention or a combination of drugs is preferably
administered in the form of a pharmaceutical composition comprising
a pharmaceutically acceptable carrier, excipient, diluent or
mixture thereof. Accordingly, a compound of the present invention
or a combination of a compound of the present invention with a
second pharmaceutical agent can be administered to a patient
separately or together in any conventional oral, rectal,
transdermal, parenteral, (for example, intravenous, intramuscular,
or subcutaneous) intracisternal, intravaginal, intraperitoneal,
intravesical, local (for example, powder, ointment or drop),
buccal, or nasal dosage form.
[0158] Compositions suitable for parenteral injection may comprise
pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions, or emulsions, and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents, or excipients include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0159] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents. Prevention
of microorganism contamination of the compositions can be
accomplished with various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride, and the like. Prolonged
absorption of injectable pharmaceutical compositions can be brought
about by the use of agents capable of delaying absorption, for
example, aluminum monostearate and gelatin.
[0160] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, the
drug (e.g., active compound or prodrug thereof) is admixed with at
least one inert customary pharmaceutical excipient (or carrier)
such as sodium citrate or dicalcium phosphate or (a) fillers or
extenders (e.g., starches, lactose, sucrose, mannitol, silicic
acid, and the like); (b) binders (e.g., carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the
like); (c) humectants (e.g., glycerol); (d) disintegrating agents
(e.g., agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates, sodium carbonate and the
like); (e) solution retarders (e.g., paraffin); (f) absorption
accelerators (e.g., quaternary ammonium compounds); (g) wetting
agents (e.g., cetyl alcohol and glycerol monostearate); (h)
adsorbents (e.g., kaolin and bentonite); and/or (i) lubricants
(e.g., talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, or mixtures thereof).
In the case of capsules and tablets, the dosage forms may also
comprise buffering agents.
[0161] Solid compositions of a similar type may also be used as
fillers in soft or hard filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene glycols, and the like.
[0162] Solid dosage forms such as tablets, dragees, capsules, and
granules can be prepared with coatings and shells, such as enteric
coatings and others well known in the art. They may also contain
opacifying agents, and can also be of such composition that they
release the drug or compounds in a delayed manner. Examples of
embedding compositions that can be used are polymeric substances
and waxes. The drug can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0163] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the drug(s), the liquid dosage
form may contain inert diluents commonly used in the art, such as
water or other solvents, solubilizing agents and emulsifiers, as
for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate,
ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
1,3-butylene glycol, dimethylformamide, oils, in particular,
cottonseed oil, groundnut oil, corn germ oil, olive oil, castor
oil, and sesame seed oil, glycerol, tetrahydrfurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, or mixtures
of these substances, and the like.
[0164] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0165] Suspensions, in addition to the drug, may further comprise
suspending agents, e.g., ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol or sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar,
tragacanth, or mixtures of these substances, and the like.
[0166] Compositions for rectal or vaginal administration preferably
comprise suppositories, which can be prepared by mixing a compound
of the present invention or combination of drugs with suitable
non-irritating excipients or carriers such as cocoa butter,
polyethylene glycol or a suppository wax, which are solid at
ordinary room temperature, but liquid at body temperature, and
therefore, melt in the rectum or vaginal cavity thereby releasing
the active component.
[0167] Dosage forms for topical administration of the compounds of
the present invention and combination therapies may comprise
ointments, powders, sprays and inhalants. The drugs are admixed
under sterile condition with a pharmaceutically acceptable carrier,
and any preservatives, buffers, or propellants that may be
required. Opthalmic formulations, eye ointments, powders, and
solutions are also intended to be included within the scope of the
present invention.
[0168] Advantageously, the present invention also provides kits for
use by a consumer having, or at risk of having, a disease or
condition associated with monocyte, lymphocyte or leucocyte
accumulation, which can be ameliorated by a CCR2 or CCR3
antagonist. Such kits include a suitable dosage form such as those
described above and instructions describing the method of using
such dosage form to mediate, reduce or prevent inflammation. The
instructions would direct the consumer or medical personnel to
administer the dosage form according to administration modes known
to those skilled in the art. Such kits could advantageously be
packaged and sold in single or multiple kit units.
[0169] Since the present invention has an aspect that relates to
the treatment of the disease/conditions described herein with a
combination of active ingredients which may be administered
separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit. comprises two
separate pharmaceutical compositions: a compound of the present
invention and a second pharmaceutical agent as described above. The
kit comprises a container (e.g., a divided bottle or a divided foil
packet). Typically, the kit comprises directions for the
administration of the separate components. The kit form is
particularly advantageous when the separate components are
preferably administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician.
[0170] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0171] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of a first compound can consist
of one tablet or capsule while a daily dose of the second compound
can consist of several tablets or capsules and vice versa. The
memory aid should reflect this.
[0172] The following Examples illustrate the preparation of
compounds represented by Formula I. The examples are not intended
to be limiting to the scope of the invention in any respect, and
should not be so construed.
EXAMPLES
[0173] Unless specified otherwise, starting materials are generally
available from commerical sources such as Aldrich Chemicals Co.
(Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, N.H.), Acros
Organics (Fairlawn, N.J.), Maybridge Chemical Company, Ltd.
(Cornwall, England), Tyger Scientific (Princeton, N.J.), and
AstraZeneca Pharmaceuticals (London, England).
General Experimental Procedures
[0174] NMR spectra were recorded on a Varian Unity.TM. 400
(available from Varian Inc., Palo Alto, Calif.) at room temperature
at 400 MHz for proton. Chemical shifts are expressed in parts per
million (.delta.) relative to residual solvent as an internal
reference. The peak shapes are denoted as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet;
2s, two singlets. Atmospheric pressure chemical ionization mass
spectra (APCI) were obtained on a Fisons.TM. Platform II
Spectrometer (carrier gas: acetonitrile, available from Micromass
Ltd, Manchester, UK). Chemical ionization mass spectra (Cl) were
obtained on a Hewlett-Packard.TM. 5989 instrument (ammonia
ionization, PBMS: available from Hewlett-Packard Company, Palo
Alto, Calif.). Where the intensity of chlorine or
bromine-containing ions are described, the expected intensity ratio
was observed (approximately 3:1 for .sup.35Cl.sup.37Cl-containing
ions and 1:1 for .sup.79Br/.sup.81Br-containing ions) and the
intensity of only the lower mass ion is given. In some cases only
representative .sup.1H NMR peaks are given. MS peaks are reported
for all examples. Optical rotations were determined on a
PerkinElmer.TM. 241 polarimeter (available from PerkinElmer Inc.,
Wellesley, Mass.) using the sodium D line (.lambda.=589 nm) at the
indicated temperature and are reported as follows
[.alpha.].sub.D.sup.temp, concentration (c=g/100 mL), and
solvent.
[0175] Column chromatography was performed with either Baker.TM.
silica gel (40 .mu.m; J. T. Baker, Phillipsburg, N. J.) or Silica
Gel 50 (EM Sciences.TM., Gibbstown, N.J.) in glass columns or in
Flash 40 Biotage.TM. columns (ISC, Inc., Shelton, Conn.) under low
nitrogen pressure.
[0176] Example 1 illustrates the preparation of bicyclic diamine
compounds having formula I where w, x, y and z are all equal to 1
and no linking group (L).
Example 1
Preparation of 1,4-dibenzyl-diazabicyclo[3.3.0]octane-2.6-dione
(I-1a)
[0177] 16
[0178] Paraformaldehyde (13.5 g) was added to a solution of
N-benzylmaleimide (10.8 g; 60 mmol) and N-benzylglycine (9.9 g; 60
mmol) in toluene (400 mL) and the resulting mixture was refluxed
with azeotropic removal of water, for 10 hours. The mixture was
cooled to room temperature and was concentrated in vacuo. The
mixture was purified by flash chromatography (30% EtOAc in hexane)
to afford 15 g (78%) of the title product (I-1a), as an amorphous
solid.
Preparation of 1-benzyl-diazabicyclo[3.3.0]octane-2,6-dione
(I-1b)
[0179] 17
[0180] A solution of the dibenzyl compound I-1a (8.6 g; 27 mmol.)
in dichloromethane (100 mL) was cooled to 0.degree. C. and
.alpha.-chloroethylchloroformate (7.7 g; 54 mmol) was added
dropwise over 30 min. The solution was then stirred-for an
additional 30 minutes. The resulting solution was refluxed for 4
hours. The solution was cooled to room temperature and was
concentrated in vacuo and methanol was added to the residue. This
mixture was stirred at 50.degree. C. for 1 hour. The mixture was
concentrated in vacuo and ether was added to afford the product
(I-1b) as white crystals (5.8 g, 94%).
Preparation of 1-benzyl-diazabicyclo[3.3.0]octane (I-1c)
[0181] 18
[0182] To a solution of the imide I-1b (0.48 g, 1.8 mmol.) in
anhydrous THF (65 mL) was added a solution of
borane-dimethylsulfide complex in THF (2M, 4.5 mL, 0.9 mmol)
dropwise. The mixture was stirred overnight at room temperature and
2N HCl solution (45 mL) was added dropwise over 4 hours. The
resulting mixture was refluxed for 30 min. The solution was cooled
and concentrated in vacuo. The pH of the resulting suspension was
adjusted to 10 (aq. NaOH) and the mixture was extracted with
CH.sub.2Cl.sub.2. The organic extract was dried (MgSO.sub.4) and
concentrated in vacuo to afford a colorless oil (335 mg; 91%).
Preparation of 1-benzyl-4-boc-diazabicyclo[3.3.0]octane (I1-d)
[0183] 19
[0184] To a solution of the diamine I-1c (0.283 g, 1.4 mmol.) in
dry CH.sub.2Cl.sub.2 (2 mL) was added boc-anhydride in
CH.sub.2Cl.sub.2 (1 mL) over 5 minutes and the resulting mixture
was stirred overnight at room temperature. The solution was
concentrated in vacuo and the crude product was purified by
preparative chromatography to afford the carbamate I-1d (275 mg,
65%).
Preparation of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
tert-butyl ester (I-1e)
[0185] 20
[0186] To a solution of the N-benzyl compound I-1d (0.325 g, 0.1
mmol) in EtOH (5 mL) was added 10% palladium on carbon (0.3 g) and
ammonium formate (0.34 g, 0.5 mmol). The resulting mixture was
refluxed for 2 hours and cooled. The solids were filtered off with
the aid of a Florisil.TM. pad (available from US Silica Company,
Berkeley Springs, W. Va.). The crude product was purified using
preparative chromatography to afford 0.185 g (82%) of the title
compound I-1e as a low melting solid. .sup.1H NMR (CDCl.sub.3)
.delta. 3.5 (m, 2H), 3.32 (m, 1H), 3.15 (m, 1H), 3.00 (M, 2H), 2.75
(br, 1H), 2.72 (br, 1H), 2.45 (m, 1 H), 1.4 (s, 9H).
Preparation of
[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2--
carboxylic acid tert-butyl ester (I-1f)
[0187] 21
[0188] 6.0 mmols of 2,4-difluorobenzaldehyde was added to a 1.0 M
tetrahydrofuran solution containing 3.0 mmols of
hexahydro-pyrrolo[3,4-c]- pyrrole-2-carboxylic acid tert-butyl
ester (I-1e). To this solution was added 24 mL of anhydrous
methanol containing 1% glacial acetic acid. This mixture was
allowed to proceed at room temperature under gentle agitation on a
shaker plate for 1 hour. Then, 9.0 mmols of sodium
tri-acetoxy-borohydride was added in one batch at room temperature.
The reaction mixture was allowed to stir overnight at room
temperature. The solvent was then removed in vacuo and 25 mL of 1.0
M sodium hydroxide was added. The crude product was extracted into
ethyl acetate, dried over sodium sulfate and the solvent removed in
vacuo. The material was purified by liquid chromatography to afford
intermediate I-1f in 75% yield (2.27 mmol).
Preparation of 1-(2,4-difluoro-benzyl)-octahydro-pyrrol[3,4]-pyrrol
(I-1g)
[0189] 22
[0190] 2.27 mmols of I-1f was dissolved in 50 mL of methylene
chloride and 50 mL of trifluoroacetic acid. The reaction was
stirred for 45 minutes at room temperature. Then, the solvent was
removed in vacuo and the material was dissolved in 25 mL of ethyl
acetate. The reaction was cooled to 0.degree. C. and basified with
6.0 M sodium hydroxide. The organic layer was collected dried over
sodium sulfate and concentrated in vacuo to dryness. 542 mg (99%
yield) of I-1g was obtained as a yellow oil.
Preparation of
[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-y-
l]-(2-ethoxy-phenyl)-methanone (1)
[0191] 23
[0192] 150 .mu.L of 2-ethoxy benzoic acid (0.2M in
N,N-dimethylacetamide (DMA) and 3.75% TEA) was added to 100 .mu.L
of 2-amino-1-[5-(2,4-difluoro-
-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethanone (I-1g)(0.2M
in 1:1 toluene/DMA) and 3.75% n-methyl morpholine (NMM) followed by
the addition of 150 .mu.L (30 .mu.mol) of
O-benzotriazol-1-yl-N,N,N',N'-tetramethyl-ur-
onium-hexa-fluoro-phosphate (HBTU) solution (0.2M in DMA). The
reaction was heated to 60.degree. C. for six hours and then allowed
to stir overnight at room temperature. Then, the reaction was
quenched with 450 .mu.L 10% NaOH, followed by the addition of 900
.mu.L of ethyl acetate. The reaction was vigorously shaken for 15
minutes, and then allowed to stand at room temperature for 30
minutes.
[0193] The reaction mixture was purified by liquid chromatography
on a 1 g SCX SPE cartridge conditioned with MeOH. The cartridge was
eluted with 1 M NH.sub.3/MeOH to afford 5.0 mg of the desired
product
[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-ethoxy-p-
henyl)-methanone (1) as a yellow oil.
[0194] MS (Cl) m/z=386.18 (M+1). .sup.1H NMR (CDCl.sub.3) was
consistent with compound (1).
[0195] The following compounds were prepared using the same general
procedures described above with the appropriate starting materials.
Table 1 below lists the compounds made and their corresponding
retention times (in minutes) using HPLC and their molecular weight
(ms (Cl) m/z (M+1)) as determined by chemical ionization mass
spectroscopy.
1TABLE 1 Time MW Compound Name (mins) (found)
2-Biphenyl-4-yl-1-[5-(2,3-dimethoxy-benzyl- )-hexahydro- 1.78
456.24 pyrrolo[3,4-c]pyrrol-2-yl]-ethanone
2-Biphenyl-4-yl-1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.89 424.25 c]pyrrol-2-yl]-ethanone 2-Biphenyl-4-yl-1-[5-(2-chlo-
ro-3,4-dimethoxy-benzyl)-hexahydro- 1.82 490.2
pyrrolo[3,4-c]pyrrol-2-yl]-ethanone 1-[5-(2,4-Dimethoxy-benzyl)-he-
xahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.77 422.26
2-(4-isopropyl-phenyl)-ethanone 1-[5-(2,3-Dimethoxy-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.74 422.26
2-(4-isopropyl-phenyl)-- ethanone
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol--
2-yl]-2- 1.86 390.27 (4-isopropyl-phenyl)-ethanone
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.78
456.22 c]pyrrol-2-yl]-2-(4-isopropyl-phenyl)-ethanone
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 394.23 2-m-tolyl-ethanone 1-[5-(2,3-Dimethoxy-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.49 394.23 2-m-tolyl-ethanone
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.62 362.24 m-tolyl-ethanone 1-[5-(2-Chloro-3,4-dimethoxy-b-
enzyl)-hexahydro-pyrrolo[3,4- 1.53 428.19
c]pyrrol-2-yl]-2-m-tolyl-- ethanone
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol- -2-yl]-
1.53 394.23 2-p-tolyl-ethanone
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.49 394.23 2-p-tolyl-ethanone 1-[5-(2,4-Dimethyl-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.62 362.24 p-tolyl-ethanone
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.54
428.19 c]pyrrol-2-yl]-2-p-tolyl-ethanone 1-[5-(2,4-Dimethoxy-benzy-
l)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.62 408.24
2-(2,5-dimethyl-phenyl)-ethanone 1-[5-(2,3-Dimethoxy-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.59 408.24
2-(2,5-dimethyl-phenyl)-ethanone 1-[5-(2,4-Dimethyl-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.7 376.25
(2,5-dimethyl-phenyl)-ethanone 1-[5-(2-Chloro-3,4-dimethoxy-benzyl-
)-hexahydro-pyrrolo[3,4- 1.63 442.2
c]pyrrol-2-yl]-2-(2,5-dimethyl-- phenyl)-ethanone
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-- c]pyrrol-2-yl]-
1.65 430.23 2-naphthalen-1-yl-ethanone
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.63 430.23 2-naphthalen-1-yl-ethanone 1-[5-(2,4-Dimethyl-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.73 398.24
naphthalen-1-yl-ethanone 1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexa-
hydro-pyrrolo[3,4- 1.66 464.19
c]pyrrol-2-yl]-2-naphthalen-1-yl-eth- anone
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-- yl]-
1.51 434.18 2-(2,3,6-trifluoro-phenyl)-ethanone
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.48 434.18 2-(2,3,6-trifluoro-phenyl)-ethanone
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.6 402.19 (2,3,6-trifluoro-phenyl)-ethanone
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.52
468.14 c]pyrrol-2-yl]-2-(2,3,6-trifluoro-phenyl)-ethanone
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.4 380.21 2-phenyl-ethanone 1-[5-(2,3-Dimethoxy-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.36 380.21 2-phenyl-ethanone
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.5 348.22 phenyl-ethanone 1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-
-hexahydro-pyrrolo[3,4- 1.42 414.17
c]pyrrol-2-yl]-2-phenyl-ethanon- e
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.65 408.24 2-(3,5-dimethyl-phenyl)-ethanone
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.61 408.24 2-(3,5-dimethyl-phenyl)-ethanone
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.68 376.25 (3,5-dimethyl-phenyl)-ethanone
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.65
442.2 c]pyrrol-2-yl]-2-(3,5-dimethyl-phenyl)-ethanone
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.63 408.24 2-(2,4-dimethyl-phenyl)-ethanone
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.59 408.24 2-(2,4-dimethyl-phenyl)-ethanone
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.7 376.25 (2,4-dimethyl-phenyl)-ethanone
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.63
442.2 c]pyrrol-2-yl]-2-(2,4-dimethyl-phenyl)-ethanone
5-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- 0.79
349.16 carbonyl]-pyrrolidin-2-one 5-[5-(2,3-Difluoro-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrole-2- 0.8 349.16 carbonyl]-pyrrolidin-2-one
5-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- 0.75
349.16 carbonyl]-pyrrolidin-2-one 5-[5-(3,5-Difluoro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrole-2- 0.86 349.16
carbonyl]-pyrrolidin-2-one N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-
-pyrrolo[3,4-c]pyrrole-2- 1.55 467.24
carbonyl]-cyclohexyl}-benzami- de
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.56 467.24 carbonyl]-cyclohexyl}-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.53 467.24 carbonyl]-cyclohexyl}-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.62 467.24 carbonyl]-cyclohexyl}-benzamide
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2-
2.6 551.2
methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methano- ne
{-[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazole-4- 2.7
604.9 carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(2,6-dich-
loro- phenyl)-methanone [1-(3,5-Bis-trifluoromethyl-phenyl)--
5-methyl-1H-pyrazol-4-yl]-[5-(3- 2.8 605.2
trifluoromethyl-benzoyl)- -hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2-
2.3 557.2
chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanon- e
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-
2.5 591.1 (3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-y-
l]- methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1-
H-pyrazol-4-yl]-[5- 2.3 575.2
(2-chloro-6-fluoro-benzyl)-hexahydro-- pyrrolo[3,4-c]pyrrol-2-yl]-
methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-
2.3 559.2
(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-p-
yrazol-4-yl]-[5- 2.3 559.2
(2,6-difluoro-benzyl)-hexahydro-pyrrolo[- 3,4-c]pyrrol-2-yl]-
methanone [1-(3,5-Bis-trifluoromethyl-ph-
enyl)-5-methyl-1H-pyrazol-4-yl]-[5-(3- 2.4 557.2
chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(3-
2.3 541.2
fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanon- e
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-(5-
2.4 577.2 (2,3,4-trifluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol--
2-yl]- methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methy-
l-1H-pyrazol-4-yl]-[5-(3- 2.5 575.1
chloro-4-fluoro-benzyl)-hexahyd- ro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2-
2.4 575.1
chloro-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- -
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H--
pyrazol-4-yl]-[5-(2- 2.3 541.2
fluoro-benzyl)-hexahydro-pyrrolo[3,4- -c]pyrrol-2-yl]-methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-met-
hyl-1H-pyrazol-4-yl]-[5-(4- 2.4 557.1
chloro-benzyl)-hexahydro-pyrr- olo[3,4-c]pyrrol-2-yl]-methanone
[1-(3,5-Bis-trifluoromethyl-phenyl- )-5-methyl-1H-pyrazol-4-yl]-[5-
2.5 591.1 (2,4-dichloro-benzyl)-hex-
ahydro-pyrrolo[3,4-c]pyrrol-2-yl]- methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-
2.6 625.1
(2,3,6-trichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl- ]-
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-
-pyrazol-4-yl]-[5- 2.9 627.1
(2,3,5-trichloro-benzyl)-hexahydro-pyr- rolo[3,4-c]pyrrol-2-yl]-
methanone [1-(3,5-Bis-trifluorometh-
yl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5- 2.4 591.1
(2,6-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol--
4-yl]-[5- 2.4 559.2
(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl]-
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-
-methyl-1H-pyrazol-4-yl]-[5- 2.3 577.1
(2,3,6-trifluoro-benzyl)-hex- ahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-
2.4 577.2
(2,4,5-trifluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl- ]-
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-
-pyrazol-4-yl]-[5-(4- 2.3 541.2
fluoro-benzyl)-hexahydro-pyrrolo[3,- 4-c]pyrrol-2-yl]-methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-me- thyl-1H-pyrazol-4-yl]-[5-
2.5 591.1 (3,5-dichloro-benzyl)-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-yl]- methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-
2.4 559.2
(3,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone [1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-p-
yrazol-4-yl]-[5- 2.5 591.1
(2,3-dichloro-benzyl)-hexahydro-pyrrolo[- 3,4-c]pyrrol-2-yl]-
methanone [1-(3,5-Bis-trifluoromethyl-ph-
enyl)-5-methyl-1H-pyrazol-4-yl]-[5- 2.3 559.2
(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
methanone [5-(2-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-
]-[1-(3,4- 2.2 491.1
dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-met- hanone
[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl- ]-[1-
2.4 525 (3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-metha- none
[5-(2-Chloro-6-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl]- 2.1 509
[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-me- thanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,4--
difluoro- 2.1 491.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-me- thanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,6--
difluoro- 2.1 491.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-me- thanone
[5-(3-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[-
1-(3,4- 2.3 491.1
dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-methan- one
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(3-fluoro- -
2.1 473.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,3,4- 2.2
509.1 trifluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-metha-
none
[5-(3-Chloro-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl]- 2.3 507.1
[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-- methanone
[5-(2-Chloro-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]- 2.2 507.1
[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4- -yl]-methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[- 5-(2-fluoro-
2.1 473.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- -methanone
[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-
]-[1-(3,4- 2.3 491.1
dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-met- hanone
[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl- ]-[1-
2.3 525.1 (3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-met-
hanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,3,6- - 2.4
559 trichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-me-
thanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,3,- 5- 2.5
559 trichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-m-
ethanone
[5-(2,6-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-- yl]-[1-
2.2 525.1 (3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-m-
ethanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,5-
-difluoro- 2.1 491.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-m- ethanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2,3- ,6- 2.1
509.1 trifluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-
]-methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(- 2,4,5- 2.2
509.1 trifluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl]-methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[- 5-(4-fluoro-
2.1 473.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- -methanone
[5-(3,5-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-- 2-yl]-[1-
2.4 525.1 (3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-
-methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(3-
,4-difluoro- 2.2 491.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- -methanone
[5-(2,3-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-- 2-yl]-[1-
2.3 525.1 (3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-
-methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2-
,3-difluoro- 2.1 491.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- -methanone
[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-[5-(2- ,4- 2.1
483.3 dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
-methanone
[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-- 4-yl]-[5-
2.3 551.3 (2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]p-
yrrol-2-yl]- methanone 1-{5-[1-(3,5-Bis-trifluoromethyl-phen-
yl)-5-methyl-1H-pyrazole-4- 2.7 565
carbonyl]-hexahydro-pyrrolo[3,4- -c]pyrrol-2-yl}-2-o-tolyl-ethanone
[1-(3,5-Bis-trifluoromethyl-phen- yl)-5-methyl-1H-pyrazol-4-yl]-(5-
2.6 543.2 cyclohexanecarbonyl-hex-
ahydro-pyrrolo[3,4-c]pyrrol-2-yl)- methanone
1-{5-[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazole-4-
2.4 503.2
carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-butan-1-one
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.35 386.18 ethoxy-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.37 386.18 ethoxy-phenyl)-methanone [5-(3,5-Difluoro-benzyl)-he-
xahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2- 1.4 386.18
ethoxy-phenyl)-methanone [5-(2,4-Difluoro-benzyl)-hexahydro-pyrrol-
o[3,4-c]pyrrol-2-yl]-(2- 1.41 410.14
trifluoromethyl-phenyl)-methan- one
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(- 2-
1.43 410.14 trifluoromethyl-phenyl)-methanone
[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.4 410.14 trifluoromethyl-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.47 410.14 trifluoromethyl-phenyl)-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.6
428.13 (fluoro-4-trifluoromethyl-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.63 428.13 fluoro-4-trifluoromethyl-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.67 428.13 fluoro-4-trifluoromethyl-phenyl)-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(2,4-difluoro-benzyl)- 1.68
478.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(2,3-difluoro-benzyl)- 1.72
478.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
2,5-Bis-trifluoromethyl-phenyl)-[5-(2,5-difluoro-benzyl)-hexahydro-
1.7 478.13 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(3,5-difluoro-benzyl)- 1.76
478.13 hexahydro-pyrrolo[3,4-c]pyrrolo-2-yl]-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.42
396.13 (2,3,4-trifluoro-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.45
396.13 (2,3,4-trifluoro-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.48
396.13 (2,3,4-trifluoro-phenyl)-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.58 428.13 fluoro-3-trifluoromethyl-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.6 428.13 fluoro-3-trifluoromethyl-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.65 428.13 fluoro-3-trifluoromethyl-phenyl)-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2,4-difluoro-benzyl)- 1.75
478.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2,3-difluoro-benzyl)- 1.79
478.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2,5-difluoro-benzyl)- 1.78
478.13
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(3,5-difluoro-benzyl)- 1.83
478.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.49 428.13 fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.51 428.13 fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.48 428.13 fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.55 428.13 fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.48 426.14 trifluoromethoxy-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.51 426.14 trifluoromethoxy-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.55 426.14 trifluoromethoxy-phenyl)-methanone
(2-Chloro-3-trifluoromethyl-phenyl)-[5-(2,4-difluoro-benzyl)- 1.62
444.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-3-trifluoromethyl-phenyl)-[5-(2,3-difluoro-benzyl)- 1.65
444.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-3-trifluoromethyl-phenyl)-[5-(3,5-difluoro-benzyl)- 1.68
444.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.37 408.15 difluoromethoxy-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.38 408.15 difluoromethoxy-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.42 408.15 difluoromethoxy-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.4 410.22 ethoxy-phenyl)-methanone [5-(2,4-Dimethyl-benzyl)-he-
xahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2- 1.52 378.23
ethoxy-phenyl)-methanone [5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahy-
dro-pyrrolo[3,4- 1.45 444.18
c]pyrrol-2-yl]-(2-ethoxy-phenyl)-metha- none
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
-(2- 1.45 434.18 trifluoromethyl-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.55 402.19 trifluoromethyl-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.5
468.14 c]pyrrol-2-yl]-(trifluoromethyl-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.65 452.17 fluoro-4-trifluoromethyl-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.62 452.17 fluoro-4-trifluoromethyl-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.74 420.18 fluoro-4-trifluoromethyl-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.68
486.13 c]pyrrol-2-yl]-(2-fluoro-4-trifluoromethyl-phenyl)-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(2,4-dimethoxy-benzyl)- 1.73
502.17 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(2,3-dimethoxy-benzyl)- 1.7
502.17 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(2,4-dimethyl-benzyl)- 1.82
470.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,5-Bis-trifluoromethyl-phenyl)-[5-(2-chloro-3,4-dimethoxy- 1.74
536.13 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.5
420.17 (2,3,4-trifluoro-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 420.17 (2,3,4-trifluoro-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.59
388.18 (2,3,4-trifluoro-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.51
454.13 c]pyrrol-2-yl]-(2,3,4-trifluoro-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.63 452.17 fluoro-3-trifluoromethyl-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.61 452.17 fluoro-3-trifluoromethyl-phenyl-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.73 420.18 fluoro-3-trifluoromethyl-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.65
486.13 c]pyrrol-2-yl]-(2-fluoro-3-trifluoromethyl-phenyl)-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2,4-dimethoxy-benzyl)- 1.79
502.17 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2,3-dimethoxy-benzyl)- 1.77
502.17 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2,4-dimethyl-benzyl)- 1.87
470.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,4-Bis-trifluoromethyl-phenyl)-[5-(2-chloro-3,4-dimethoxy- 1.8
536.13 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.54 452.17 fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.52 452.17 fluoro-2-trifluoromethyl-phenyl)-methanone
5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-
1.65 420.18 fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.57
486.13 c]pyrrol-2-yl]-(4-fluoro-2-trifluoromethyl-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.55 450.18 trifluoromethoxy-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.51 450.18 trifluoromethoxy-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.64 418.19 trifluoromethoxy-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.56
484.14 c]pyrrol-2-yl]-(2-trifluoromethoxy-phenyl)-methanone
(2-Chloro-3-trifluoromethyl-phenyl)-[5-(2,4-dimethoxy-benzyl)- 1.66
468.14 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-3-trifluoromethyl-phenyl)-[5-(2,3-dimethoxy- 1.64 468.14
benzylhexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-3-trifluoromethyl-phenyl)-[5-(2,4-dimethyl-benzyl)- 1.76
436.15 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.67
502.1 c]pyrrol-2-yl]-(2-chloro-3-trifluoromethyl-phenyl)-methanone
(2-Difluoromethoxy-phenyl)-[5-(2,4-dimethoxy-benzyl)-hexahydro-
1.44 432.19 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Difluoromethoxy-phenyl)-[5-(2,3-dimethoxy-benzyl)-hexahydro-
1.42 432.19 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Difluoromethoxy-phenyl)-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.54
400.2 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.46
466.15 c]pyrrol-2-yl]-(2-difluoromethoxy-phenyl)-methanone
(2,6-Dichloro-phenyl)-[5-(2,4-difluoro-benzyl)-hexahydro- 1.36
410.08 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,6-Dichloro-phenyl)-[5-(- 2,3-difluoro-benzyl)-hexahydro- 1.39
410.08 pyrrolo[3,4-c]pyrrol-2-- yl]-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]-(2,6- 1.38 370.19 dimethyl-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6-
1.4 370.19 dimethyl-phenyl)-methanone [5-(2,5-Difluoro-benzyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6- 1.37 370.19
dimethyl-phenyl)-methanone [5-(3,5-Difluoro-benzyl)-hexahydro-pyrr-
olo[3,4-c]pyrrol-2-yl]-(2,6- 1.44 370.19 dimethyl-phenyl)-methanone
(2-Chloro-6-fluoro-phenyl)-[5-(2,4-difluoro-benzyl)-hexahydro- 1.3
394.11 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-6-fluoro-phenyl)-[5-(2,3-difluoro-benzyl)-hexahydro- 1.34
394.11 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-6-fluoro-phenyl)-[5-(3,5-difluoro-benzyl)-hexahydro- 1.38
394.11 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6-
1.24 378.14 difluoro-phenyl)-methanone [5-(2,3-Difluoro-benzyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6- 1.26 378.14
difluoro-phenyl)-methanone [5-(3,5-Difluoro-benzyl)-hexahydro-pyrr-
olo[3,4-c]pyrrol-2-yl]-(2,6- 1.3 378.14 difluoro-phenyl)-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.33
396.13 (2,3,6-trifluoro-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.35
396.13 (2,3,6-trifluoro-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.4
396.13 (2,3,6-trifluoro-phenyl)-methanone [5-(2,4-Difluoro-benzyl)-
-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2- 1.42 428.13
fluoro-6-trifluoromethyl-phenyl)-methanone [5-(2,3-Difluoro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2- 1.45 428.13
fluoro-6-trifluoromethyl-phenyl)-methanone [5-(2,5-Difluoro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2- 1.42 428.13
fluoro-6-trifluoromethyl-phenyl)-methanone [5-(3,5-Difluoro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2- 1.49 428.13
fluoro-6-trifluoromethyl-phenyl)-methanone [5-(2,4-Difluoro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.31 396.13
(2,4,6-trifluoro-phenyl)-methanone [5-(2,3-Difluoro-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.34 396.13
(2,4,6-trifluoro-phenyl- )-methanone
[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol- -2-yl]-
1.28 396.13 (2,4,6-trifluoro-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.38
396.13 (2,4,6-trifluoro-phenyl)-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6-
1.26 402.18 dimethoxy-phenyl)-methanone [5-(2,3-Difluoro-benzyl)-
-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6- 1.28 402.18
dimethoxy-phenyl)-methanone [5-(2,5-Difluoro-benzyl)-hexahydro-pyr-
rolo[3,4-c]pyrrol-2-yl]-(2,6- 1.24 402.18
dimethoxy-phenyl)-methano- ne
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
,6- 1.31 402.18 dimethoxy-phenyl)-methanone
[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.31
432.19 (2,3,6-trimethoxy-phenyl)-methanone
[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.32
432.19 (2,3,6-trimethoxy-phenyl)-methanone
[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.28
432.19 (2,3,6-trimethoxy-phenyl)-methanone
[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.36
432.19 (2,3,6-trimethoxy-phenyl)-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(2,4-difluoro-benzyl)- 1.49
436.14 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(2,3-difluoro-benzyl)- 1.48
436.14 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(2,5-difluoro-benzyl)- 1.45
436.14 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(3,5-difluoro-benzyl)- 1.54
436.14 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,6-Dichloro-phenyl)-[5-(2,4-dimethoxy-benzyl)-hexahydro- 1.44
434.12 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,6-Dichloro-phenyl)-[5-- (2,3-dimethoxy-benzyl)-hexahydro- 1.4
434.12 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2-Chloro-3,4-dimethoxy-be- nzyl)-hexahydro-pyrrolo[3,4- 1.45
468.08 c]pyrrol-2-yl]-(2,6-dichlo- ro-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,- 4-c]pyrrol-2-yl]-
1.44 394.23 (2,6-dimethyl-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.41 394.23 (2,6-dimethyl-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6-
1.55 362.24 dimethyl-phenyl)-methanone [5-(2-Chloro-3,4-dimethox-
y-benzyl)-hexahydro-pyrrolo[3,4- 1.47 428.19
c]pyrrol-2-yl]-(2,6-dimethyl-phenyl)-methanone
(2-Chloro-6-fluoro-phenyl)-[5-(2,4-dimethoxy-benzyl)-hexahydro-
1.38 418.15 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-6-fluoro-phenyl)-[5-(2,3-dimethoxy-benzyl)-hexahydro-
1.35 418.15 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2-Chloro-6-fluoro-phenyl)-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.5
386.16 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.41
452.11 c]pyrrol-2-yl]-(2-chloro-6-fluoro-phenyl)-methanone
(2,6-Difluoro-phenyl)-[5-(2,4-dimethoxy-benzyl)-hexahydro- 1.34
402.18 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,6-Difluoro-phenyl)-[5-- (2,3-dimethoxy-benzyl)-hexahydro- 1.3
402.18 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(2,6-Difluoro-phenyl)-[5-(2,4- -dimethyl-benzyl)-hexahydro- 1.45
370.19 pyrrolo[3,4-c]pyrrol-2-yl]- -methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- - 1.35
436.14 c]pyrrol-2-yl]-(2,6-difluoro-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 420.17 (2,3,6-trifluoro-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.38 420.17 (2,3,6-trifluoro-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.48 452.17 fluoro-6-trifluoromethyl-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.45 452.17 fluoro-6-trifluoromethyl-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-
1.61 420.18 fluoro-6-trifluoromethyl-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.5
486.13 c]pyrrol-2-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.4
420.17 (2,4,6-trifluoro-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.36 420.17 (2,4,6-trifluoro-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.51
388.18 (2,4,6-trifluoro-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.43
454.13 c]pyrrol-2-yl]-(2,4,6-trifluoro-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 426.22 (2,6-dimethoxy-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.31 426.22 (2,6-dimethoxy-phenyl)-methanone
(2,6-Dimethoxy-phenyl)-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.44
394.23 pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2-Chloro-3,4-dimethox- y-benzyl)-hexahydro-pyrrolo[3,4- 1.36
460.18 c]pyrrol-2-yl]-(2,6-dimethoxy-phenyl)-methanone
[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.39 456.23 (2,3,6-trimethoxy-phenyl)-methanone
[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.35 456.23 (2,3,6-trimethoxy-phenyl)-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 1.46
424.24 (2,3,6-trimethoxy-phenyl)-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.4
490.19 c]pyrrol-2-yl]-(2,3,6-trimethoxy-phenyl)-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(2,4-dimethoxy-benzyl)- 1.56
460.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(2,3-dimethoxy-benzyl)- 1.5
460.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
(3-Chloro-2,6-dimethoxy-phenyl)-[5-(2,4-dimethyl-benzyl)- 1.66
428.19 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.56
494.14 c]pyrrol-2-yl]-(3-chloro-2,6-dimethoxy-phenyl)-methanone
5-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- 0.92
373.2 carbonyl]-pyrrolidin-2-one
5-[5-(2,3-Dimethoxy-benzyl)-hexa-
hydro-pyrrolo[3,4-c]pyrrole-2- 0.86 373.2
carbonyl]-pyrrolidin-2-on- e
5-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- 1.01
341.21 carbonyl]-pyrrolidin-2-one
5-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 0.93
407.16 c]pyrrole-2-carbonyl]-pyrrolidin-2-one
N-{2-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.59 491.28 carbonyl]-cyclohexyl}-benzamide
N-{2-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.56 491.28 carbonyl]-cyclohexyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.7 459.29 carbonyl]-cyclohexyl}-benzamide
N-{2-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.61
525.24 c]pyrrole-2-carbonyl]-cyclohexyl}-benzamide
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-o-
1.43 370.19 tolyl-ethanone 1-[5-(2,3-Difluoro-benzyl)-hexahydro--
pyrrolo[3,4-c]pyrrol-2-yl]-2-o- 1.44 370.19 tolyl-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-o-
1.4 370.19 tolyl-ethanone 1-[5-(3,5-Difluoro-benzyl)-hexahydro--
pyrrolo[3,4-c]pyrrol-2-yl]-2-o- 1.47 370.19 tolyl-ethanone
2-Biphenyl-4-yl-1-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.77 432.2 c]pyrrol-2-yl]-ethanone 2-Biphenyl-4-yl-1-[5-(2,3-dif-
luoro-benzyl)-hexahydro-pyrrolo[3,4- 1.78 432.2
c]pyrrol-2-yl]-ethanone 2-Biphenyl-4-yl-1-[5-(2,5-difluoro-benzyl)-
-hexahydro-pyrrolo[3,4- 1.77 432.2 c]pyrrol-2-yl]-ethanone
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.72 398.22 (4-isopropyl-phenyl)-ethanone
1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.74 398.22 (4-isopropyl-phenyl)-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.72 398.22 (4-isopropyl-phenyl)-ethanone
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.77 398.22 (4-isopropyl-phenyl)-ethanone
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.46 370.19 m-tolyl-ethanone 1-[5-(2,3-Difluoro-benzyl)-hexahydr-
o-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.46 370.19 m-tolyl-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.43 370.19 m-tolyl-ethanone 1-[5-(3,5-Difluoro-benzyl)-hexahydr-
o-pyrroto[3,4-c]pyrrol-2-yl]-2- 1.5 370.19 m-tolyl-ethanone
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-p-
1.45 370.19 tolyl-ethanone 1-[5-(2,3-Difluoro-benzyl)-hexahydro--
pyrrolo[3,4-c]pyrrol-2-yl]-2-p- 1.48 370.19 tolyl-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-p-
1.44 370.19 tolyl-ethanone 1-[5-(3,5-Difluoro-benzyl)-hexahydro--
pyrrolo[3,4-c]pyrrol-2-yl]-2-p- 1.51 370.19 tolyl-ethanone
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.55 384.2 (2,5-dimethyl-phenyl)-ethanone
1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.57 384.2 (2,5-dimethyl-phenyl)-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.55 384.2 (2,5-dimethyl-phenyl)-ethanone
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.61 384.2 (2,5-dimethyl-phenyl)-ethanone
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.59 406.19 naphthalen-1-yl-ethanone 1-[5-(2,3-Difluoro-benzyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.61 406.19
naphthalen-1-yl-ethanone 1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrr-
olo[3,4-c]pyrrol-2-yl]-2- 1.58 406.19 naphthaten-1-yl-ethanone
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.65 406.19 naphthalen-1-yl-ethanone 1-[5-(2,4-Difluoro-benzyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.43 410.14
(2,3,6-trifluoro-phenyl)-ethanone 1-[5-(2,3-Difluoro-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.45 410.14
(2,3,6-trifluoro-phenyl)-ethanone 1-[5-(2,5-Difluoro-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.41 410.14
(2,3,6-trifluoro-phenyl)-ethanone 1-[5-(3,5-Difluoro-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.49 410.14
(2,3,6-trifluoro-phenyl)-ethanone 1-[5-(2,4-Difluoro-benzyl)-hexah-
ydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.32 356.17 phenyl-ethanone
1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.33 356.17 phenyl-ethanone 1-[5-(2,5-Difluoro-benzyl)-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.29 356.17 phenyl-ethanone
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrof-2-yl]-2-
1.37 356.17 phenyl-ethanone 1-[5-(2,4-Difluoro-benzyl)-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.58 384.2
(3,5-dimethyl-phenyl)-eth- anone
1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-y-
l]-2- 1.6 384.2 (3,5-dimethyl-phenyl)-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.56 384.2 (3,5-dimethyl-phenyl)-ethanone
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.63 384.2 (3,5-dimethyl-phenyl)-ethanone
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-C]pyrrol-2-yl]-2-
1.56 384.2 (2,4-dimethyl-phenyl)-ethanone
1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.58 384.2 (2,4-dimethyl-phenyl)-ethanone
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.55 384.2 (2,4-dimethyl-phenyl)-ethanone
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.61 384.2 (2,4-dimethyl-phenyl)-ethanone
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.45 394.23 2-o-tolyl-ethanone 1-[5-(2,4-Dimethyl-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.59 362.24 o-tolyl-ethanone
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.5
428.19 c]pyrrol-2-yl]-2-o-tolyl-ethanone
[0196] Example 2 illustrates the preparation of bicyclic diamine
compounds of Formula I where x=1, y=1, w=1, z=1 and the linking
group (L) is an amino acid.
Example 2
Preparation of
[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-y-
l]-(2-oxo-ethyl}carbamic acid tert-butylester (I-2a)
[0197] 24
[0198] 150 .mu.L of Boc-protected glycine (0.2M in
N,N-dimethylacetamide (DMA) and 3.75% TEA) was added to 100 .mu.L
of intermediate I-1g (0.2M in toluene (or DMA) and 3.75% n-methyl
morpholine (NMM) followed by the addition of 150 .mu.L (30 mol) of
O-benzotriazol-1-yl-N,N,N',N'-tetrameth-
yl-uronium-hexa-fluoro-phosphate (HBTU) solution.(0.2M in DMA). The
reaction was heated to 60.degree. C. for six hours and then ran
overnight at room temperature. Then, the reaction was quenched with
450 .mu.l 10% NaOH, followed by the addition of 900 .mu.L of ethyl
acetate. The reaction was vigorously shaken for 15 minutes, and
then let stand at room temperature for 30 minutes.
[0199] The reaction mixture was purified by liquid chromatography
on a 1 g SCX SPE cartridge conditioned with MeOH. Elution with 1M
NH.sub.3/MeOH afforded 5.0 mg of the desired product
[5-(2,4-difluoro-benzyl)-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-oxo-ethyl}carbamic acid tert-butylester
(I-2a) as a yellow oil.
Preparation of
2-amino-1-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl[-ethanone (I-2b)
[0200] 25
[0201] 5.0 mg of desired
[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-oxo-ethyl]carbamic acid tert-butylester (I-2a) was
dissolved in 250 .mu.L of methylene chloride followed by addition
of 250 .mu.L of trifluoroacetic acid. The mixture was allowed to
stir at room temperature for 30 minutes. Then, the solvent was
removed in vacuo and the mixture was disolved in 250 .mu.L of
ethylacetate. The organic layer was basified with 1.0 N NaOH. The
organic layer was collected, dried (MgSO.sub.4) and concentrated in
vacuo. The desired product 2-amino-1-[5-(2,4-difluoro-ben-
zyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethanone (I-2b) was used
immediately in the next reaction.
Preparation of
3,4-diclhoro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrol-
o[3,4-c]pyrrol-2-yl]-(2-oxo-ethyl}benzamide (2)
[0202] 26
[0203] 50 .mu.L of 3,4-dichlorobenzoic acid (0.2 M in
N,N-dimethylacetamide (DMA) and 3.75% triethylamine (TEA)) was
added to 33 .mu.L of
2-amino-1-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]py-
rrol-2-yl]-ethanone I-2b)(0.2M in 1:1 toluene/DMA) and 3.75%
n-methyl morpholine (NMM) followed by the addition of 50 .mu.L (10
.mu.mol) of
O-benzotriazol-1-yl-N,N,N',N'-tetramethyl-uronium-hexa-fluoro-phosphate
(HBTU) solution (0.2 M in DMA). The reaction was heated to
60.degree. C. for six hours and then allowed to stir overnight at
room temperature. Then, the reaction was quenched with 150 .mu.L
10% NaOH, followed by the addition of 300 .mu.L ethyl acetate. The
reaction was vigorously shaken for 15 minutes, and then allowed to
stand at room temperature for 30 minutes.
[0204] The reaction mixture was purified by liquid chromatography
on a 1 g SCX SPE cartridge conditioned with with MeOH. Elution with
1M NH.sub.3/MeOH afforded 2.5 mg of the desired product (2) as a
yellow oil.
[0205] The following compounds were prepared using the same general
procedures described above for the preparation of compound (2) with
the appropriate starting materials. Table 2 below lists the
compounds made and their corresponding retention times (in minutes)
using HPLC and their molecular weight (MS (Cl) m/z (M+1)) as
determined by chemical ionization mass spectroscopy.
2TABLE 2 Time MW Compound Name (mins) (found)
N-{1-[5-(2,4-Difluoro-benzyl)-hexahydro-py- rrolo[3,4-c]pyrrole-2-
1.62 455.24 carbonyl]-3-methyl-butyl}-benzam- ide
N-{1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- -
1.63 455.24 carbonyl]-3-methyl-butyl}-benzamide
N-{1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.61 455.24 carbonyl]-3-methyl-butyl}-benzamide
N-{1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.69 455.24 carbonyl]-3-methyl-butyl}-benzamide
N-{1-Benzyl-2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.68
503.24 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{1-Benzyl-2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.68
503.24 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{1-Benzyl-2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.67
503.24 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{1-Benzyl-2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.73
503.24 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.28 413.19 1-methyl-2-oxo-ethyl}-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.28 413.19 1-methyl-2-oxo-ethyl}-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.25 413.19 1-methyl-2-oxo-ethyl}-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 413.19 1-methyl-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.63
489.22 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.65
489.22 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.62
489.22 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.7
489.22 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.48 441.22 carbonyl]-2-methyl-propyl}-benzamide
N-{1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.48 441.22 carbonyl]-2-methyl-propyl}-benzamide
N-{1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.46 441.22 carbonyl]-2-methyl-propyl}-benzamide
N-{1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.54 441.22 carbonyl]-2-methyl-propyl}-benzamide
1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-
1.84 482.21
methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)-butan-1-one
1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-
1.85 482.21 methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)-butan-1-
-one
1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-
]-3- 1.84 482.21
methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)-but- an-1-one
1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol--
2-yl]-3- 1.92 482.21
methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)- -butan-1-one
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl]- 0.85 351.18 1-methyl-2-oxo-ethyl}-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
0.85 351.18 1-methyl-2-oxo-ethyl}-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
0.8 351.18 1-methyl-2-oxo-ethyl}-acetamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.55
425.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.55
425.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.91 527.2 yl]-2-oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.68 459.21 yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
4-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.48
480.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.38
510.13 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methoxy-benzamide
3,4-Dichloro-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-
1.59 470.13 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-tert-Butyl-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-
1.71 458.27 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.57
494.13 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
3-Bromo-4-chloro-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro- 1.62
514.08 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.59
494.13 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.46
480.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.56 470.19 yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
3-Fluoro-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.31
420.2 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Difluoro-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-
1.38 438.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Fluoro-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.31
420.2 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.37 416.22 yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Fluoro-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.45
434.21 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.24 402.21 yl]-2-oxo-ethyl}-benzamide 3-Chloro-N-{2-[5-(1H-indo-
l-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.43 436.17
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide 3,5-Difluoro-N-{2-[5-(1H-ind-
ol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.38 438.19
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(1H-Indol-3-ylmethyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.38 416.22
yl]-2-oxo-ethyl}-4-methyl-benzamide N-{2-[5-(1H-Indol-3-ylmethyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.48 430.24
yl]-2-oxo-ethyl}-3,4-dimethyl-benzamide 4-Chloro-N-{2-[5-(1H-indol-
-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.44 436.17
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(1H-Indol-3-ylmethyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.55 470.19
yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Ethylsulfanyl-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro- 1.57
462.21 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Butyl-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.78
458.27 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.62 444.25 yl]-2-oxo-ethyl}-4-isopropyl-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.52 460.25 yl]-2-oxo-ethyl}-4-isopropoxy-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.57 460.25 yl]-2-oxo-ethyl}-4-propoxy-benzamide
4-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.54
494.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-methyl-benzamide
2-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.43
494.13 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
2-Bromo-N-{2-[5-(1H-indol-3-ylmethyl)-hexahydro-pyrrolo[3,4- 1.44
494.13 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methyl-benzamide
N-{2-[5-(1H-Indol-3-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.34 448.19 yl]-2-oxo-ethyl}-2-methylsulfanyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.68 477.2 yl]-2-oxo-ethyl}-3-fluoro-4-trifluoromethyl-benzamide
4-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.58
469.14 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.52
499.15 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methoxy-benzamide
3,4-Dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.71 459.15 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-tert-Butyl-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.81 447.29 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.69
483.15 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
3-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.73
503.1 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
4-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.7
483.15 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.53
469.14 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.44 409.22 yl]-2-oxo-ethyl}-3-fluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.52 427.21 yl]-2-oxo-ethyl}-3,4-difluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.43 409.22 yl]-2-oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.49 405.24 yl]-2-oxo-ethyl}-3-methyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.49 423.23 yl]-2-oxo-ethyl}-3-fluoro-4-methyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.37 391.23 yl]-2-oxo-ethyl}-benzamide N-{2-[5-(2,4-Dimethyl-ben-
zyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.3 391.23
yl]-2-oxo-ethyl}-3,5-difluoro-benzamide N-{2-[5-(2,4-Dimethyl-benz-
yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.5 427.21
yl]-2-oxo-ethyl}-4-methyl-benzamide N-{2-[5-(2,4-Dimethyl-benzyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.43 405.24
yl]-2-oxo-ethyl}-3,4-dimethyl-benzamide N-{2-[5-(2,4-Dimethyl-benz-
yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.49 405.24
yl]-2-oxo-ethyl}-4-ethylsulfanyl-benzamide 4-Butyl-N-{2-[5-(2,4-di-
methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.58 419.26
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(2,4-Dimethyl-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.67 451.23
yl]-2-oxo-ethyl}-4-isopropyl-benzamide N-{2-[5-(2,4-Dimethyl-benzy-
l)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.88 447.29
yl]-2-oxo-ethyl}-4-trifluoromethoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.73 433.27 yl]-2-oxo-ethyl}-3,4,5-trifluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.73 475.21 yl]-2-oxo-ethyl}-4-isopropoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.6
455.2 yl]-2-oxo-ethyl}-4-propoxy-benzamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.61
443.18 c]pyrrolo-2-yl]-oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.73 477.2 yl]-2-oxo-ethyl}-3-fluoro-5-trifluoromethyl-benzamide
2-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.44
469.14 c]pyrrolo-2-yl]-oxo-ethyl}-benzamide
Bromo-2-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.61 503.1
pyrrol[3,4-c]pyrrolo-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-5-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.59
503.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.54
487.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
4-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.64
483.15 c]pyrrolo-2yl]-oxo-ethyl}-2-methyl-benzamide
4-Bromo-2-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.64
503.1 pyrrolo[3,4-c]pyrrolo-2yl]-2-oxo-ethyl}-benzamide
2-Bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.63
503.1 pyrrolo[3,4-c]pyrrol-2yl]-2-oxo-ethyl}-benzamide
2-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.49
483.15 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
2-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.56
483.15 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methyl-benzamide
3-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.63
483.15 c]pyrrol-2-yl]-2-oxo-ethyl}-2-methyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.46 437.21 yl]-2-oxo-ethyl}-2-methylsulfanyl-benzamide
3-Fluoro-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.7
463.19 c]pyrrol-2-yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
4-Bromo-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.53
455.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-5-methoxy-N-{2-[5-- (4-methyl-benzyl)-hexahydro- 1.45
485.13 pyrrolo[3,4-c]pyrrol-2-yl]- -2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(4-methyl-benzyl)-hexa- hydro-pyrrolo[3,4-
1.65 445.13 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamid- e
4-tert-Butyl-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.77
433.27 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Methyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.87 513.19 oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
3-Bromo-4-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.64 469.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.68 489.08
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-3-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.66 469.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.52
455.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-methyl-benzyl)-- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.61 445.2 oxo-ethyl}-4-trifluoromethyl-benzamide
3-Fluoro-N-{2-[5-(4-methyl-- benzyl)-hexahydro-pyrrolo[3,4- 1.36
395.2 c]pyrrol-2-yl]-2-oxo-ethy- l}-benzamide
3,4-Difluoro-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrro- lo[3,4-
1.43 413.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Fluoro-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.35
395.2 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Methyl-N-{2-[5-(4-methyl- -benzyl)-hexahydro-pyrrolo[3,4- 1.42
391.23 c]pyrrol-2-yl]-2-oxo-et- hyl}-benzamide
3-Fluoro-4-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydr- o- 1.49
409.22 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.28 377.21 oxo-ethyl}-benzamide 3-Chloro-N-{2-[5-(4-methyl-
-benzyl)-hexahydro-pyrrolo[3,4- 1.48 411.17
c]pyrrol-2-yl]-2-oxo-et- hyl}-benzamide
3,5-Difluoro-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyr- rolo[3,4-
1.43 413.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.43
391.23 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dimethyl-N-{2-[5-(4-m- ethyl-benzyl)-hexahydro-Pyrrolo[3,4-
1.54 405.24 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(4-methyl-b- enzyl)-hexahydro-pyrrolo[3,4- 1.49
411.17 c]pyrrol-2-yl]-2-oxo-ethy- l}-benzamide
N-{2-[5-(4-Methyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr- ol-2-yl]-2-
1.63 445.2 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Ethylsulfanyl-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4-
1.64 437.21 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Butyl-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.85 433.27 2-yl]-2-oxo-ethyl}-benzamide 4-Isopropyl-N-{2-[5-(4--
methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.69 419.26
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(4-Methyl-benzyl)-he-
xahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.68 461.19
oxo-ethyl}-4-trifluoromethoxy-benzamide 3,4,5-Trifluoro-N-{2-[5-(4-
-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.54 431.18
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide 4-Isopropoxy-N-{2-[5-(4-meth-
yl-benzyl)-hexahydro-pyrrolo[3,4- 1.58 435.25
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(4-Methyl-benzyl)-he-
xahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.64 435.25
oxo-ethyl}-4-propoxy-benzamide 3-Chloro-4-fluoro-N-{2-[5-(4-methyl-
-benzyl)-hexahydro- 1.56 429.16
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-et- hyl}-benzamide
3-Fluoro-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo- [3,4- 1.68
463.19 c]pyrrol-2-yl]-2-oxo-ethyl}-5-trifluoromethyl-ben- zamide
2-Bromo-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.38
455.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
5-Bromo-2-chloro-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.56 489.08
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-5-chloro-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.53 489.08
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-2-fluoro-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.54 473.11
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-2-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.6 469.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-2-chloro-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.58 489.08
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-4-chloro-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.58 489.08
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-3-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.49 469.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-5-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.5 469.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-2-methyl-N-{2-[5-(4-methyl-benzyl)-hexahydro- 1.58 469.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Methyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.4 423.2 oxo-ethyl}-2-methylsulfanyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.83 517.09 yl]-2-oxo-ethyl}-3-fluoro-4-trifluoromethyl-benzamide
4-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.66
509.03 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.58
539.04 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methoxy-benzamide
3,4-Dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-
1.8 499.04 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-tert-Butyl-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-
1.89 487.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
2.01 567.09 yl]-2-oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
3-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.78
523.04 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
3-Bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro- 1.82
542.99 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.8
523.04 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.66
509.03 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.76 499.1 yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.5
449.11 yl]-2-oxo-ethyl}-3-fluoro-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.58 467.1 yl]-2-oxo-ethyl}-3,4-difluoro-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.5
449.11 yl]-2-oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.57 445.13 yl]-2-oxo-ethyl}-3-methyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.48 463.12 yl]-2-oxo-ethyl}-3-fluoro-4-methyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.44 431.12 yl]-2-oxo-ethyl}-benzamide 3-Chloro-N-{2-[5-(2,4-dic-
hloro-benzyl)-hexahydro-pyrrolo[3,4- 1.63 465.08
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(2,4-Dichloro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.58 467.1
yl]-2-oxo-ethyl}-3,5-difluoro-benzamide N-{2-[5-(2,4-Dichloro-benz-
yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.57 445.13
yl]-2-oxo-ethyl}-4-methyl-benzamide N-{2-[5-(2,4-Dichloro-benzyl)--
hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.68 459.15
yl]-2-oxo-ethyl}-3,4-dimethyl-benzamide 4-Chloro-N-{2-[5-(2,4-dich-
loro-benzyl)-hexahydro-pyrrolo[3,4- 1.65 465.08
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(2,4-Dichloro-benzyl-
)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.76 499.1
yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.77 491.12 yl]-2-oxo-ethyl}-4-ethylsulfanyl-benzamide
4-Butyl-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.98
487.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.82 473.16 yl]-2-oxo-ethyl}-4-isopropyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.82 515.1 yl]-2-oxo-ethyl}-4-trifluoromethoxy-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.68 485.09 yl]-2-oxo-ethyl}-3,4,5-trifluoro-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.71 489.16 yl]-2-oxo-ethyl}-4-isopropoxy-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.78 489.16 yl]-2-oxo-ethyl}-4-propoxy-benzamide
3-Chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.7
483.07 c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.82 517.09 yl]-2-oxo-ethyl}-3-fluoro-5-trifluoromethyl-benzamide
2-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.51
509.03 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
5-Bromo-2-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro- 1.69
542.99 poyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-5-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro- 1.68
542.99 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.68
527.02 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
4-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.74
523.04 c]pyrrol-2-yl]-2-oxo-ethyl}-2-methyl-benzamide
4-Bromo-2-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro- 1.73
542.99 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro- 1.73
542.99 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4 1.63
523.04 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
2-Bromo-N-{2-[5-(2,4-dicloro-benzyl)-hexahydro-pyrrolo[3,4- 1.64
523.04 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methyl-benzamide
3-Bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.72
523.04 c]pyrrol-2-yl]-2-oxo-ethyl}-2-methyl-benzamide
N-{2-[5-(2,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.55 477.1 yl]-2-oxo-ethyl}-2-methylsulfanyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.74 459.21 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.61
425.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.63 491.2 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.61
425.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.78 459.15 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.79 481.2 yl)-2-oxo-ethyl]-3-trifluoromethyl-benzamide
3-Bromo-4-chloro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.82
525.08 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4-Dichloro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.79 481.13
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.74 481.2 yl)-2-oxo-ethyl]-3-trifluoromethyl-benzamide
3-Bromo-4-chloro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.78
525.08 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4-Dichloro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.75 481.13
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.66 482.19 2-yl)-ethyl]-3-trifluoromethyl-benzamide
3-Bromo-4-chloro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.69
526.08 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3,4-Dichloro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.66
482.13 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3,4-Dichloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro- 1.69 491.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.73 499.1 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.76
543.05 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo(3,4- 1.7
499.17 c]pyrrol-2-yl]-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
1.82 499.1 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.85
543.05 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.79 499.17 c]pyrrol-2-yl]-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 1.8
517.09 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 1.84
561.04 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Fluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.84
499.19 c]pyrrol-2-yl)-2-oxo-ethyl]-4-trifluoromethyl-benzamide
3-Fluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.79
499.19 c]pyrrol-2-yl)-2-oxo-ethyl]-4-trifluoromethyl-benzamide
3-Fluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.72 500.18
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-4-trifluoromethyl-benzamide
4-Bromo-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.68
491.12 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Bromo-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.64
491.12 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Bromo-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.54 492.12
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
2-Bromo-5-methoxy-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.61
521.13 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
2-Bromo-5-methoxy-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.56
521.13 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
2-Bromo-5-methoxy-N-[2-oxo-2-(5-quinolin-2-ylmethyl- 1.47 522.13
hexahdro-pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
4-tert-Butyl-N-[2-(5-naphthale-2-ylmethyl-hexahydro-pyrrolo[3,4-
1.9 469.27 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-tert-Butyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-
1.86 469.27 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-tert-Butyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.78
470.27 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.98 549.19 yl)-2-oxo-ethyl]-3,5-bis-trifluoromethyl-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.96 549.19 yl)-2-oxo-ethyl]-3,5-bis-trifluoromethyl-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.87 550.18 2-yl)-ethyl]-3,5-bis-trifluoromethyl-benzamide
3-Bromo-4-methyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.79
505.14 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3Bromo-4-methyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.74
505.14 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide 3
Bromo-4-methyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.65
506.13 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl}-benzamide
4-Bromo-3-methyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.78
505.14 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Bromo-3-methyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.74
505.14 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Bromo-3-methyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.67
506.13 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Bromo-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.67
491.12 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Bromo-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.64
491.12 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Bromo-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.53 492.12
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Bromo-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.67 492.12
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.76 481.2 yl)-2-oxo-ethyl]-4-trifluoromethyl-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.73 481.2 yl)-2-oxo-ethyl]-4-trifluoromethyl-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c ]pyrrol-
1.64 482.19 2-yl)ethyl]-4-trifluoromethyl-benzamide
N-[2-Oxo-2-(5-quinolin-4-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.79 482.19 2-yl)-ethyl]-4-trifluoromethyl-benzamide
3-Fluoro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.85
517.16
pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-trifluoromethyl-benzamide
3-Fluoro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.78
517.16 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-trifluoromethyl-benzami-
de 3-Fluoro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro-
1.84 535.15 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-trifluoromet-
hyl-benzamide
4-Bromo-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexa- hydro- 1.7
509.09 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Bromo-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.6
509.09 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Bromo-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.7
527.08 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.66
527.08 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-5-methoxy-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.63
539.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
2-Bromo-5-methoxy-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.52
539.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
2-Bromo-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.59
557.09 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-methoxy-benzamide
4-tert-Butyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
1.92 487.24 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-tert-Butyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.84 487.24 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-tert-Butyl-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro-
1.92 505.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-tert-Butyl-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro-
1.93 505.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
2.02 567.16 c]pyrrol-2-yl]-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.97 567.16 c]pyrrol-2-yl]-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 2.04
585.15
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3,5-bis-trifluoromethyl-
benzamide 3-Bromo-4-methyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzy-
l)- 1.81 523.11
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzami- de
3-Bromo-4-methyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.72
523.11 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.79
541.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
3-Bromo-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.78
541.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
4-Bromo-3-methyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.83
523.11 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Bromo-3-methyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.74
523.11 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Bromo-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.83
541.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
4-Bromo-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.81
541.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Bromo-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.71
509.09 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.61
509.09 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.67
527.08 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.81 499.17 c]pyrrol-2-yl]-ethyl}-4-trifluoromethyl-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.71 499.17 c]pyrrol-2-yl]-ethyl}-4-trifluoromethyl-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.78 517.16
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
3-Fluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.56
431.2 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Fluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.51
431.2 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Fluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.42 432.2
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3,4-Difluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.63 449.19
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4-Difluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.59 449.19
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4-Difluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.5
450.19 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
4-Fluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.56
431.2 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Fluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.5
431.2 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Fluoro-N-[2-oxo-2-(5-- quinolin-2-ylmethyl-hexahydro- 1.4 432.2
pyrrolo[3,4-c]pyrrol-2-yl)- -ethyl]-benzamide
3-Methyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-- pyrrolo[3,4-
1.61 427.23 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Methyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.56
427.23 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Methyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.46 428.22
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Fluoro-4-methyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.68
445.22 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Fluoro-4-methyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.63
445.22 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Fluoro-4-methyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.54
446.21 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Fluoro-4-methyl-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 2.14
446.21 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrolo-2-
1.48 413.21 yl)-2-oxo-ethyl]-benzamide N-[2-(5-Naphthalen-1-ylme-
thyl-hexahydro-pyrrolo[3,4-c]pyrrolo-2- 1.44 413.21
yl)-2-oxo-ethyl]-benzamide N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexah-
ydro-pyrrolo[3,4-c]pyrrol- 1.33 414.21 2-yl)-ethyl]-benzamide
3-Chloro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.68
447.17 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Chloro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.64
447.17 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Chloro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.52 448.17
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Chloro-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.66 448.17
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3,5-Difluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.62 449.19
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,5-Difluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.59 449.19
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,5-Difluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.48
450.19 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
4-Methyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.61
427.23 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Methyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.57
427.23 c]pyrrol-2-yl-2-oxo-ethyl]-benzamide
4-Methyl-N-[2-oxo(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-
1.46 428.22 pyrrolo[3,4-c ]pyrrol-2-yl)-ethy]-benzamide
3,4-Dimethyl-N-[2-(5-naphthalenl-2-ylmethyl-hexahydro- 1.7 441.24
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4-Dimethyl-N-[2-(5-naphthalenl-1-ylmethyl-hexahydro- 1.66 441.24
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4-Dimethyl-N-[2-oxo2(5-quinolin-2-ylmethyl-hexahydro 1.57 442.24
pyrrolo[3,4-c]pyrrol-2-yl)ethyl]-benzamide 4-Chloro-N-[2-(5-naphth-
alen-2-ylmehyl-hexahydro-pyrrolo[3,4- 1.68 447.17
c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide 4-Chloro-N-[2-(5-naphthalen--
1-ylmethyl-hexahydro-pyrrolol[3,4 1.64 447.17
c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide 4-Chloro-N-[2-(5-naphthalen--
2-ylmehyl-hexahydro- 1.5 448.17
pyrrolo[3,4-c]pyrrolo-2-yl-ethyl]-b- enzamide
3-Fluoro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydr- o- 1.57
449.17 pyrrolo[3,4-c]pyrrol-2-yl-ethyl}-benzamide
3-Fluoro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.44
449.17 pyrrolo[3,4-c]pyrrol-2-yl-ethyl}-bbenzamide
3-Fluoro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro-
1.51 467.16 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Difluoro-N-(2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
1.65 467.16 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,4-Difluoro-N-(2-oxo-2-[5-(2-trifloromethyl-benzyl)-hexahydro-
1.52 467.16 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,4-Difluoro-N-(2-oxo-2-[5-(4-fluoro-2-trifloromethyl-benzyl)- 1.59
485.15 hexahdro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Fluoro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.57
449.17 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Fluoro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.43
449.17 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Fluoro-N-{2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.51 467.16
pyrrolo[3,4-c]pyrrol-2-yl-2-oxo-ethyl}-benzamide
3-Methyl-N-{2-oxo-2-[5(4-trifluoromethyl-benzyl)-hexahydro- 1.63
445.2 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Methyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.5
445.2 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.62 463.19
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
N-{-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.58 463.19
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Fluoro-4-methyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.71
463.19 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Fluoro-4-methyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl) 1.59
463.19 hexahdro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Fluoro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro-
1.64 481.18
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.51 431.18 c]pyrrolo-2-yl]-ethyl}-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.37 431.18 c]pyrrolo-2-yl]-ethyl}-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.43 449.17
pyrrolo[3,4-c]pyrrolo-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.7
465.14 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Chloro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.57
465.14 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Chloro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro-
1.65 483.13
pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-4-methyl-benzamide
3,5-Difluoro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.52 467.16 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,5-Difluoro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 1.59
485.15 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Methyl-N-2{-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.64
445.2 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Methyl-N-2{-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.51
445.2 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.62 463.19
pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-4-methyl-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.57 463.19
pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-4-methyl-benzamide
3,4-Dimethyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
1.73 459.21 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,4-Dimethyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.62 459.21 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.72 477.2
pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}3,4-dimethyl-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.68 477.2
pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}3,4-dimethyl-benzamide
4-Chloro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.7
465.14 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Chloro-N-{2-oxo-2-[5 -(2-trifluoromethyl-benzyl)-hexahydro- 1.59
465.14 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Chloro-N-{2-oxo-2-[5
-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.69 483.13
pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexahydro-
1.66 483.13 pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-benzamide
4-Ethylsulfanyl-N-[2-(5-naphthalenl-2-ylmethyl-hexahydro- 1.78
473.21 pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-benzamide
4-Ethylsulfanyl-N-[2-(5-naphthalenl-1-ylmethyl-hexahydro- 1.74
473.21 pyrrolo[3,4-c]pyrrol-2-yl]2-oxo-ethyl}-benzamide
4-Ethylsulfanyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.65
474.21 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Butyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.99
469.27 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Butyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.95
469.27 c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Butyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-
1.88 470.27 c]pyrrol-2-yl)-ethyl]-benzamide
4-Isopropyl-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.84 455.26
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Isopropyl-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.8 455.26
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Isopropyl-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.71
456.25 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.83 497.19 yl)-2-oxo-ethyl]-4-trifluoromethoxy-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.79 497.19 yl)-2-oxo-ethyl]-4-trifluoromethoxy-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.71 498.19 2-yl)-ethyl]-4-trifluoromethoxy-benzamide
3,4,5-Trifluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.72
467.18 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4,5-Trifluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.67
467.18 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3,4,5-Trifluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.57
468.18 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.85 455.26 yl)-2-oxo-ethyl]-4-propyl-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.82 455.26 yl)-2-oxo-ethyl]-4-propyl-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.74 456.25 2-yl)-ethyl]-4-propyl-benzamide
N-[2-Oxo-2-(5-quinolin-4-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.85 456.25 2-yl)-ethyl]-4-propyl-benzamide
4-Isopropoxy-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.73 471.25
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Isopropoxy-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.7 471.25
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
4-Isopropoxy-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.61
472.25 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.79 471.25 yl)-2-oxo-ethyl]-4-propoxy-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.76 471.25 yl)-2-oxo-ethyl]-4-propoxy-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.66 472.25 2-yl)-ethyl]-4-propoxy-benzamide
3-Chloro-4-fluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 1.73
465.25 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Chloro-4-fluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.68
465.25 pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Chloro-4-fluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.57
466.16 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Fluoro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4- 1.83
499.19 c]pyrrol-2-yl)-2-oxo-ethyl]-5-trifluoromethyl-benzamide
3-Fluoro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 1.8
499.19 c]pyrrol-2-yl)-2-oxo-ethyl]-5-trifluoromethyl-benzamide
3-Fluoro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.71 500.18
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-5-triflouromethyl benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.77 517.16
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Ethylsulfanyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.8
491.19 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Ethylsulfanyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.7
491.19 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Ethylsulfanyl-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)- 1.8
509.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Ethylsulfanyl-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 1.77
509.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Butyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 2.02
487.24 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Butyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro- 1.94
487.24 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Butyl-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro- 2.02
505.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Butyl-N-{2-[5-(4-fluoro-4-trifluoromethyl-benzyl)-hexahydro- 2.01
505.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Isopropyl-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
1.86 473.23 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Isopropyl-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.77
473.23 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.86 491.22
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-isopropyl-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.84 491.22
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-isopropyl-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.86 515.16 c]pyrrol-2-yl]-ethyl}-4-trifluoromethoxy-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.77 515.16 c]pyrrol-2-yl]-ethyl}-4-trifluoromethoxy-benzamid
3,4,5-Trifluoro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.75
485.15 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,4,5-Trifluoro-N-{2-oxo-2-[5-(2-trifluofomethyl-benzyl)- 1.63
485.15 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.89 473.23 c]pyrrol-2-yl]-ethyl}-4-propyl-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.8
473.23 c]pyrrol-2-yl]-ethyl}-4-propyl-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.89 491.22
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-propyl-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.86 491.22
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-propyl-benzamide
4-Isopropoxy-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
1.78 489.22 pyrrolo[3,4-c]pyrrol-2-yl]ethyl}-benzamide
4-Isopropoxy-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.67 489.22 pyrrolo[3,4-c]pyrrol-2-yl]ethyl}-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.76 507.21
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-isopropoxy-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.73 507.21
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-isopropoxy-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.84 489.22 c]pyrrol-2-yl]-ethyl}-4-propoxy-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.73 489.22 c]pyrrol-2-yl]-ethyl}-4-propoxy-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 1.82 507.21
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-propoxy-benzamide
N-{2-[5-(4-Fluoro-2-trifluoromethyl-benzyl)-hexahydro- 1.79 507.21
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-propoxy-benzamide
3-Chloro-4-fluoro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 1.76
483.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Chloro-4-fluoro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.64
483.13 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Chloro-4-fluoro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 1.71
501.12 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Fluoro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro- 1.87
517.16 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-5-trifluoromethyl-benzami-
de 3-Fluoro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
1.78 517.16 pyrrolo[3,4-c]pyrrolo-2-yl]-ethyl}-5-trifluoromethyl-b-
enzamide
3-Fluoro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)-hexah- ydro-
1.86 535.15 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-trifluo-
romethyl-benzamide
N-{2-[5-(1-Methyl-1H-indol-3-ylmethyl)-hexahydro- -pyrrolo[3,4-
1.69 484.21 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluorome-
thyl-benzamide
4-Chloro-N-{2-[5-(1-methyl-1H-indol-3-ylmethyl)-hexa- hydro- 1.58
450.18 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamid- e
3,4-Dichloro-N-{2-[5-(1-methyl-1H-indol-3-ylmethyl)-hexahydro 1.73
484.14 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(1-methyl-1H-indol-3-ylmethyl)-hexahydro- 1.57
450.18 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-[2-Oxo-2-(5-quinolin-3-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.58 482.19 2-yl)-ethyl]-3-trifluoromethyl-benzamide
3,4-Dichloro-N-[2-oxo-2-(5-quinolin-3-ylmethyl-hexahydro- 1.58
482.13 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
3-Chloro-N-[2-oxo-2-(5-quinolin-3-ylmethyl-hexahydro- 1.39 448.17
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
4-Chloro-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.34 448.17
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.66 465.14 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.55
431.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(4-c- hloro-benzyl)-hexahydro-pyrrolo[3,4- 1.7
465.08 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(4-chloro-b- enzyl)-hexahydro-pyrrolo[3,4- 1.55
431.12 c]pyrrol-2-yl]-2-oxo-ethy- l}-benzamide
N-{2-[5-(5-Bromo-2-methoxy-benzyl)-hexahydro-pyrrolo[3- ,4- 1.74
539.1 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzam- ide
N-{2-[5-(5-Bromo-2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.63
505.08 c]pyrrol-2-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(5-Bromo-2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.78
539.04 c]pyrrol-2-yl]-2-oxo-ethyl}-3,4-dichloro-benzamide
N-{2-[5-(5-Bromo-2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.62
505.08 c]pyrrol-2-yl]-2-oxo-ethyl}-3-chloro-benzamide
N-{2-[5-(3-Bromo-4-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.7 539.1
c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(3-Bromo-4-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.59
505.08 c]pyrrol-2-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(3-Bromo-4-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.56
505.08 c]pyrrol-2-yl]-2-oxo-ethyl}-3-chloro-benzamide
N-{2-[5-(3,5-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.79 499.1 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3,5-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.68
465.08 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(3,5-dichloro-benzyl)-hexahydro-pyrrolo[3,4-
1.83 499.04 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(3,5-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.67
465.08 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3-Bromo-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.72 527.08 2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(3-Bromo-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.6 493.06 2-yl]-2-oxo-ethyl}-3-chloro-benzamide
N-{2-[5-(3-Bromo-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.76 527.02 2-yl]-2-oxo-ethyl}-3,4-dichloro-benzamide
N-{2-[5-(3-Bromo-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.61 493.06 2-yl]-2-oxo-ethyl}-3,4-chloro-benzamide
N-{2-[5-(3-Chloro-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.7 483.13 2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3-chloro-4-fluoro-benzyl)-hexahydro- 1.59 449.11
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(3-chloro-4-fluoro-benzyl)-hexahydro- 1.74
483.07 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(3-chloro-4-fluoro-benzyl)-hexahydro- 1.59 449.11
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Bromo-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.7 509.09 oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(4-Bromo-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.58 475.07 oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(4-Bromo-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.73 509.03 oxo-ethyl}-3,4-dichloro-benzamide
N-{2-[5-(4-Bromo-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.57 475.07 oxo-ethyl}-3-chloro-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.79 499.1 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.69
465.08 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-
1.83 499.04 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.69
465.08 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.5
411.17 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(2-methyl- -benzyl)-hexahydro-pyrrolo[3,4- 1.5
411.17 c]pyrrol-2-yl]-2-oxo-eth- yl}-benzamide
N-[2-(5-Biphenyl-4-ylmethyl-hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl)-
1.82 473.19 2-oxo-ethyl]-4-chloro-benzamide
N-[2-(5-Biphenyl-4-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-
1.96 507.15 2-oxo-ethyl]-3,4-dichloro-benzamide
N-[2-(5-Biphenyl-4-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-
1.82 473.19 2-oxo-ethyl]-3-chloro-benzamide
N-[2-Oxo-2-[5-(3-phenoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.93 523.21
c]pyrrol-2-yl]-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-oxo-2-[5-(3-phenoxy-benzyl)-hexahydro- 1.84 489.18
pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,4-Dichloro-N-{2-oxo-2-[5-(3-phenoxy-benzyl)-hexahydro- 1.98
523.14 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Chloro-N-{2-oxo-2-[5-(3-phenoxy-benzyl)-hexahydro- 1.83 489.18
pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-[5-(2-Methoxy-naphthalen-1-ylmethyl)-hexahydro- 1.8 511.21
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-methoxy-naphthalen-1-ylmethyl)-hexahydro- 1.69
477.18 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2-methoxy-naphthalen-1-ylmethyl)- 1.84 511.14
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2-methoxy-naphthalen-1-ylmethyl)-hexahydro- 1.69
477.18 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Ethoxy-naphthalen-1-ylmethyl)-hexahydro-pyrrolo[3,4-
1.87 525.22 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-ethoxy-naphthalen-1-ylmethyl)-hexahydro- 1.78
491.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2-ethoxy-naphthalen-1-ylmethyl)- 1.92 525.16
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2-ethoxy-naphthalen-1-ylmethyl)-hexahydro- 1.78
491.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-Oxo-2-[5-(3-p-tolyloxy-benzyl)-hexahydro-pyrrolo[3,4- 2.03
537.22 c]pyrrol-2-yl]-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-oxo-2-[5-(3-p-tolyloxy-benzyl)-hexahydro- 1.94 503.2
pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3,4-Dichloro-N-{2-oxo-2-[5-(3-p-tolyloxy-benzyl)-hexahydro- 2.07
537.16 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Chloro-N-{2-oxo-2-[5-(3-p-tolyloxy-benzyl)-hexahydro- 1.94 503.2
pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-[5-(4-Methyl-naphthalen-1-ylmethyl)-hexahydro-pyrrolo[3,4-
1.84 495.21 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-methyl-naphthalen-1-ylmethyl)-hexahydro- 1.74
461.19 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(4-methyl-naphthalen-1-ylmethyl)- 1.89 495.15
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxoethyl}-benzamide
3-Chloro-N-{2-[5-(4-methyl-naphthalen-1-ylmethyl)-hexahydro- 1.73
461.19 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2'-Methyl-biphenyl-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.95
521.23 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2'-methyl-biphenyl-2-ylmethyl)-hexahydro- 1.84
487.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2'-methyl-biphenyl-2-ylmethyl)-hexahydro-
1.98 521.16 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2'-methyl-biphenyl-2-ylmethyl)-hexahydro- 1.85
487.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2'-Methoxy-biphenyl-2-ylmethyl)-hexahydro-pyrrolo[3,4-
1.87 537.22 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2'-methoxy-biphenyl-2-ylmethyl)-hexahydro- 1.77
503.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2'-methoxy-biphenyl-2-ylmethyl)- 1.92 537.16
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2'-methoxy-biphenyl-2-ylmethyl)-hexahydro- 1.78
503.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(6-Methoxy-naphthalen-2-ylmethyl)-hexahydro- 1.89 511.21
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-[5-(6-methoxy-naphthalen-2-ylmethyl)- 1.71 477.18
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(6-methoxy-naphthalen-2-ylmethyl)-hexahydro- 1.85
511.14 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.7
477.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.53
457.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.53
457.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Methyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.61 445.2 oxo-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-[5-(2-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.67
445.13 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Ethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.7 475.21 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-ethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.57
441.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2-e- thoxy-benzyl)-hexahydro-pyrrolo[3,4-
1.73 475.14 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2-ethoxy-b- enzyl)-hexahydro-pyrrolo[3,4- 1.57
441.18 c]pyrrol-2-yl]-2-oxo-ethy- l}-benzamide
N-{2-[5-(2-Methoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyr- rol-2-yl]-
1.59 461.19 2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.46
427.17 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.64
461.13 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.45
427.17 c]prrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,5-Dimethoxy-be- nzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.63 491.2 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,5-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.52
457.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2,5-dimethoxy-benzyl)-hexahydro- 1.67 491.14
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2,5-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.5
457.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,5-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.72 459.21 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.61
425.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(2,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
1.77 459.15 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.61
457.19 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Methoxy-2,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.76
489.22 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-methoxy-2,5-dimethyl-benzyl)-hexahydro- 1.65
455.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(4-methoxy-2,5-dimethyl-benzyl)-hexahydro-
1.82 489.16 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(4-methoxy-2,5-dimethyl-benzyl)-hexahydro- 1.65
455.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Methoxy-2,3-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.78
489.22 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-methoxy-2,3-dimethyl-benzyl)-hexahydro- 1.66
455.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(4-methoxy-2,3-dimethyl-benzyl)-hexahydro-
1.81
489.16 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(4-methoxy-2,3-dimethyl-benzyl)-hexahydro- 1.66
455.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Benzyloxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.93
537.22 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2-Benzyloxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.83
503.2 yl]-2-oxo-ethyl}-4-chloro-benzamide N-{2-[5-(2-Benzyloxy-be-
nzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.98 537.16
yl]-2-oxo-ethyl}-3,4-dichloro-benzamide N-{2-[5-(2-Benzyloxy-benzy-
l)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.84 503.2
yl]-2-oxo-ethyl}-3-chloro-benzamide N-{2-[5-(3-Cyclopentyloxy-4-me-
thoxy-benzyl)-hexahydro- 1.86 545.25
pyrrolo[3,4-c]pyrrol-yl]-2-oxo- -ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3-cyclopentyl- oxy-4-methoxy-benzyl)- 1.75 511.22
hexahydro-pyrrolo[3,4-c]pyrrol-2- -yl]-2-oxo-ethyl}-benzamide
3,4-Dichloro-N-{2-[5-(3-cyclopentyloxy-- 4-methoxy-benzyl)- 1.9
545.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]--
2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(3-cyclopentyloxy-4-methoxy- -benzyl)- 1.75 511.22
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-et- hyl}-benzamide
3,4-Dichloro-N-[2-(hexahydro-pyrrolo-[3,4-c]pyrro-2-- yl)-2-oxo-
2.14 342 ethyl]-benzamide 3,4-Dichloro-N-[2-(oxo--
2-(5-quinolin-2-ylmethyl-hexahydro- 2 483, 485
pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide dichloro
1H-Indole-2-carboxylic acid [2-oxo-2-(5-quinolin-2-ylmethyl- 2.1
454 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-amide
3-Bromo-4-chloro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 2.1
528 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
2-Amino-5-chloro-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.8
464 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
2-Amino-5-bromo-N-[2-oxo-2-(5-quinolin-2-ylmethyl-hexahydro- 1.9
510 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-Oxo-2-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.9 483 2-yl)-ethyl]-3-trifluoromethyl-benzamide
3,4-Dichloro-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.8 483,
485 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide dichloro
1H-Indole-2-carboxylic acid [2-oxo-2-(5-quinolin-4-ylmethyl- 1.5
454 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-amide
3-Bromo-4-chloro-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.9
529 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
2-Amino-5-chloro-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.4
464 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
2-Amino-5-bromo-N-[2-oxo-2-(5-quinolin-4-ylmethyl-hexahydro- 1.5
510 pyrrolo[3,4-c]pyrrol-2-yl)-ethyl]-benzamide
N-[2-Oxo-2-(5-quinolin-4-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.7 483 2-yl)-ethyl]-3-trifluoromethyl-benzamide
3,4-Dichloro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 2.1 483
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
1H-Indole-2-carboxylic acid [2-(5-naphthalen-1-ylmethyl- 2 454
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-amide
3-Bromo-4-chloro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 2.2 528
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
2-Amino-5-chloro-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 1.9 463
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
2-Amino-5-bromo-N-[2-(5-naphthalen-1-ylmethyl-hexahydro- 2 509
yl)-2-oxo-ethyl]-3-trifluoromethyl-benzamide
N-[2-(5-Naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
483 yl)-2-oxo-ethyl]-3-trifluoromethyl-benzamide
3,4-Dichloro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 2.2 483
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
3-Bromo-4-chloro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 2.2 528
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
2-Amino-5-chloro-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 2 463
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
2-Amino-5-bromo-N-[2-(5-naphthalen-2-ylmethyl-hexahydro- 2.1 509
pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-benzamide
N-[2-(5-Naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
482 yl)-2-oxo-ethyl]-3-trifluoromethyl-benzamide
2-Amino-1-(5-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-
1.85 310 2-yl)-ethanone
2-Amino-1-(5-quinolin-4-ylmethyl-hexahydro-p- yrrolo-[3,4-c]pyrrol-
1.84 310 2-yl)-ethanone
2-Amino-1-(5-naphthalen-1-ylmethyl-hexahydro-pyrrolo[3,4- 2.3 309
c]pyrrol-2-yl)-ethanone 2-Amino-1-(5-naphthalen-2-ylmethyl-hexahyd-
ro-pyrrolo[3,4- 2.25 309 c]pyrrol-2-yl)-ethanone
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
2 536.2 2-oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.7 468.3 2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
2 536.2 2-oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.7 468 2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
478.1 yl]-2-oxo-ethyl}-2-fluoro-3-trifluoromethyl-benzamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
426.1 c]pyrrol-2yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-be- nzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
2.2 484.2 yl]-2-oxo-ethyl}-2-phonox-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-- hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.7 424.1 yl]-2-oxo-ethyl}-5-fluo- ro-2-methyl-benzamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahy- dro-pyrrolo[3,4- 1.9
444.1 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-ben- zamide
N-{2-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrro- l-2-
1.9 492.1 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
426.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-b- enzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
2.3 528.1 yl]-2-oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
460.1 yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
2-Amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.9 487.1
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.8
451.1 yl]-2-oxo-ethyl}-2-methyl-5-nitro-benzamide
2-Amino-5-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.9 441.1
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}benzamide
5-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
471.1 c]pyrrol-2-yl]-2-oxo-ethyl}-2-nitro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
505.1 yl]-2-oxo-ethyl}-3-nitro-5-trifluoromethyl-benzamide
2-Amino-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.6
541.3 c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide
2-Amino-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.3
460.5 c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
436.2 yl]-2-oxo-ethyl}-2-ethoxy-benzamide
2,4-Dichloro-N-{2-[5-(2,4- -dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
2 460.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl- )-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.5 428.2 yl]-2-oxo-ethyl}-2,6-difluoro-benzamide
2-Chloro-N-{2-[5-(2,4-dime- thyl-benzyl)-hexahydro-pyrrolo[3,4- 1.7
444.2 c]pyrrol-2-yl]-2-oxo-ethyl}-6-fluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7
428.2 yl]-2-oxo-ethyl}-2,4-difluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7
428.2 yl]-2-oxo-ethyl}-2,3-difluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
460.2 yl]-2-oxo-ethyl}-2-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
446.2 yl]-2-oxo-ethyl}-2,3,4-trifluoro-benzamide
2,3-Dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2
460.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.2
528.2 yl]-2-oxo-ethyl}-2,4-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
478.2 yl]-2-oxo-ethyl}-2-fluoro-4-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
478.2 yl]-2-oxo-ethyl}-4-fluoro-2-trifluoromethyl-benzamide
2-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.8
444.2 c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide
2-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
462.2 c]pyrrol-2-yl]-2-oxo-ethyl}-4,5-difluoro-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
446.2 yl]-2-oxo-ethyl}-2,4,5-trifluoro-benzamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
486.2 c]pyrrol-2-yl]-2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
478.2 yl]-2-oxo-ethyl}-2-fluoro-6-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
476.2 yl]-2-oxo-ethyl}-2-trifluoromethoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7
482.3 yl]-2-oxo-ethyl}-2,3,6-trimethoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.6
452.2 yl]-2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7
420.2 yl]-2-oxo-ethyl}-2,6-dimethyl-benzamide
4-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
444.2 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
2-Amino-3,5-dibromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.3
565 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.2
478.2 yl]-2-oxo-ethyl}-2-fluoro-5-trifluoromethyl-benzamide
2-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.2
494.1 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
2-Acetylamino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.1
529.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.2
475.2 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
422.2 yl]-2-oxo-ethyl}-2-methoxy-benzamide
2-Amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.7
425.1 c]pyrrol-2-yl]-2-oxo-ethyl}-5-fluoro-benzamide
2-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.8
418.1 yl]-2-oxo-ethyl}-isoindole-1,3-dione Naphthalene-2-carboxylic
acid {2-[5-(2,4-dimethyl-benzyl)- 1.8 442.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.6 482.3 2-oxo-ethyl}-2-(2-trifluoromethyl-phenyl)-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.6 482.3 2-oxo-ethyl}-2-(2-trifluoromethyl-phenyl)-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.7 468.3 2-oxo-ethyl-3-trifluoromethl-benzamide
5-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
440.1 c]pyrrol-2-yl]-2-oxo-ethyl}-2-methyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
528.1 yl]-2-oxo-ethyl}-2,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.6
437.1 yl]-2-oxo-ethyl}-2-nitro-benzamide N-{2-[5-(2,4-Dimethyl-be-
nzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9 460
yl]-2-oxo-ethyl}-2-nitro-benzamide N-{2-[5-(2,4-Dimethyl-benzyl)-h-
exahydro-pyrrolo[3,4-c]pyrrol-2- 1.7 406.1
yl]-2-oxo-ethyl}-2-methy- l-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]p- yrrol-2-
1.9 420.1 yl]-2-oxo-ethyl}-2,5-dimethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.5
436.1 yl]-2-oxo-ethyl}-3-(4-hydroxy-phenyl)-propionamide
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid {2-[5-(2,4- 2
462.2 dimethylbenzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-
ethyl}amide 1-(4-Chloro-phenyl)-cyclopropanecarboxylic acid
{2-[5-(2,4- 2.1 466.1 dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]-2-oxo- ethyl}-amide 1-p-Tolyl-cyclopropanecarboxyl- ic
acid {2-[5-(2,4-dimethyl- 2.1 446.2 benzyl)-hexahydro-pyrrolo[3,-
4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
2-(4-Chloro-phenyl)-N-{2-[5-(2,- 4-dimethyl-benzyl)-hexahydro- 2.2
468.1 pyrrolo[3,4-c]pyrrol-2-yl]-- 2-oxo-ethyl}-isobutyramide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-- pyrrolo[3,4-c]pyrrol-2-
2.4 514.2 yl]-2-oxo-ethyl}-2-(2-fluoro-biph-
enyl-4-yl)-propionamide 1H-Indole-3-carboxylic acid
{2-[5-(2,4-dimethyl-benzyl)- 1.8 431.1 hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]-2-oxo-ethyl}-amide
1-(4-Chloro-phenyl)-5-trifluoromethyl-- 1H-pyrazole-4-carboxylic
2.3 560.2 acid {2-[5-(2,4-dimethyl-benzyl)-
-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl]-2-oxo-ethyl}-amide
1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid {2-[5- 2.1
526.2
(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-
ethyl}-amide 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid
{2-[5-(2,4- 1.9 472.2 dimethyl-benzyl)-hexahydro-pyrrolo[3,4--
c]pyrrol-2-yl]-2-oxo- ethyl}-amide N-{2-[5-(2,4-Dimethyl-ben-
zyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2 474.1
yl]-2-oxo-ethyl}-2-(2-trifluoromethyl-phenyl)-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
456.3 yl]-2-oxo-ethyl}-2-naphthalen-1-yl-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7
406.2 yl]-2-oxo-ethyl}-2-phenyl-acetamide 2-Biphenyl-4-yl-N-{2-[5-
-(2,4-dimethyl-benzyl)-hexahydro- 2.3 482.3
pyrrolo[3,4-c]pyrrol-2-- yl]-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-- pyrrolo[3,4-c]pyrrol-2-
1.9 420.2 yl]-2-oxo-ethyl}-2-o-tolyl-acetam- ide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
420.2 yl]-2-oxo-ethyl}-2-m-tolyl-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
420.2 yl]-2-oxo-ethyl}-2-p-tolyl-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
474.2 yl]-2-oxo-ethyl}-2-(3-trifluoromethyl-phenyl)-acetamide
2-(3,5-Bis-trifluoromethyl-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)-
2.4 542.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
492.2 yl]-2-oxo-ethyl}-2-(2-fluoro-3-trifluoromethyl-phenyl)-a-
cetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr- ol-2-
1.9 460.2 yl]-2-oxo-ethyl}-2-(2,3,6-trifluoro-phenyl)-acetami- de
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
460.2 yl]-2-oxo-ethyl}-2-(2,4,6-trifluoro-phenyl)-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.2
492.2 yl]-2-oxo-ethyl}-2-(3-fluoro-4-trifluoromethyl-phenyl)-aceta-
mide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- -
2.1 492.2 yl]-2-oxo-ethyl}-2-(5-fluoro-2-trifluoromethyl-phenyl)--
acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyr- rol-2-
2.2 448.3 yl]-2-oxo-ethyl}-2-(4-isopropyl-phenyl)-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
434.3 yl]-2-oxo-ethyl}-2-(2,5-dimethyl-phenyl)-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
474.2 yl]-2-oxo-ethyl}-2-(4-trifluoromethyl-phenyl)-acetamide
2-(3,4-Difluoro-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-
1.9 442.2 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
2-(2,4-Bis-trifluoromethyl-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)-
2.3 542.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
9H-Xanthene-9-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 2.3
496.2 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
1-Methyl-1H-indole-3-carboxylic acid {2-[5-(2,4-dimethyl- 1.9 445.5
benzyl)=hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
2-Amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
452.1 c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide
2-Amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.2
533.1 c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
437.1 yl]-2-oxo-ethyl}-3-nitro-benzamide N-{2-[5-(2,4-Dimethyl-be-
nzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7 475.1
yl]-2-oxo-ethyl}-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide
3-(3,4-Dichloro-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-
2.3 486.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acrylamide
5-Fluoro-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
2.1 449.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
7-Nitro-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
2.1 476.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
1-Benzyl-1H-indole-3-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
2.3 521.2 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
5-Bromo-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
2.2 511 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
1H-Indole-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 1.7 431.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
3,4-Dichloro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-
2.1 500.3 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 2.1
545.9 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
2-Amino-5-chloro-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.9
481.3 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
2-Amino-5-bromo-N-{2-oxo-2-[5-(2-trifluoromethyl-benzyl)- 1.9 525.3
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-Oxo-2-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4- 2
500.2 c]pyrrol-2-yl]-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-
2.2 500.3 pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 2.2
545.9 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
2-Amino-5-bromo-N-{2-oxo-2-[5-(4-trifluoromethyl-benzyl)- 2 527.3
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
N-{2-Oxo-2-[5-(4-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.1
500.1 c]pyrrol-2-yl]-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)- 2.2 518.1
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)- 2.3
563.9 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Fluoro-4-trifluoromethyl-benzyl)-hexahydro- 2.1 518.4
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
3,4-Dichloro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 2.1 518.3
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
1H-Indole-2-carboxylic acid {2-[5-(2-fluoro-4-trifluoromethyl- 2
489.2
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
3-Bromo-4-chloro-N-{2-[5-(4-fluoro-2-trifluoromethyl-benzyl)- 2.2
564.2 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Amino-5-chloro-N-{2-[5-(2-fluoro-4-trifluoromethyl-benzyl)- 2
499.3 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Amino-1-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- NA 296.1
c]pyrrol-2-yl]-ethanone 2-Amino-1-[5-(2,3-difluoro-benzyl)-hexahyd-
ro-pyrrolo[3,4- NA 296.1 c]pyrrol-2-yl]-ethanone
2-Amino-1-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 0.2 296.4
c]pyrrol-2-yl]-ethanone 2-Amino-1-[5-(2,5-difluoro-benzyl)-hexahy-
dro-pyrrolo[3,4- NA 296.2 c]pyrrol-2-yl]-ethanone
2-Amino-1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 0.3 288.3
c]pyrrol-2-yl]-ethanone N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-p-
yrrolo[3,4-c]pyrrol-2- 2 496.1
yl]-2-oxo-ethyl}-3-trifluoromethyl-b- enzenesulfonamide
2-Amino-1-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyr- rolo[3,4- 0.2
320.1 c]pyrrol-2-yl]-ethanone
2-Amino-1-[5-(2-trifluoromethyl-benzyl)-hexahydro-pyrrolo[3,4- 0.3
328.5 c]pyrrol-2-yl]-ethanone 2-Amino-1-[5-(4-trifluoromethyl-ben-
zyl)-hexahydro-pyrrolo[3,4- 0.4 328.5 c]pyrrol-2-yl]-ethanone
2-Amino-1-[5-(2-fluoro-4-trifluoromethyl-benzyl)-hexahydro- NA
346.1 pyrrolo[3,4-c]pyrrol-2-yl]-ethanone
2-Amino-1-[5-(4-fluoro-2-tr- ifluoromethyl-benzyl)-hexahydro- NA
346.2 pyrrolo[3,4-c]pyrrol-2-yl- ]-ethanone
1-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]py- rrol-2- 2
475.5 yl]-2-oxo-ethyl}-3-(3-trifluoromethyl-phenyl)-urea
3,4-Dichloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro- 2 492.4
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro- 2.1
538.3 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Amino-5-bromo-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro- 1.9 517.4
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Amino-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 2
565.3 c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide
5-Bromo-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethoxy- 2.1 541.4
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
7-Nitro-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethoxy-benzyl)- 2
508.4 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
3,5-Dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
2.2 460 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid {2-[5-(2,4- 2 450.1
dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-
ethyl}-amide Biphenyl-4-carboxylic acid {2-[5-(2,4-dimethyl-benzyl-
)- 2.3 468.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amid- e
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.7
452.2 yl]-2-oxo-ethyl}-3,4-dimethoxy-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
422.1 yl]-2-oxo-ethyl}-2-phenoxy-acetamide
2-(3,4-Dimethoxy-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)- 1.7 466.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
436.2 yl]-2-oxo-ethyl}-3-phenoxy-propionamide
Thiophene-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 1.6 398.1
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
440.1 yl]-2-oxo-ethyl}-4-thiophen-2-yl-butyramide
Benzofuran-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 2 432.1
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.1
393.1 yl]-2-oxo-ethyl}-nicotinamide 2-(4-Chloro-phenoxy)-N-{2-[5--
(2,4-dimethyl-benzyl)-hexahydro- 2.1 456.1
pyrrolo[3,4-c]pyrrol-2-y- l]-2-oxo-ethyl}-acetamide
5-Methyl-3-phenyl-isoxazole-4-carboxylic acid {2-[5-(2,4- 2 473.1
dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]- pyrrol-2-yl]-2-oxo-
ethyl}-amide Cinnoline-4-carboxylic acid
{2-[5-(2,4-dimethyl-benzyl)- 1.6 445.2 hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydr- o-pyrrolo[3,4-c]pyrrol-2-
2.5 478.2 yl]-2-oxo-ethyl}-4-pentyloxy-be- nzamide
Biphenyl-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 2.1 468.2
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
1-Methyl-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
2.1 445.2 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
424.1 yl]-2-oxo-ethyl}-2-(3-fluoro-phenyl)-acetamide
Pyridine-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-hexahydro-
1.5 393.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
Furan-3-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.3
382.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
450.2 yl]-2-oxo-ethyl}-3-(4-methoxy-phenyl)-propionamide
1-Methyl-1H-pyrrole-2-carboxylic acid {2-[5-(2,4-dimethyl- 2 395.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
3-Methoxy-cyclohexanecarboxylic acid {2-[5-(2,4-dimethyl- 1.7 428.2
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.5
412 yl]-2-oxo-ethyl}-2-thiophen-2-yl-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.3
498.2 yl]-2-oxo-ethyl}-2-(4-phenoxy-phenyl)-acetamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2
456.1 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methoxy-benzamide
1,2,3,4-Tetrahydro-naphthalene-2-carboxylic acid {2-[5-(2,4- 2.1
446.2 dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-
ethyl}-amide 3-(4-Chloro-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)-hex-
ahydro- 2.1 454.1
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionam- ide
2-(2,4-Difluoro-phenyl)-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- -
1.9 442.1 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
2-Cyclopentyl-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.9 398.1
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.4
496.2 yl]-2-oxo-ethyl}-2-phenethyl-benzamide
2-Ethoxy-naphthalene-1-carboxylic acid {2-[5-(2,4-dimethyl- 2.1
486.2
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
4-Cyclohexyl-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.5 474.2
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.1
440.1 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
436.1 yl]-2oxo-ethyl}-3-ethoxy-benzamide
4-Diethylamino-N-{2-[5-(2,- 4-dimethyl-benzyl)-hexahydro- 2 463.2
pyrrolo[3,4-c]pyrrol-2-yl]-2-- oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrol- o[3,4-c]pyrrol-2-
2.1 420.1 yl]-2-oxo-ethyl}-4-ethyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.3
464.2 yl]-2-oxo-ethyl}-2-(4-isopropyl-phenoxy)-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
450.2 yl]-2-oxo-ethyl}-2-(4-ethoxy-phenyl)-acetamide
N-{2-(5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.9
510.2 yl]-2-oxo-ethyl}-3-(3,4,5-trimethoxy-phenyl)-propionamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
434.2 yl]-2-oxo-ethyl}-3-m-tolyl-propionamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2
438.1 yl]-2-oxo-ethyl}-3-(4-fluoro-phenyl)-propionamide
3-Methyl-benzofuran-2-carboxylic acid {2-[5-(2,4-dimethyl- 2.2
445.2
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
7-Methoxy-benzofuran-2-carboxylic acid {2-[5-(2,4-dimethyl- 2.1
462.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl-amide
5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {2-[5-(2,4-
2.3 473.1
dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-
ethyl}-amide N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrol-
o[3,4-c]pyrrol-2- 1.9 440.1
yl]-2-oxo-ethyl}-3-fluoro-4-methoxy-ben- zamide
Chroman-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 2.1 448.1
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
5-Pyridin-2-yl-thiophene-2-carboxylic acid {2-[5-(2,4-dimethyl- 2
475.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
2-Cyclopropyl-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 1.4 370.1
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.3
470.2 yl]-2-oxo-ethyl}-3-naphthalen-1-yl-propionamide
2-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
440.1 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
3-Chloro-thiophene-2-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
1.9 432 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
2,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[5- 1.6
461.1 (2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
oxoethyl}-amide 4-Methoxy-thiophene-3-carboxylic acid
{2-[5-(2,4-dimethyl- 1.8 428.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]-2-oxo-ethyl}-amide
2-(5-Chloro-3-methyl-benzo[b]thiophen-- 2-yl)-N-{2-[5-(2,4- 2.4
510.1 dimethyl-benzyl)-hexahydro-pyrrolo[3,-
4-c]pyrrol-2-yl]-2-oxo- ethyl}-acetamide
2,5-Dimethyl-furan-3-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
1.9 410.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.1
457.2 yl]-2-oxo-ethyl}-4-pyrrol-1-yl-benzamide
2-Pyrazin-2-yl-thiazole-4-carboxylic acid {2-[5-(2,4-dimethyl- 1.7
477.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
Isoxazole-5-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)- 1.2 383.1
hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
Benzo[1,2,5]oxadiazole-5-carboxylic acid {2-[5-(2,4-dimethyl- 1.9
434.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
5-Methyl-isoxazole-4-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
1.5 397.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
5-Methyl-isoxazole-3-carboxylic acid {2-[5-(2,4-dimethyl-benzyl)-
1.5 397.1 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
4,6-Dichloro-1H-indole-2-carboxylic acid {2-[5-(2,4-dimethyl- 2.5
499.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-amide
4-Chloro-N-{2-[5-(2-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.6 412.4
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide 4-Chloro-N-{2-oxo-2-[5--
(3-trifluoromethyl-benzyl)-hexahydro- 1.9 466.3
pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-benzamide
4-Chloro-N-{2-[5-(5-methoxy-1H-indol-3-ylmethyl)-hexahydro- 1.7
467.4 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Chloro-N-{2-[5-(2-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.6 412.4
c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide 3-Chloro-N-{2-oxo-2-[5-(3-t-
rifluoromethyl-benzyl)-hexahydro- 1.9 466.4
pyrrolo[3,4-c]pyrrol-2-- yl]-ethyl}-benzamide
1-(3,4-Dichloro-benzyl)-3-methyl-4-oxo-4,5,6,7- -tetrahydro-1H- 2.3
621.4 indole-2-carboxylic acid
{2-[5-(2,4-dimethyl-benzyl)-hexahydro- pyrrolo[3,4-c]pyrrol-2-yl]--
2-oxo-ethyl}-amide
1-(3,4-Dichloro-benzyl)-2-[5-(2,4-dimethyl-benzy- l)-hexahydro- 2.3
564.3 pyrrolo[3,4-c]pyrrole-2-carbonyl]-3-methyl--
1,5,6,7-tetrahydro- indol-4-one 2-Amino-1-[5-(3,4-dichloro-b-
enzyl)-hexahydro-pyrrolo[3,4- NA 327.9 c]pyrrol-2-yl]-ethanone
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.63 449.11 yl]-2-oxo-ethyl}-3-fluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.47 415.15 oxo-ethyl}-3-fluoro-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.71 467.1 yl]-2-oxo-ethyl}-3,4-difluoro-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.64 449.11 yl]-2-oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.48 415.15 oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.54 411.17 oxo-ethyl}-3-methyl-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.77 463.12 yl]-2-oxo-ethyl}-3-fluoro-4-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.6 429.16 oxo-ethyl}-3-fluoro-4-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.4 397.16 oxo-ethyl}-benzamide N-{2-[5-(3,4-Dichloro-benzyl)-h-
exahydro-pyrrolo[3,4-c]pyrrol-2- 1.7 467.1
yl]-2-oxo-ethyl}-3,5-dif- luoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl]-2-
1.54 433.14 oxo-ethyl}-3,5-difluoro-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.69 445.13 yl]-2-oxo-ethyl}-4-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.53 411.17 oxo-ethyl}-4-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.65 425.19 oxo-ethyl}-3,4-dimethyl-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.87 491.12 yl]-2-oxo-ethyl}-4-ethylsulfanyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.74 457.16 oxo-ethyl}-4-ethylsulfanyl-benzamide
4-Butyl-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 2.07
487.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Butyl-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
1.96 453.22 2-yl]-2-oxo-ethyl}-benzamide N-{2-[5-(4-Chloro-benzy-
l)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.8 439.2
oxo-ethyl}-4-isopropyl-benzamide N-{2-[5-(4-Chloro-benzyl)-hexahyd-
ro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.8 481.14
oxo-ethyl}-4-trifluorom- ethoxy-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,- 4-c]pyrrol-2-
1.8 485.09 yl]-2-oxo-ethyl}-3,4,5-trifluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.66 451.13 oxo-ethyl}-3,4,5-trifluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.83 439.2 oxo-ethyl}-4-propyl-benzamide N-{2-[5-(4-Chloro-benzy-
l)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.7 455.2
oxo-ethyl}-4-isopropoxy-benzamide N-{2-[5-(4-Chloro-benzyl)-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 1.76 455.2
oxo-ethyl}-4-propoxy-benzamide 3-Chloro-N-{2-[5-(3,4-dichloro-benz-
yl)-hexahydro-pyrrolo[3,4- 1.83 483.07
c]pyrrol-2-yl]-2-oxo-ethyl}-- 4-fluoro-benzamide
3-Chloro-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyr- rolo[3,4- 1.67
449.11 c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamid- e
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.8 483.13 oxo-ethyl}-3-fluoro-5-trifluoromethyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.84 483.13 oxo-ethyl}-3-fluoro-4-trifluoromethyl-benzamide
4-Bromo-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.82
509.03 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-Bromo-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.66
475.07 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Bromo-N-{2-[5-(3,4-dichl- oro-benzyl)-hexahydro-pyrrolo[3,4- 1.72
539.04 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methoxy-benzamide
2-Bromo-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.57
505.08 c]pyrrol-2-yl]-2-oxo-ethyl}-5-methoxy-benzamide
4-tert-Butyl-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-
2.03 487.18 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
4-tert-Butyl-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.9
453.22 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
2.12 567.09 yl]-2-oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- 2
533.13 oxo-ethyl}-3,5-bis-trifluoromethyl-benzamide
3-Bromo-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.79
489.08 c]pyrrol-2-yl]-2-oxo-ethyl}-4-methyl-benzamide
3-Bromo-4-chloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro- 1.97
542.99 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-[5-(4-chloro-benzyl)-hexahydro- 1.83 509.03
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.81
509.03 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.65
475.07 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3,4-Dichloro-benz- yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.89 499.1 yl]-2-oxo-ethyl}-4-trifluoromethyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.77 465.14 oxo-ethyl}-4-trifluoromethyl-benzamide
2-Chloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.75
479.09 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
2-Chloro-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.57
445.13 c]pyrrol-2-yl]-2-oxo-ethyl}-3-methyl-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.73 463.12 yl]-2-oxo-ethyl}-2-fluoro-5-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.58 429.16 oxo-ethyl}-2-fluoro-5-methyl-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 1.6
449.11 yl]-2-oxo-ethyl}-2-fluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.43 415.15 oxo-ethyl}-2-fluoro-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.58 425.19 oxo-ethyl}-2,5-dimethyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.51 429.16 oxo-ethyl}-5-fluoro-2-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.6 425.19 oxo-ethyl}-2,4-dimethyl-benzamide
2-Chloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.63
465.08 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2-Chloro-N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.46
431.12 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Chloro-benzyl)- -hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
1.57 425.19 oxo-ethyl}-2,3-dimethyl-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-he- xahydro-pyrrolo[3,4-c]pyrrol-2-
1.7 463.12 yl]-2-oxo-ethyl}-3-fluor- o-2-methyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,- 4-c]pyrrol-2-yl]-2-
1.53 429.16 oxo-ethyl}-3-fluoro-2-methyl-benzam- ide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-- 2-
1.46 411.17 oxo-ethyl}-2-methyl-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.86 459.21 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.82 465.14 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.73
431.12 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(5-Bromo-2-methox- y-benzyl)-hexahydro-pyrrolo[3,4- 1.86
539.1 b]pyrrol-1-yl]-2-oxo-et- hyl}-3-trifluoromethyl-benzamide
N-{2-[5-(5-Bromo-2-methoxy-benzyl)- -hexahydro-pyrrolo[3,4- 1.76
505.08 b]pyrrol-1-yl]-2-oxo-ethyl}-4-c- hloro-benzamide
N-{2-[5-(3-Bromo-4-methoxy-benzyl)-hexahydro-pyrrol- o[3,4- 1.85
539.1 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-ben- zamide
N-{2-[5-(3-Bromo-4-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.75
505.08 b]pyrrol-1-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(3-Chloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.81 465.14 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3-chloro-benzyl)-hexahydro-pyrrolo[3,4- 1.7
431.12 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3,5-Dichloro-benz- yl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.97 499.1 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3,5-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.86
465.08 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3-Bromo-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.89
527.08 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(3-Bromo-4-fluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.81
493.06 b]pyrrol-1-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(4-Bromo-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.89 509.09 oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(4-Bromo-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.79 475.07 oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(3,4-Dibromo-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1- 2.05
587 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(3,4-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1- 2
499.1 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4- 1.91
465.08 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(5-Methyl-thiophen-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.72
451.15 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(5-methyl-thiophen-2-ylmethyl)-hexahydro- 1.59
417.03 pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(5-Bromo-thiophen-2-ylmethyl)-hexahydro-pyrrolo[3,4 1.84
515.05 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(5-Bromo-thiophen-2-ylmethyl)-hexahydro-pyrrolo[3,4 1.74
481.02 b]pyrrol-1-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(5-Methyl-furan-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.63
435.18 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(5-methyl-furan-2-ylmethyl)-hexahydro- 1.49 401.15
pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3-Methyl-thiophen-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.67
451.15 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(5-methyl-thiophen-2-ylmethyl)-hexahydro- 1.61
417.13 pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Bromo-thiophen-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.81
515.05 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(4-Bromo-thiophen-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.72
481.02 b]pyrrol-1-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-Oxo-2-(5-thiazol-2-ylmethyl-hexahydro-pyrrolo[3,4-b]pyrrol-
1.45 438.13 1-yl)-ethyl]-3-trifluoromethyl-benzamide
4-Chloro-N-[2-oxo-2-(5-thiazol-2-ylmethyl-hexahydro-pyrrolo[3,4-
1.32 404.11 b]pyrrol-1-yl)-ethyl]-benzamide
N-[2-(5-Benzofuran-2-ylmethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.82 471.18 yl)-2-oxo-ethyl]-3-trifluoromethyl-benzamide
N-[2-(5-Benzofuran-2-ylmethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.72 437.15 yl)-2-oxo-ethyl]-4-chloro-benzamide
N-{2-[5-(4-Bromo-furan-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.72
499.07 b]pyrrol-1yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(4-Bromo-furan-2-ylmethyl)-hexahydro-pyrrolo[3,4- 1.61
465.05 b]pyrrol-1-yl]-2-oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(5-Methylsulfanyl-thiophen-2-ylmethyl)-hexahydro- 1.84
483.13 pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-
benzamide 4-Chloro-N-{2-[5-(5-methylsulfanyl-thiophen-2-ylmethyl)-
1.74 449.1 hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benza-
mide
N-{2-[5-(3-Methyl-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]- -2-
1.77 445.2 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.66
411.17 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3-Bromo-benzyl)-- hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.85 509.09 oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(3-Bromo-benzyl)-he- xahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.76 475.07 oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(4-Methyl-benzyl)-hexahydro-- pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.77 445.2 oxo-ethyl}-3-trifluromethy- l-benzamide
4-Chloro-N-{2-[5-(4-methyl-benzyl)-hexahydro-pyrrolo[3,- 4- 1.67
411.17 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Isopropyl-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-
2 473.23 2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-isopropyl-benyl)-hexahydro-pyrrolo[3,4- 1.89
439.2 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-tert-Butyl-be-
nzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]- 2.07 487.24
2-oxo-ethyl}-3-trifluoromethyl-benzamide N-{2-[5-(4-tert-Butyl-ben-
zyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]- 1.99 453.22
2-oxo-ethyl}-4-chloro-benzamide N-{2-[5-(4-Ethyl-benzyl)-hexahydro-
-pyrrolo[3,4-b]pyrrol-1-yl]-2- 1.9 459.21
oxo-ethyl}-3-trifluoromet- hyl-benzamide
4-Chloro-N-{2-[5-(4-ethyl-benzyl)-hexahydro-pyrrolo[3- ,4-b]pyrrol-
1.79 425.19 1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(3,5-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.88 459.21 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(3,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.79
425.19 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-[2-(5-Benzyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-2-oxo-ethyl]-
1.65 431.18 3-trifluoromethyl-benzamide N-[2-(5-Benzyl-hexahydro-
-pyrrolo[3,4-b]pyrrol-1-yl)-2-oxo-ethyl]- 1.53 397.16
4-chloro-benzamide N-(2-[5-(4-Butyl-benzyl)-hexahydro-pyrrolo[3,4--
b]pyrrol-1-yl]-2- 2.15 487.24
oxo-ethyl}-3-trifluoromethyl-benzamid- e
N-{2-[5-(4-Butyl-benzyl)-hexahydro-pyrrolol[3,4-b]pyrrol-1-yl]-2-
2.06 453.22 oxo-ethyl}-4-chloro-benzamide
N-{2-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.75 491.2 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.74
457.18 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Methyl-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.74 445.2 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-methyl-benzyl)-hexahydro-pyrrolo[3,4- 1.74
411.17 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Ethoxy-benzyl)- -hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-
1.8 475.21 oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-ethoxy-- benzyl)-hexahydro-pyrrolo[3,4- 1.7
441.18 b]pyrrol-1-yl]-2-oxo-ethy- l}-benzamide
N-{2-[5-(2-Methoxy-benzyl)-hexahydro-pyrrolo[3,4-b]pyr- rol-1-yl]-
1.71 461.19 2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2-methoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.59
427.17 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,5-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.74 491.2 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,5-dimethoxy-benzyl)-hexahydro- 1.62 457.18
pyrrolo[3,4b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,5-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-
1.85 459.21 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(2,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.74
425.19 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Methoxy-2,5-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.89
489.22 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
4-Chloro-N-{2-[5-(4-methoxy-2,5-dimethyl-benzyl)-hexahydro- 1.8
455.2 pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(4-Methoxy-2,3-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
489.22 b]pyrrol-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzami
4-Chloro-N-{2-[5-(4-methoxy-2,3-dimethyl-benzyl)-hexahydro- 1.8
455.2 pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
4-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.75
425.19 b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Benzyloxy-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1- 2.05
537.22 yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2-Benzyloxy-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1- 1.96
503.2 yl]-2-oxo-ethyl}-4-chloro-benzamide N-{2-[5-(3-Cyclopentylo-
xy-4-methoxy-benzyl)-hexahydro- 1.98 545.25
pyrrolo[3,4-b]pyrrol-1-- yl]-2-oxo-ethyl}-3-trifluoromethyl-
benzamide 4-Chloro-N-{2-[5-(3-cyclopentyloxy-4-methoxy-benzyl)- 1.9
511.22 hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.67 459.21 yl]-2-oxo-ethyl}-3-triflouromethyl-benzamide
N-{1-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.66 512.26 2-oxo-ethylcarbamoyl}-3-methylbutyl)-benzamide
N-{1-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.69 512.26 2-oxo-ethylcarbamoyl}-3-methylbutyl)-benzamide
N-{1-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.67 512.26 2-oxo-ethylcarbamoyl}-3-methylbutyl)-benzamide
N-{1-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.75 512.26 2-oxo-ethylcarbamoyl}-3-methylbutyl)-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.8 560.26 2-oxo-ethyl}-3-phenylacetyl amino-propioamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.8 560.26 2-oxo-ethyl}-3-phenyl-2-phenylacetylamino-propioamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.78 560.26 2-oxo-ethyl}-3-phenyl-2-phenylacetylamino-propionamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.84 560.26 2-oxo-ethyl}-3-phenyl-2-phenylacetylamino-propionamide
N-(1-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.34 470.21 yl]-2-oxo-ethylcarbamoyl}-ethyl)-benzamide
N-(1-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.35 470.21 yl]-2-oxo-ethylcarbamoyl}-ethyl)-benzamide
N-(1-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.32 470.21 yl]-2-oxo-ethylcarbamoyl}-ethyl)-benzamide
N-(1-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.41 470.21 yl]-2-oxo-ethylcarbamoyl}-ehtyl)-benzamide
N-(1-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.75 546.24 yl]-2-oxo-ethylcarbamoyl}-2-phenyl-ethyl)-benzamide
N-(1-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.75 546.24 yl]-2-oxo-ethylcarbamoyl}-2-phenyl-ethyl)-benzamide
N-(1-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.72 546.24 yl]-2-oxo-ethylcarbamoyl}-2-phenyl-ethyl)-benzamide
N-(1-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.79 546.24 yl]-2-oxo-ethylcarbamoyl}-2-phenyl-ethyl)-benzamide
N-(1-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.53 498.24 yl]-2-oxo-ethylcarbamoyl}-2-methyl-propyl)-benzamide
N-(1-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.54 498.24 yl]-2-oxo-ethylcarbamoyl}-2-methyl-propyl)-benzamide
N-(1-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.52 498.24 yl]-2-oxo-ethylcarbamoyl}-2-methyl-propyl)-benzamide
N-(1-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.59 498.24 yl]-2-oxo-ethylcarbamoyl}-2-methyl-propyl)-benzamide
5-Oxo-pyrrolidine-2-carboxylic acid {2-[5-(3,5-difluoro-benzyl)-
1.05 406.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}amide
2-Acetylamino-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro- 1.07 408.2
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
N-(2-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.6 524.26 yl]-2-oxo-ethylcarbamoyl}-cyclohexyl)-benzamide
N-(2-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.59 524.26 yl]-2-oxo-ethylcarbamoyl}-cyclohexyl)-benzamide
N-(2-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.57 524.26 yl]-2-oxo-ethylcarbamoyl}-cyclohexyl)-benzamide
N-(2-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.65 524.26 yl]-2-oxo-ethylcarbamoyl}-cyclohexyl)-benzamide
3-Cyclohexyl-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.78 433.25 c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-Cyclohexyl-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.79 433.25 c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-Cyclohexyl-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.77 433.25 c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-Cyclohexyl-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.85 433.25 c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.9 501.22 2-oxo-ethyl}-2-(9H-fluoren-9-yl)-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.9 501.22 2-oxo-ethyl}-2-(9H-fluoren-9-yl)-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.88 501.22 2-oxo-ethyl}-2-(9H-fluoren-9-yl)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.95 501.22 2-oxo-ethyl}-2-(9H-fluoren-9-yl)-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
2.11 493.1
2-oxo-ethyl}-2-(2-isopropyl-5-methyl-cyclohexyloxy)-acetamid- e
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-
]- 2.11 491.3
2-oxo-ethyl}-2-(2-isopropyl-5-methyl-cyclohexyloxy)-a- cetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]- 2.1 491.3
2-oxo-ethyl}-2-(2-isopropyl-5-methyl-cyclohexyl- oxy)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4--
c]pyrrol-2-yl]- 2.17 491.3
2-oxo-ethyl}-2-(2-isopropyl-5-methyl-cyc- lohexyloxy)-acetamide
5-Oxo-5-phenyl-pentanoic acid {2-[5-(2,4-difluoro-benzyl)- 1.53
469.22 hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl]-2-oxo-ethyl}-amide
5-Oxo-5-phenyl-pentanoic acid {2-[5-(2,3-difluoro-benzyl)- 1.53
469.22 hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl]-2-oxo-ethyl}-amide
5-Oxo-5-phenyl-pentanoic acid {2-[5-(2,5-difluoro-benzyl)- 1.51
469.22 hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl]-2-oxo-ethyl}-amide
5-Oxo-5-phenyl-pentanoic acid {2-[5-(3,5-difluoro-benzyl)- 1.59
469.22 hexahydro-pyrrolo[3,4-c]p- yrrol-2-yl]-2-oxo-ethyl}-amide
3-Cyclopentyl-N-{2-[5-(2,4-difluoro-- benzyl)-hexahydro- 1.65
419.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-eth- yl}-propionamide
3-Cyclopentyl-N-{2-[5-(2,3-difluoro-benzyl)-hexahy- dro- 1.66
419.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionami- de
3-cyclopentyl-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro- 1.64 419.24
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-cyclopentyl-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro- 1.72 419.24
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.65 441.22 2-oxo-ethyl}-4-phenyl-butyramide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.64 441.22 2-oxo-ethyl}-4-phenyl-butyramide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.63 441.22 2-oxo-ethyl}-4-phenyl-butyramide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.7 441.22 oxo-ethyl}-4-phenyl-butyramide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.63 441.22 2-oxo-ethyl}-3-o-tolyl-propionamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.64 441.22 2-oxo-ethyl}-3-o-tolyl-propionamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.62 441.22 2-oxo-ethyl}-3-o-tolyl-propionamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol2-yl]-
1.69 441.22 2-oxo-ethyl]-3-o-tolyl-propionamide
3-(3,5-Bis-trifluoromethyl-phenyl)-N-{2-[5-(2,4-difluoro-benzyl)-
2.06 563.18
hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionam- ide
3-(3,5-Bis-trifluoromethyl-phenyl)-N-{2-[5-(2,3-difluoro-benzyl- )-
2.07 563.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-pr-
opionamide
3-(3,5-Bis-trifluoromethyl-phenyl)-N-{2-[5-(2,5-difluoro- -benzyl)-
2.06 563.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-et-
hyl}-propionamide
3-(3,5-Bis-trifluoromethyl-phenyl)-N-{2-[5-(3,5-d- ifluoro-benzyl)-
2.12 563.18 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-
-oxo-ethyl}-propionamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-py-
rrolo[3,4-c]pyrrol-2-yl]- 1.61 441.22
2-oxo-ethyl}-3-phenyl-butyram- ide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2--
yl]- 1.61 441.22 2-oxo-ethyl}-3-phenyl-butyramide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.58 441.22 2-oxo-ethyl}-3-phenyl-butyramide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.67 441.22 2-oxo-ethyl}-3-phenyl-butyramide
4-Bromo-phenyl)-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro- 1.73
533.11 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-oxo-butyramide
4-(4-Bromo-phenyl)-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro- 1.75
533.11 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-oxo-butyramide
4-(4-Bromo-phenyl)-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro- 1.72
533.11 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-oxo-butyramide
4-(4-Bromo-phenyl)-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro- 1.79
533.11 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-oxo-butyramide
3-(2-Chloro-phenyl)-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro- 1.68
461.17 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-(2-Chloro-phenyl)-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro- 1.68
461.17 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-(2-Chloro-phenyl)-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro- 1.65
461.17 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
3-(2-Chloro-phenyl)-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro- 1.74
461.17 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-propionamide
2,4-Dichloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.65 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,4-Dichloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.64 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,4-Dichloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.6 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,4-Dichloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.69 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,5-Dichloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.58 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,5-Dichloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.58 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,5-Dichloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.56 467.1 c]pyrrol-2-yl]-2-oxo-ethyl]-benzamide
2,5-Dichloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.65 467.1 c]pyrrol-2-yl]-2-oxo-ethyl]-benzamide
2,3-Dichloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.61 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,3-Dichloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro- 1.62 467.1
pyrrolo[3,4,c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,3-Dichloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-Pyrrolo[3,4-
1.59 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,3-Dichloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.67 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.44 435.16 2-oxo-ethyl}-2,5-difluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 435.16 2-oxo-ethyl}-2,5-difluoro-benzamide
N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 435.16 2-oxo-ethyl}-2,5-difluoro-benzamide
N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 435.16 2-oxo-ethyl}-2,5-difluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 435.16 2-oxo-ethyl}-2,3-difluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 435.16 2-oxo-ethyl}-2,3-difluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 435.16 2-oxo-ethyl}-2,3-difluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 435.16 2-oxo-ethyl}-2,3-difluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 435.16 2-oxo-ethyl}-2,4-difluoro-benzamide
N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.45 435.16 2-oxo-ethyl}-2,4-difluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.44 435.16 2-oxo-ethyl}-2,4-difluoro-benzamide
N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 435.16 2-oxo-ethyl}-2,4-difluoro-benzamide
2-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.48
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide
2-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.49
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide
2-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.47
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide
2-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro- 1.54 451.13
pyrrolo[3,4,c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.54 453.15 2-oxo-ethyl}-2,4,5-trifluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.55 453.15 2-oxo-ethyl}-2,4,5-trifluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 453.15 2-oxo-ethyl}-2,4,5-trifluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.61 453.15 2-oxo-ethyl}-2,4,5-trifluoro-benzamide
2-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.56
469.12 c]pyrrol-2-yl]-2-oxo-ethyl}-4,5-difluoro-benzamide
2-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.56
469.12 c]pyrrol-2-yl]-2-oxo-ethyl}-4,5-difluoro-benzamide
2-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.52
469.12 c]pyrrol-2-yl]-2-oxo-ethyl}-4,5-difluoro-benzamide
2-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.62
469.12 c]pyrrol-2-yl]-2-oxo-ethyl}-4,5-difluoro-benzamide
4-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.6
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
4-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.61
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
4-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.58
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
4-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.66
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
3-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.58
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
3-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.59
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
3-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.55
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
3-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.63
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-2-fluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 443.2 2-oxo-ethyl}-2-ethoxy-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.41 443.2 2-oxo-ethyl}-2-ethoxy-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.41 443.2 2-oxo-ethyl}-2-ethoxy-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 443.2 2-oxo-ethyl}-2-ethoxy-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.36 467.16 2-oxo-ethyl}-2-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.36 467.16 2-oxo-ethyl}-2-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.33 467.16 2-oxo-ethyl}-2-trifluoromethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.41 467.16 2-oxo-ethyl}-2-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.55 485.15 2-oxo-ethyl}-2-fluoro-4-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.55 485.15 2-oxo-ethyl}-2-fluoro-4-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.54 485.15 2-oxo-ethyl}-2-fluoro-4-trifluoromethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.6 485.15 2-oxo-ethyl}-2-fluoro-4-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.61 535.15 2-oxo-ethyl}-2,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.62 535.15 2-oxo-ethyl}-2,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.59 535.15 2-oxo-ethyl}-2,5-bis-trifluoromethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.66 535.15 2-oxo-ethyl}-2,5-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.35 453.15 2-oxo-ethyl}-2,3,4-trifluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.37 453.15 2-oxo-ethyl}-2,3,4-trifluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 453.15 2-oxo-ethyl}-2,3,4-trifluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.41 453.15 2-oxo-ethyl}-2,3,4-trifluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 485.15 2-oxo-ethyl}-2,3,4-trifluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.54 485.15 2-oxo-ethyl}-2-fluoro-3-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.51 485.15 2-oxo-ethyl}-2-fluoro-3-trifluoromethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.58 485.15 2-oxo-ethyl}-2-fluoro-3-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.67 535.15 2-oxo-ethyl}-2,4-bis-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.69 535.15 2-oxo-ethyl}-2,4-bis-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.67 535.15 2-oxo-ethyl}-2,4-bis-trifluoromethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.73 535.15 2-oxo-ethyl}-2,4-bis-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 485.15 2-oxo-ethyl}-4-fluoro-2-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 485.15 2-oxo-ethyl}-4-fluoro-2-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.41 485.15 2-oxo-ethyl}-4-fluoro-2-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.48 485.15 2-oxo-ethyl}-4-fluoro-2-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 483.16 2-oxo-ethyl}-2-trifluoromethoxy-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.44 483.16 2-oxo-ethyl}-2-trifluoromethoxy-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 483.16 2-oxo-ethyl}-2-trifluoromethoxy-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.48 483.16 2-oxo-ethyl}-2-trifluoromethoxy-benzamide
2-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.54
501.12 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
2-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.55
501.12 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
2-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.53
501.12 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
2-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.59
501.12 c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 465.17 2-oxo-ethyl}-2-difluoromethoxy-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.35 465.17 2-oxo-ethyl}-2-difluoromethoxy-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.31 465.17 2-oxo-ethyl}-2-difluoromethoxy-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.39 465.17 2-oxo-ethyl}-2-difluoromethoxy-benzamide
2,6-Dichloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.27 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,6-Dichloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.27 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,6-Dichloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4-
1.24 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
2,6-Dichloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4
1.33 467.1 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.28 427.21 2-oxo-ethyl}-2,6-dimethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.29 427.21 2-oxo-ethyl}-2,6-dimethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.25 427.21 2-oxo-ethyl}-2,6-dimethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.32 427.21 2-oxo-ethyl}-2,6-dimethyl-benzamide
2-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.23
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-6-fluoro-benzamide
2-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.23
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-6-fluoro-benzamide
2-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.19
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-6-fluoro-benzamide
2-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.28
451.13 c]pyrrol-2-yl]-2-oxo-ethyl}-6-fluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.16 435.16 2-oxo-ethyl}-2,6-difluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.16 435.16 2-oxo-ethyl}-2,6-difluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.08 435.16 2-oxo-ethyl}-2,6-difluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.21 435.16 2-oxo-ethyl}-2,6-difluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.23 453.15 2-oxo-ethyl}-2,3,6-trifluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.25 453.15 2-oxo-ethyl}-2,3,6-trifluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.21 453.15 2-oxo-ethyl}-2,3,6-trifluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.29 453.15 2-oxo-ethyl}-2,3,6-trifluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.33 485.15 2-oxo-ethyl}-2-fluoro-6-trifluoromethyl-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.35 485.15 2-oxo-ethyl}-2-fluoro-6-trifluoromethyl-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.31 485.15 2-oxo-ethyl}-2-fluoro-6-trifluoromethyl-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.39 485.15 2-oxo-ethyl}-2-fluoro-6-trifluoromethyl-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.23 453.15 2-oxo-ethyl}-2,4,6-trifluoro-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.22 453.15 2-oxo-ethyl}-2,4,6-trifluoro-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.2 453.15 2-oxo-ethyl}-2,4,6-trifluoro-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.28 453.15 2-oxo-ethyl}-2,4,6-trifluoro-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.15 459.2 2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.16 459.2 2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.09 459.2 2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.21 459.2 2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.2 489.21 2-oxo-ethyl}-2,3,6-trimethoxy-benzamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.21 489.21 2-oxo-ethyl}-2,3,6-trimethoxy-benzamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.18 489.21 2-oxo-ethyl}-2,3,6-trimethoxy-benzamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.25 489.21 2-oxo-ethyl}-2,3,6-trimethoxy-benzamide
3-Chloro-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.36
493.16 c]pyrrol-2-yl]-2-oxo-ethyl}-2,6-dimethoxy-benzamide
3-Chloro-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.37
493.16 c]pyrrol-2-yl]-2-oxo-ethyl}-2,6-dimethoxy-benzamide
3-Chloro-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.34
493.16 c]pyrrol-2-yl]-2-oxo-ethyl}-2,6-dimethoxy-benzamide
3-Chloro-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro-pyrrolo[3,4- 1.41
493.16 c]pyrrol-2-yl]-2-oxo-ethyl}-2,6-dimethoxy-benzamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 427.21 2-oxo-ethyl}-2-o-tolyl-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 427.21 2-oxo-ethyl}-2-o-tolyl-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.32 427.21 2-oxo-ethyl}-2-o-tolyl-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.39 427.21 2-oxo-ethyl}-2-o-tolyl-acetamide
2-Biphenyl-4-yl-N-{2-[5-(2,4-difluoro-benzyl)-hexahydro- 1.69
489.22 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
2-Biphenyl-4-yl-N-{2-[5-(2,3-difluoro-benzyl)-hexahydro- 1.7 489.22
pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
2-Biphenyl-4-yl-N-{2-[5-(2,5-difluoro-benzyl)-hexahydro- 1.69
489.22 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
2-Biphenyl-4-yl-N-{2-[5-(3,5-difluoro-benzyl)-hexahydro- 1.73
489.22 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.65 455.24 2-oxo-ethyl}-2-(4-isopropyl-phenyl)-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.65 455.24 2-oxo-ethyl}-2-(4-isopropyl-phenyl)-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.64 455.24 2-oxo-ethyl}-2-(4-isopropyl-phenyl)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.69 455.24 2-oxo-ethyl}-2-(4-isopropyl-phenyl)-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.38 427.21 2-oxo-ethyl}-2-m-tolyl-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.38 427.21 2-oxo-ethyl}-2-m-tolyl-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.35 427.21 2-oxo-ethyl}-2-m-tolyl-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.42 427.21 2-oxo-ethyl}-2-m-tolyl-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.38 427.21 2-oxo-ethyl}-2-p-tolyl-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.39 427.21 2-oxo-ethyl}-2-p-tolyl-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.36 427.21 2-oxo-ethyl}-2-p-tolyl-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.43 427.21 2-oxo-ethyl}-2-p-tolyl-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.47 441.22 2-oxo-ethyl}-2-(2,5-dimethyl-phenyl)-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.48 441.22 2-oxo-ethyl}-2-(2,5-dimethyl-phenyl)-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.46 441.22 2-oxo-ethyl}-2-(2,5-dimethyl-phenyl)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 441.22 2-oxo-ethyl}-2-(2,5-dimethyl-phenyl)-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.5 463.21 2-oxo-ethyl}-2-naphthalen-1-yl-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.52 463.21 2-oxo-ethyl}-2-naphthalen-1-yl-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.49 463.21 2-oxo-ethyl}-2-naphthalen-1-yl-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.56 463.21 2-oxo-ethyl}-2-naphthalen-1-yl-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 467.16 2-oxo-ethyl}-2-(2,3,6-trifluoro-phenyl)-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.34 467.16 2-oxo-ethyl}-2-(2,3,6-trifluoro-phenyl)-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.32 467.16 2-oxo-ethyl}-2-(2,3,6-trifluoro-phenyl)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.4 467.16 2-oxo-ethyl}-2-(2,3,6-trifluoro-phenyl)-acetamide
N-{2-[5 (2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.24 413.19 2-oxo-ethyl}-2-phenyl-acetamide
N-{2-[5-(2,3-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.25 413.19 2-oxo-ethyl}-2-phenyl-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.22 413.19 2-oxo-ethyl}-2-phenyl-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.3 413.19 2-oxo-ethyl}-2-phenyl-acetamide
N-{2-[5-(2,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.5 441.22 2-oxo-ethyl}-2-(3,5-dimethyl-phenyl)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.56 441.22 2-oxo-ethyl}-2-(3,5-dimethyl-phenyl)-acetamide
N-{2-[5-(2,4-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.48 441.22 2-oxo-ethyl}-2-(2,4-dimethyl-phenyl)-acetamide
N-{2-[5-(3,5-Difluoro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.53 441.22 2-oxo-ethyl}-2-(2,4-dimethyl-phenyl)-acetamide
2-Amino-1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 0.6 330.6
c]pyrrol-2-yl]-3-methyl-butan-1-one [5-(2,4-Dimethyl-benzyl)-hexa-
hydro-pyrrolo[3,4-c]pyrrol-2-yl]- 0.4 328.6
pyrrolidin-2-yl-methano- ne
2-Amino-1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 0.4 302.6
c]pyrrol-2-yl]-propan-1-one N-{1-[5-(2,4-Dimethyl-ben-
zyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- 2.3 502.2
carbonyl]-2-methyl-propyl}-3-trifluoromethyl-benzamide
2-Amino-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.1
467.2 c]pyrrole-2-carbonyl]-2-methyl-propyl}-5-fluoro-benzamide
2-Amino-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.3
575.2 c]pyrrole-2-carbonyl]-2-methyl-propyl}-5-iodo-benzamide
N-{1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrolo-2-
2.5 547.2
carbonyl]-2-methyl-propyl}-3-nitro-5-trifluoromethyl-benzami- de
5-Chloro-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.2
513.2 c]pyrrole-2-carbonyl]-2-methyl-propyl}-2-nitro-benzamide
2-Amino-5-bromo-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.3 529.1
pyrrolo[3,4-c]pyrrole-2-carbonyl]-2-methyl-propyl}-benzamide
2-Amino-5-chloro-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.2 483.2
pyrrolo[3,4-c]pyrrole-2-carbonyl]-2-methyl-propyl}-benzamide
3-Bromo-4-chloro-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.4 548.1
pyrrolo[3,4-c]pyrrole-2-carbonyl]-2-methyl-propyl}-benzamide
3-Bromo-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.4
528.2 c]pyrrole-2-carbonyl]-2-methyl-propyl}-4-methyl-benzamide
3,4-Dichloro-N-{1-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-
2.3 502.4 c]pyrrole-2-carbonyl]-2-methyl-propyl}-benzamide
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[1-
2.2 500.2 (3-trifluoromethyl-benzoyl)-pyrrolidin-2-yl]-methanone
[1-(2-Amino-5-fluoro-benzoyl)-pyrrolidin-2-yl]-[5(2,4-dimethyl- 1.9
465.2 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(2-Amino-5-iodo-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl- 2.1
573.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2yl]-[1-
2.2 545.2
(3-nitro-5-trifluoromethyl-benzoyl)-pyrrolidin-2-yl]-methano- ne
[1-(5-Chloro-2-nitro-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl-
2.1 511.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(2-Amino-5-bromo-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl 2.1
527.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(2-Amino-5-chloro-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl-
2.1 481.2 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(3-Bromo-4-chloro-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl-
2.3 546.1
benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(3-Bromo-4-methyl-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl-
2.2 526.1 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
[1-(3,4-Dichloro-benzoyl)-pyrrolidin-2-yl]-[5-(2,4-dimethyl-benzyl)-
2 500.4 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.2
474.2 yl]-1-methyl-2-oxo-ethyl}-3-trifluoromethyl-benzamide
2-Amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.8
439.2 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-5-fluoro-benzamide
2-Amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.1
547.1 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-5-iodo-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2.3
519.2 yl]-1-methyl-2-oxo-ethyl}-3-nitro-5-trifluoromethyl-benzamide
5-Chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.9
485.1 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-2-nitro-benzamide
2-Amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.1 501.1
pyrrolo[3,4-c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-benzamide
2-Amino-5-chloro-N-{2-(5-(2,4-dimethyl-benzyl)-hexahydro- 2 455.1
pyrrolo[3,4-c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-benzamide
3-Bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro- 2.3 520
pyrrolo[3,4-c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-benzamide
3-Bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2.2
500.1 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-4-methyl-benzamide
3,4-Dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 2
474.4 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-benzamide
(1-{5-[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazole-4-
2.8 632.2
carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-2-meth- yl-
propyl)-carbamic acid tert-butyl ester
N-{1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-
1.66 479.28 2-carbonyl]-3-methyl-butyl}-benzamide
N-{1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-
1.63 479.28 2-carbonyl]-3-methyl-butyl}-benzamide
N-{1-[5(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.71 447.29 carbonyl]-3-methyl-butyl}-benzamide
N-{1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.67
513.24 c]pyrrole-2-carbonyl]-3-methyl-butyl}-benzamide
N-{1-Benzyl-2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.71
527.28 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{1-Benzyl-2-[5-(2,3-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.68
527.28 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{1-Benzyl-2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.8
495.29 c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{1-Benzyl-2-[5-(2-chloro-3,4-dimethoxy-benzyl)-hexahydro- 1.72
561.24 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-2-phenyl-acetamide
N-{2-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.35 437.23 yl]-1-methyl-2-oxo-ethyl}-benzamide
N-{2-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.31 437.23 yl]-1-methyl-2-oxo-ethyl}-benzamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.45 405.24 yl]-1-methyl-2-oxo-ethyl}-benzamide
N-{2-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.35
471.19 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.67
513.26 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2,3-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.65
513.26 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4- 1.72
481.27 c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-Benzyl-2-[5-(2-chloro-3,4-dimethoxy-benzyl)-hexahydro- 1.68
547.22 pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide
N-{1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-
1.53 465.26 2-carbonyl]-2-methyl-propyl}-benzamide
N-{1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole- 1.5
465.26 2-carbonyl]-2-methyl-propyl}-benzamide
N-{1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-
1.63 433.27 carbonyl]-2-methyl-propyl}-benzamide
N-{1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 1.54
499.22 c]pyrrole-2-carbonyl]-2-methyl-propyl}-benzamide
1-[5-(2,4-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.83 506.25
3-methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)-butan-1-on- e
1-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
1.81 506.25 3-methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)-butan-
-1-one
1-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2--
yl]-3- 1.92 474.26
methyl-2-(5-trifluoromethyl-pyridin-2-ylamino)-b- utan-1-one
1-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3- ,4- 1.84
540.21 c]pyrrol-2-yl]-3-methyl-2-(5-trifluoromethyl-pyridi-
n-2-ylamino)- butan-1-one N-{2-[5-(2,4-Dimethoxy-benzyl)-hex-
ahydro-pyrrolo[3,4-c]pyrrol-2- 0.98 375.22
yl]-1-methyl-2-oxo-ethyl- }-acetamide
N-{2-[5-(2,3-Dimethoxy-benzyl)-hexahydro-pyrrolo[3,4-c]- pyrrol-2-
0.93 375.22 yl]-1-methyl-2-oxo-ethyl}-acetamide
N-{2-[5-(2,4-Dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-
1.07 343.23 yl]-1-methyl-2-oxo-ethyl}-acetamide
N-{2-[5-(2-Chloro-3,4-dimethoxy-benzyl)-hexahydro-pyrrolo[3,4- 0.81
409.18 c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl}-acetamide * NA = not
available
[0206] Example 3 illustrates the preparation of bicyclic diamine
compounds of Formula I where x=0, w=2, y=1, z=1 (enantiomer: x=2,
w=0, y=1, z=1).
Example 3
Preparation of Ethyl N-(2,2-dimethoxyethyl)-carbamate (I-3a)
[0207] 27
[0208] A two-liter, three-necked round bottom flask was fitted with
a 125-mL addition funnel and a digital thermometer probe. To this
flask was added 65 g (618 mmol) of aminoacetaldehyde dimethyl
acetal, 310 mL of toluene, and a solution of 27.8 g (695 mmol) of
NaOH in 155 mL of water. This reaction mixture was cooled to
10.degree. C. via ice bath. Ethyl chloroformate (59.1 mL, 618 mmol)
was then added dropwise to the reaction mixture via addition funnel
over a 15-20 minute period making sure the reaction temperature
stayed near 10.degree. C. Once addition was complete the reaction
was stirred at room temperature for two hours. The aqueous layer
was then separated, saturated with solid sodium chloride, and
extracted with 3.times.50 mL of toluene. The toluene layers were
combined, dried over magnesium sulfate, filtered, and concentrated
in vacuo.
[0209] The .sup.1H NMR was consistent with pure product (I-3a).
[0210] Yield: 108.5 g (99%), pale yellow oil.
Preparation of Ethyl N-(2,2-dimethoxyethyl)-carbamate (I-3b)
[0211] 28
[0212] To a two-liter, three-necked round bottom flask fitted with
a 125-mL addition funnel was added 108.5 g (612 mmol) of ethyl
N-(2,2-dimethoxyethyl)-carbamate (I-3a), 585 mL of toluene, 135.6
grams of powdered KOH (crushed KOH pellets in a mortar &
pestle, added portionwise), and 2.17 g (9.5 mmol) of
triethylbenzylammonium chloride. Finally, 53.5 mL (618 mmol) of
allyl bromide was added dropwise via addition funnel over a 15
minute period to the reaction mixture at room temperature. Once
addition was complete, the reaction mixture was stirred at room
temperature overnight. The reaction mixture was then filtered to
remove salts and unreacted KOH. The filtrate was washed once with
500 mL of brine, was then dried over potassium carbonate, and
finally concentrated in vacuo.
[0213] .sup.1H NMR was consistent with product I-3b (77% pure).
[0214] Yield: 123.25 g (71% of theory, accounting for purity).
Preparation of Ethyl N-allyl-N-(2-oxoethyl)-carbamate (I-3c)
[0215] 29
[0216] To a two-liter round bottom flask was added 123 g (566 mmol,
77% pure) of ethyl N-(2,2-dimethoxyethyl)-carbamate (I-3b) and 270
mL of formic acid. The reaction mixture was refluxed for one hour.
The reaction mixture was then poured over 1.5 liters of crushed
ice, and extracted with (5.times.300 mL) dichloromethane. The
organic extracts were combined, washed with (2.times.500 mL)
saturated sodium bicarbonate solution, dried over magnesium
sulfate, filtered, and concentrated in vacuo. .sup.1H NMR was
consistent with product (I-3c) and was carried on as the crude
material. Mass spectrometry was consistent with product (I-3c).
(MH.sup.+) 172, FW=171.20.
[0217] Yield: 87.1 grams (89%).
Preparation of N-Benzylglycine (I-3d)
[0218] 30
[0219] N-benzylglycine ethyl ester (97.0 g, 503 mmol) was refluxed
in 260 mL of water (with 480 mg of KOH, 0.5 wt %) overnight. The
reaction mixture was filtered. The filtercake was washed with
chloroform and dried under vacuum. The filtrate was extracted with
tert-butyl methyl ether. The aqueous phase from this extraction was
separated, adjusted to pH 2 with 6M HCl, and then concentrated in
vacuo. The residue was filtered and this filtercake was washed with
chloroform and dried under vacuum. The two filtercakes were
combined.
[0220] .sup.1H NMR spectrum was consistent with product. Mass
spectrometry was consistent with product (I-3d). (MH.sup.+) 275,
FW=274.32.
[0221] Yield: 78.8 grams (95%).
Preparation of Ethyl
2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate (I-3e)
[0222] 31
[0223] To a two-liter round bottom flask was added 81.5 g (476
mmol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate (I-3c), 78.6 g (476
mmol) of N-benzylglycine (I-3d), and 1.2 liters of toluene. The
reaction mixture was refluxed for 24 hours. The reaction mixture
was then decanted to remove sludge residue which formed on the
bottom of the flask. The decanted solution was concentrated in
vacuo to a brown syrup.
[0224] .sup.1H NMR was consistent with crude product. Mass
spectrometry was consistent with product (I-3e). (MH.sup.+) 166,
FW=165.19.
[0225] Yield: 75.04 grams (58%).
Preparation of 2-Benzyl-2,7-diazabicyclo[3.3.0]octane (I-3f)
[0226] 32
[0227] To a one-liter flask fitted with a condenser was added 37.5
g (137 mmol) ethyl
2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate (I-3e) and 225
mL of concentrated hydrochloric acid. The reaction mixture was
refluxed overnight under a positive pressure of nitrogen. The
exhaust gases were bubbled through a solution of saturated sodium
bicarbonate in order to neutralize any HCl fumes present in the
exhaust. The reaction mixture was then adjusted to pH 9 with solid
potassium carbonate and extracted with 3.times.180 mL chloroform.
The organic extracts were combined, dried over potassium carbonate,
filtered, and concentrated in vacuo to a black oil.
[0228] .sup.1H NMR was consistent with product I-3f (75% pure).
Mass spectrometry was consistent with product (I-3f). (MH.sup.+)
203, FW=202.30.
[0229] Yield: 22.7 grams (61% of theory, accounting for purity)
Preparation of
7-Benzyl-hexahydro-pyrrolo[3,4,b]pyrrole-5-carboxylic acid t-butyl
ester (I-3a)
[0230] 33
[0231] A 250 mL, three-necked flask was fitted with a 125 mL
addition funnel and a digital thermometer. To this flask was added
15.18 g (75 mmol) of 2-benzyl-2,7-diazabicyclo[3.3.0]octane (I-3f),
50 mL of water, and 31.2 mL (225 mmol) of triethylamine. This
mixture was cooled to 0.degree. C. via an ice bath, and 90 mL (90
mmol) of di-tert-butyl dicarbonate (1.0 M in tetrahydrofuran) was
added dropwise over a 15 minute period while keeping the reaction
temperature below 5.degree. C. The reaction mixture was stirred at
0.degree. C. for 2 hours. The reaction mixture was then
concentrated in vacuo to remove the tetrahydrofuran. The residue
was poured into 250 mL of saturated sodium bicarbonate and was
extracted with 3.times.200 mL chloroform. The organic layers were
combined, dried over sodium sulfate, filtered, and concentrated in
vacuo to give a black oil (crude weight=24 grams). Product was
purified by flash column chromatography (silica gel packed Biotage
flash 75 m),using a 0.5 to 2% methanol/chloroform solvent gradient.
Purification yielded a light brown oil.
[0232] .sup.1H NMR was consistent with product (I-3g). Mass
spectrometry was consistent with product (I-3g). MH.sup.+ is 303,
FW=302.42.
[0233] Yield: 16.2 grams (71% of theory).
Preparation of Hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid
t-butyl ester (I-3h)
[0234] 34
[0235] To a 2.5 liter Parr shaker bottle, flushed with nitrogen,
was added 4.05 grams (25 wt %) of palladium on activated carbon
catalyst (10% Pd). Next was added 100 mL of ethanol, followed by a
solution of 1-benzyl-hexahydro-pyrrolo[3,4,b]pyrrole-5-carboxylic
acid tert-butyl ester I-3g (16.2 grams, 53.6 mmol) in 600 mL of
ethanol. The reaction mixture was shaken under an atmosphere of
hydrogen (45 psi or 0.3 MPa) for one day at room temp. Mass
spectroscopy showed the reaction was incomplete so another 0.25
equivalent (4.05 grams) of palladium on carbon catalyst was added.
The reaction mixture was then shaken under an atmosphere of
hydrogen at room temperature for 3 days. Mass spectroscopy showed
that the reaction was complete. The reaction mixture was then
filtered through diatomaceous earth and the filtrate was
concentrated in vacuo.
[0236] .sup.1H NMR was consistent with product (I-3h). Mass
spectrometry was consistent with product (I-3h). MH.sup.+ is 213,
FW=212.29. Yield: 11.25 grams
Preparation of
1-[(3-Trifluoromethyl-benzoylamino)-acetyl]-hexahydro-pyrro-
le-5-carboxylic acid tert-butyl ester (I-3i)
[0237] 35
[0238] Intermediate I-3h (72.7 mg, 0.342 mmoles) was dissolved in 5
mL anhydrous dichloromethane and 84.6 mg (0.342 mmoles) of
{3-trifluoromethylbenzoylamino}-acetic acid was added. To this
mixture at room temperature was then added 78.7 mg
1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (0.41
mmoles). This mixture was stirred at room temperature for 16 hours.
The dichloromethane was evaporated and the residue was dissolved in
5 mL EtOAc in a separatory tunnel. This was then washed with
1.times.2 mL of 0.1 N NaOH, 1.times.2 mL 0.1N HCl and 1.times.2 mL
brine. The ethyl acetate layer was dried over sodium sulfate,
filtered and concentrated in vacuo to a hard pale yellow foam (120
mg, 0.272 mmoles, 79% yield.
[0239] H.sup.1 NMR(CD.sub.3OD) and MS (441) were consistent with
product (I-3i).
Preparation of
N-[2-(Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-2-oxo-ethyl]-3-t-
rifluoromethy-benzamide (I-3j)
[0240] 36
[0241] Intermediate I-3i (120 mg, 0.272 mmoles) was dissolved in 1
mL dichloromethane and this was cooled in a wet-ice acetone bath
and 0.5 mL of trifluoroacetic acid was added. This mixture was then
stirred at room temperature for 20 minutes. The reaction mixture
was then concentrated by evaporation and the residue was dissolved
in 2 mL 2N HCl and this was washed with 2.times.1 mL ETOAc. The
aqueous layer was made basic (pH=10) by adding 6N NaOH with ice
bath cooling and the product was extracted into 2.times.2 mL ETOAc.
The ETOAc layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to a clear pale yellow gum (90 mg, 0.263
mmoles, 97% yield).
[0242] H.sup.1 NMR (CD.sub.3OD) and MS (341) were consistent with
compound I-3i.
Preparation of
N-{2-[5-(2,4-Dimethylbenzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-
-1-yl-2-oxo-ethyl}-3-trifluoromethyl-benzamide (3)
[0243] 37
[0244] Intermediate !-3i (90 mg, 0.264 mmoles) was dissolved in
1.35 mL MeOH and then 106 mg (0.396 mmoles, 1.5 equivalents) of
2,4-dimethylbenzaldehyde was added and this mixture was stirred at
room temperature for 16 hours. Then, 30 mg (0.792 mmoles, 3
equivalents) of sodium borohydride was added. This mixture: was
stirred at room temperature for 2 hours. The MeOH was evaporated
and the residue was partitioned between 3 mL EtOAc and 1 mL 1N NaOH
in a separatory funnel. The organic layer was separated and the
aqueous layer was washed with 2.times.2 mL EtOAc. The EtOAc layers
were combined, dried over sodium sulfate and concentrated in vacuo
to a pale yellow gum. This gum was dissolved in 0.5 mL
dichloromethane and charged onto a Biotage 12S cartridge and the
column was eluted with the following gradient. 60 mL 5:1
EtOAc:hexanes, 60 mL 9:1 EtOAc:hexanes and finally 120 mL EtOAc.
The fractions containing the desired product were combined and
concentrated in vacuo to a hard white foam (70 mg, 0.152 mmoles,
58% yield).
[0245] H.sup.1 NMR (CD.sub.3OD) and MS (460) were consistent with
the desired product (3). The enantiomers were separated using a
Chiralpak.TM.AD column (5 cm.times.50 cm), 75 mL/min flow rate and
an 85/15 ratio of heptanes/isopropyl alcohol. Enantiomer 3A had a
retention time of 7.061 min. and enantiomer 3B at 8.567 min.
[0246] Example 4 illustrates the preparation of bicyclic diamine
compounds of Formula I where w=1, x=1, y=1, z=0 (enantiomer: w=1,
x=1, y=0, z=1) and the linking group (L) is an amino acid.
Example 4
Preparation of 3-(Benzyl-ethoxycarbonylmethylamino) prolionic acid
ethyl ester (I-4a)
[0247] 38
[0248] Ethyl N-benzylglycinate (0.1295 mol, 1 eq), ethyl acrylate
(0.142 mol, 1.1 eq) and 155 .mu.L of Triton.TM. B (available from
Sigma-Aldrich, St. Louis, Mo.) were combined at room temperature
under N.sub.2. The mixture was then heated to reflux overnight. An
aliquot was removed and NMR spectrum was taken of the crude
material. The product was present plus both starting materials. The
excess of the ethyl acrylate was removed under vacuum at 10 mmHg
(60.degree. C. water bath). The crude amber oil that resulted was
dissolved in 50 mL of CH.sub.2Cl.sub.2 and was charge onto a
Biotage.TM. 75 L cartridge and eluted with the following gradient
0.5% by volume acetone in hexanes, 1% (1200 mL), 1.5% (1200 mL) and
2.5% (3600 mL). The fractions containing the desired product were
combined and concentrated to a colorless oil which was dried under
high vacuum for 2 hours to afford 29 g (76%) of product (I-4a).
.sup.1H NMR spectrum (CDCl.sub.3) and LC/MS (294) were consistent
with the compound I-4a.
Preparation of 1-Benzyl-4-oxo-pyrrolidine-3-carboxylic acid ethyl
ester (I-4b)
[0249] 39
[0250] Potassium t-butoxide (0.099 mol, 11.1 g, 1 eq) was slurried
in 100 mL of anhydrous toluene under N.sub.2. The slurry was cooled
to 5.degree. C. and intermediate I-4a (0.099 mol, 29 g, 1 eq) in 50
mL of anhydrous toluene was added dropwise over a 2 hour period
maintaining the temperature below 10.degree. C. The reaction
mixture was allowed to warm to room temperature over a period of 3
hours. The mixture was cooled to 0.degree. C. and 100 mL of water
was added in 5 mL portions over a period of 2 hours. The solution
was placed in a separation funnel and 100 mL of 1 N NaOH was added.
The organic layer was separated and washed with 4.times.100 mL of
water. The aqueous layers were combined and extracted with 100 mL
of EtOAc. During this first extraction a white solid began to
precipitate out of the organic layer. This solid was filtered and
dried under high vacuum overnight affording 7.96 g (32%).
[0251] .sup.1H NMR spectrum on 5 mg of the residue and LC/MS (248)
were consistent with the structure for compound I-4b.
Preparation of 1-Benzyl-4-hydroxymethyl-pyrrolidin-3-ol (I-4c)
[0252] 40
[0253] Intermediate I-4b (0.0162 mol, 4.0 g, 1 eq) was dissolved in
60 mL of MeOH and the cooled to 0.degree. C. NaBH.sub.4 (0.0971,
3.67 g, 6 eq) was added in 250 mg portions over an hour period. The
mixture was warmed to room temperature and allowed to stir
overnight. The MeOH was removed in vacuo and the residue was taken
up in EtOAc (60 mL) and 2N NaOH (20 mL). The mixture was shaken for
approximately 2 to 3 minutes in a separation funnel. The organic
phase was separated and the aqueous phase was washed with
2.times.50 mL more EtOAc. The organic layers were combined, dried
over sodium sulfate and concentrated in vacuo to a pale yellow oil
which was placed under high vacuum for 2 hours to afford a clear
pale yellow gum 2.06 g (65%).
[0254] .sup.1H NMR spectrum (CD.sub.3OD) and LC/MS (208) was
consistent with the desired product (I-4c).
Preparation of methanesulfonic acid
1-benzyl-4-methanesulfonylmethyl-pyrro- lidine-3-yl ester-trans
isomer (I-4d)
[0255] 41
[0256] Intermediate I-4c (0.00995 mol, 2.06 g, 1 eq) was dissolved
in 30 mL of CH.sub.2Cl.sub.2 and TEA (0.0248 mol, 3.45 mL, 2.5 eq)
was added. This solution was cooled to 0.degree. C. and methane
sulfonyl chloride was added dropwise over a 30 minute period. The
mixture was allowed to warm to room temperature and was stirred
vigorously for 2 hours. The reaction mixture was then concentrated
to dryness, taken up in 100 mL of EtOAc and washed with 2.times.25
mL of 1 N NaOH and 25 mL of brine. The organic layer was dried over
sodium sulfate and concentrated in vacuo to a dark brown gum. The
crude product was dissolved in 7 mL of CH.sub.2Cl.sub.2 and this
was charge onto a Biotage 40 M cartridge and eluted with the
following gradient: 2.5% by volume EtOAc in CH.sub.2Cl.sub.2 (200
mL), 5% (200 mL), 7.5% (200 mL), 10% (200 mL) 15% (200 mL), 20%
(200 mL), 25% (200 mL), 33% (400 mL). Fractions were collected in
succession and fractions containing the trans isomer (confirmed by
TLC and NMR spectroscopy) were combined and concentrated in vacuo
to a clear very pale brown gum. The gum was dried overnight under
high vacuum.
[0257] .sup.1H NMR spectrum (CD.sub.3OD) confirmed thepresence of
the desired product (I-4d): Yield; 1.98 g (55%).
Preparation of methane sulfonic acid
4-azidomethyl-1-benzyl-pyrrolidine-3-- yl ester (I-4e)
[0258] 42
[0259] Intermediate I-4d (0.00545 moles, 1.98 g) and 30 mL of DMF
were combined. Then sodium azide (0.00545 moles, 354 mg) was added
in 25 mg portions over a 1 hour period. The mixture was stirred at
room temperature for 82 hours. TLC (hexanes-acetones, 2:1, two
passes) indicated complete conversion to the less polar product.
The reaction mixture was placed in a separation funnel, diluted
with 900 mL EtOAc and this solution was washed with 9.times.50 mL
H.sub.2O. The organic layer was dried over anhydrous sodium sulfate
and concentrated in vacuo to a clear pale yellow gum. This was
dried under high vacuum overnight affording 1.67 g (98%). The
.sup.1H NMR spectrum and LC/MS (311) were consistent with the
structure for compound I-4e.
Preparation of Methane sulfonic
acid-4-aminomethyl-1-benzyl-pyrrolidine-3-- yl ester (I-4f)
[0260] 43
[0261] In a Parr bottle were mixed intermediate I-4e (0.00506 mol,
1.5 g), PtO.sub.2 (157 mg) and MeOH (23.5 mL) and agitated at 2 psi
(0.01 MPa) H.sub.2 for 30 minutes. Thin layer chromatography
(CH.sub.2Cl.sub.2-EtOAc 2:1 with 3% diethylamine) indicated less
polar impurity, nostarting material and a single more polar spot at
Rf 0.1. The reaction mixture was filtered through Celite.TM. and
the, pad was washed with 6.times.30 mL of MeOH. The filtrate was
concentrated in vacuo to a clear pale yellow gum that contains more
polar impurity by thin layer chromatography (TLC) and LC/MS. The
crude product was dissolved in 7 mL of THF and charged onto a
Biotage.TM. 40M cartridge and eluted with the following solvent
gradient: CH.sub.2Cl.sub.2-EtOAc 2:1 (600 mL), with 5% diethylamine
(200 mL), CH.sub.2Cl.sub.2-EtOAc 1:1 with 5% diethylamine (200 mL),
2:1 EtOAc-CH.sub.2Cl.sub.2 with 5% diethylamine (200 mL),
EtOAc-MeOH 3:1 with 5% diethylamine (200 mL), EtOAc-MeOH 2:1 with
5% diethylamine (600 mL). The fractions containing the desired
product were combined and concentrated in vacuo to a clear
colorless gum, which was dried under high vacuum overnight
affording 860 mg (60%) of compound I-4f.
[0262] .sup.1H NMR and LC/MS (284) were consistent with the
structure for compound I-4f.
Preparation of 3-benzyl-3,6-diazabicyclo[3.2.0]heotane (I-4g)
[0263] 44
[0264] Intermediate I-4f (350 mg) was refluxed in 1,4-dioxane for 2
hrs. MS (188) and .sup.1H NMR (CD.sub.3OD) indicated product
present plus side product impurities. Due to the extreme polarity
of the product, the crude material was taken on as is.
Approximately 35 mg (10% yield).
Preparation of
N-[2-(3-benzyl-3,6-diazabicyclo[3.2.0]hept-6-yl)-2-oxo-ethy-
l]-3-trifluoromethyl-benzamide (4A)
[0265] 45
[0266] 35 mg (0.186 mmoles) of intermediate I-4g was dissolved in
0.53 mL of CH.sub.2Cl.sub.2 in a 1 dram micro reaction vial fitted
with a magnetic stir bar. To this solution was then added 46 mg
(0.186 mmoles) of (3-trifluoromethylbenzoyl-amino)-acetic acid and
then 43 mg (0.223 mmoles, 1.2 equivalents) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The
mixture was stirred at room temperature for 16 hours. The
dichloromethane was removed in vacuo and the residue was taken up
into 4 mL ethyl acetate and washed with 0.5 mL 0.1N NaOH and 0.5 mL
brine. The organic layer was dried over anhydrous sodium sulfate
and then concentrated in vacuo to a clear pale yellow gum. The gum
was dissolved in 0.5 mL dichloromethane and charged onto a
Biotage.TM. 12S cartridge. The column was eluted with ethyl
acetate:hexanes 9:1 (50 mL), ethyl acetate:hexanes 5:1 (50 mL) and
ethyl acetate 200 mL. The fractions containing the desired product
were combined and concentrated in vacuo to a clear colorless gum
(25 mg, 33% yield).
[0267] .sup.1H NMR spectrum (CD.sub.3OD) and LC/MS (417) were
consistent with the structure for compound 4A.
[0268] Compound 4A can be further modified to produce other
compounds of Formula (I) using the following general
procedures.
Preparation of
N-[2-(3,6-diazabicyclo[3.2.0]hept-6-yl)-2-oxo-ethyl]-3-trif-
luoromethyl-benzamide (I-4h)
[0269] 46
[0270] Compound 4A (25 mg) was dissolved in 0.5 mL methanol in a
125 mL Parr bottle. Then 2 mL of 0.1 N aqueous hydrochloric acid, 1
drop of 6N aqueous hydrochloric acid and 5 mg of 10% Pd/C (50%
water wet) were added. This mixture was agitated under 3 psi (0.02
MPa) H.sub.2 for 14 hours. The reaction mixture was filtered
through Celite.TM. and the pad was washed with 3.times.10 mL
portions of methanol. The filtrate was concentrated in vacuo to
dryness and the residue was taken up into 5 mL 1N hydrochloric acid
and was washed with 2.times.3mL ethyl acetate. The aqueous layer
was made basic (pH=10) and washed with 3.times.5 mL ethyl acetate.,
The organic layers were dried over anhydrous sodium sulfate and
concentrated in vacuo to a colorless gum (9 mg, 50% yield).
[0271] .sup.1H NMR spectrum (CD.sub.3OD) and MS (327) were
consistent with compound I-4h.
Preparation of
N{2[3-2,4-dimethyl-benzyl)-3,6-diazabicyclo[3.2.0]hept-6-yl-
)-2-oxo-ethyl}-3-trifluoromethyl-benzamide (4B)
[0272] 47
[0273] Intermediate I-4h (9 mg, 0.0275 mmoles) was dissolved in
0.25 mL of methanol and then 5.5 mg (0.041 mmoles, 1.5 equivalents)
of 2,4-dimethylbenzaldehyde was added at room temperature under a
nitrogen atmosphere. This mixture was stirred for 16 hours. Then 3
mg of sodium borohydride was added and the mixture was stirred at
room temperature for 1.5 hours. The methanol was evaporated and the
residue was partitioned between 3 mL ethyl acetate and 0.75 mL 1N
NaOH. The layers were separated and the aqueous was washed with
3.times.2 mL ethyl acetate. The organic layers were combined, dried
over anhydrous sodium sulfate and concentrated in vacuo to a clear
pale yellow gum (10 mg). The crude product was separated using a
Biotage.TM. 12S cartridge with the following solvent gradient
EtOAc:hexanes (5:1, 40 mL), EtOAc:hexanes 9:1(40 mL) and EtOAc 100
mL. The product was isolated in the latter fractions (2.1 mg,
0.00472 mmoles, 17% yield).
[0274] .sup.1H NMR spectrum (CD.sub.3OD) and MS (445) were
consistent with the structure for compound 4B.
Biological Assays
[0275] The utility of the compounds of Formula (I), the
stereoisomers and prodrugs thereof, and the pharmaceutically
acceptable salts of the compounds, stereoisomers, and prodrugs in
the practice of the instant invention, can be evidenced by activity
in at least one of the protocols described hereinbelow.
Chemotaxis Activity
[0276] Chemotaxis activity of the compounds of the present
invention can be determined by the amount of monocytes that migrate
in response to the chemoattractant MCP-1 relative to control, in
THP-1 cells. THP-1 monocytes are rinsed 2 times with PBS and then
suspended at a concentration of 1.0.times.10.sup.6 cells/mL in
chemotaxis buffer consisting of RPMI 1640 medium supplemented with
0.1% BSA. Three microliters of MCP-1 (available from Peprotech,
Inc. Rocky Hill, N.J.) is added to the lower chamber of a 48-well
microchemotaxis Boyden chamber at a concentration of 10 nM in
chemotaxis buffer (RPMI Medium available from Gibco, Rockville,
Md., 0.10% BSA (Bovine Serum Albumin available from Sigma, St.
Louis, Mo.), endotaxin free). Three microliters of the compound
diluted in chemotaxis buffer are then added to appropriate wells at
concentrations of 10, 1, 0.1 and 0.01 .mu.M. Chemotaxis buffer (23
.mu.L) is added to the wells for a final volume of 29 .mu.L/well.
The cell suspension (45 .mu.L) is added to the upper chamber, which
is separated from the lower chamber by a 5-.mu.m-pore-size
polycarbonate membrane (Poretics.TM. available from Osmonics, Inc.
Livermore, Calif.). After incubation for 1 hour at 37.degree. C. in
a 5% CO.sub.2 atmosphere, the side of the polycarbonate membrane in
contact with the cell suspension is scraped and washed to remove
any cells. 5 After fixation, the migrated cells adhering to the
underside of the membrane facing the chemoattractant are stained
with thiazine, dye mixture (Diff-Quik Stain Set available from Dade
Behring, Inc. Newark, Del.). The number of cells that migrate
through the filter is determined by counting the cells in 20.times.
fields under a microscope. Chemotaxis induced by MCP-1 without
compound is considered the positive control.
[0277] The effect of these compounds to inhibit integrin expression
is determined using whole human blood. Human peripheral blood is
collected by venipuncture into EDTA Vacutainer tubes. NUNC Minisorp
tubes (12.times.75 mm) (available from Nalge Nunc Internantional
Naperville, Ill.) containing 400 .mu.L blood and 40 .mu.L of PBS
(Dulbecco's phopshate buffered saline available from Gibco,
Rockville, Md.) supplemented with 0.2% BSA, pH 7.4 or compound
diluted in PBS/BSA at concentrations of 10, 1, 0.1 and 0.01 .mu.M
are placed in a 37.degree. C. water bath for 5 minutes. MCP-1 (20
.mu.L) is added to a second set of NUNC Minisorp tubes (12.times.75
mm) at a final concentration of 10.sup.-9M and placed in a
37.degree. C. water bath. The blood is gently mixed and 200 .mu.L
added to the second set of tubes containing MCP-1. After incubation
for 15 minutes at 37.degree. C. the tubes are removed from the
water bath and placed in an ice water bath. The cells are washed
with PBS supplemented with 2% FBS and 0.2% sodium azide, then
centrifuged at 1000.times.g for 10 minutes at 4.degree. C. The
supernatant is aspirated, and cells resuspended by gently shaking
tubes, followed by the addition of 10 .mu.L heat aggregated (HA)
IgG (1 mg HA IgG/mL PBS-wash) (available from Jackson
ImmunoResearch Lab, West Grove, Pa.) to each tube. After incubating
the tubes for 10 minutes at 4.degree. C., 20 .mu.L mouse IgG1 FITC
is added to appropriate tubes (Isotype Controls); 20 .mu.L CD11b
FITC antibody (available from CALTAG Lab, Burlingame, Calif.) is
added to appropriate tubes (Compound effect) and 20 .mu.L
Anti-CD14-PE (available from PharMingen, San Diego, Calif.) is
added to all tubes. After mixing gently by shaking, the samples are
shielded from direct light and samples incubated for 30 minutes at
4.degree. C. Samples are then washed 1.times. with PBS, supernatant
aspirated and 1.5 mL of FACS Brand Lysing solution (available from
Becton Dickinson Immunocytometry Systems, San Jose, Calif.) added
to all tubes. After an incubation at room temperature for 10
minutes (vortex every 5 minutes for complete RBC lysis), cells are
centrifuged, supernatant aspirated and washed 2.times. with PBS
wash buffer. Cells are then resuspended in 0.5 mL of 0.5%
Paraformaldehyde and vortexed immediately. Samples can then be
stored at 4.degree. C. up to one week before quantitation of
fluorescent staining of CD11b by flow cytometry.
In Vivo Atherosclerosis Assay
[0278] Anti-atherosclerotic effects of the compounds can be
determined by the amount of compound required to reduce the lipid
deposition in rabbit aorta. Male New Zealand White rabbits are fed
a diet containing 0.2% cholesterol and 10% coconut oil for 4 days
(meal-fed once per day). Rabbits are bled from the marginal ear
vein and total plasma cholesterol values are determined from these
samples. The rabbits are then assigned to treatment groups so that
each group has a similar mean .+-.SD for total plasma cholesterol
concentration, HDL cholesterol concentration and triglyceride
concentration. After group assignment, rabbits are dosed daily with
compound given as a dietary admix or on a small piece of gelatin
based confection. Control rabbits receive only the dosing vehicle,
be it the food or the gelatin confection. The cholestero/coconut
oil diet is continued along with the compound administration
throughout the study. Plasma cholesterol, HDL-cholesterol, LDL
cholesterol and triglyceride values can be determined at any point
during the study by obtaining blood from the marginal ear vein.
After 3-5 months, the rabbits are sacrificed and the aortae are
removed from the thoracic arch to the branch of the iliac arteries.
The aortae are cleaned of adventitia, opened longitudinally and
then stained with Sudan IV as described by Holman et. al. (Lab.
Invest, 7, 42-47 (1958)). The percent of the surface area stained
is quantitated by densitometry using an Optimas Image Analyzing
System (Image Processing Solutions; North Reading Mass.). Reduced
lipid deposition is indicated by a reduction in the percent surface
area stained in the compound-receiving group in comparison with the
control rabbits.
Inhibtion of Eotaxin Binding to its Receptor
[0279] The inhibition of eotaxin binding to, its receptor is done
in whole cells containing buffer medium: RPMI 1640 with
L-glutamine, 10 mM HEPES, 1% penicillin/streptomycin, 0.5% FBS
(available from GI.BCO, Rockville, Ms.) in 96 well polypropylene
U-bottom plates (available from Falcon, Franklin Lakes, N.J.) in a
volume of 95 .mu.L buffer/well. Log dilutions of compounds were
made in DMSO, and 5 .mu.L added per well in triplicate. Controls
were 5 .mu.L DMSO or 5 .mu.L 10 .mu.M recombinant human eotaxin
(R&D Systems, Minneapolis, Minn.). .sup.I125-Bolton-Hunter
labeled eotaxin (100 .mu.Ci/mL, available from PerkinElmer, Boston,
Mass.) diluted to 1 .mu.Ci/mL then 50 .mu.L/well was added at a
final concentration of 10-100 pM [.sup.I125] eotaxin. Finally 100
.mu.L of CCR3-expressed 300-19 cells were added. There murine
pre-B-cells, stably expressing human CCR3, were passed daily in
culture medium: Hybridoma-SFM (serum free medium), 10% FBS, 2 mM
L-glutamine, 1% penicillin/streptomycin, 0.4 mg/mL geneticin, 10 mM
HEPES buffer solution, and 55 .mu.M 2-mercaptoethanol (GIBCO).
Cells were pelleted just before the assay then resuspended to 5e+6
cells/mL in binding buffer and 100 .mu.L were added to each well.
Final assay volume was 250 .mu.L. Assay plates were incubated at
room temperature for 2 hours. Cells were then harvested onto
96-well GF/B Unifilter plates (Unifilter-96 Harvester, Packard
Instrument Co., Meriden, Conn.) pre-soaked for 2 hours at RT in
0.3% polyethyleneimine and washed 4 times with 500 mM NaCl with 10
mM HEPES. The Unifilter plates were air-dried overnight at room
temperature, followed by addition of scintillation cocktail
microscinto (available from Packard Instrument Co.), then counted
on a Top Count (available from Packard Instrument Co.).
[0280] In general, the compounds listed in the Examples provided
CCR2 activity based on chemotaxis from about 5 to about 100%
inhibition at 1 .mu.M concentration. The compounds having the
general Formula (1B) below provided higher activity for inhibition
of binding to its CCR2 receptor and showed less activity for
inhibition of binding to the CCR3 receptor. Whereas, compounds
having the general Formula (1C) provided higher activity for
inhibition of binding to the CCR3 receptor and less activity for
binding to the CCR2 receptor. 48
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