Piperazine derivatives with ccr1 receptor antagonist activity

Observations

A diskette is also attached with this application and a CD with the memories in Spanish

SIGNATURE OF THE APPLICANT

SIGNATURE OF ATTORNEY

Dr. Alejandro Ponce Martinez

Dr. Alejandro Ponce Martínez Mat. 960 CAP

APM/mbp

CASE PC11806ACSL PCT/IB02/03989

TECHNICAL MEMORY

NEW PIPERAZINE DERIVATIVES

This application claims the priority benefit of Provisional Patent Application Serial Number 60/338,601 filed October 22, 2001, which is incorporated herein in its entirety for all purposes.

Background of the invention

The present invention relates to new piperazine derivatives, methods of use and pharmaceutical compositions containing them.

The compounds of the invention are potent and selective inhibitors of MIP-1a (CCL3) that bind to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is also sometimes called the CC-CKR1 receptor. These compounds also inhibit chemotaxis induced by MIP-1a (and related chemokines shown to interact with CCR1 (eg, RANTES (CCL5), MCP-2 (CCL8), MCP-3 (CCL7), HCC-1 (CCL 4 ) and HCC-2 (CCL 5))) from THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (new onset), lupus, intestinal inflammation, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, Adult Respiratory Distress Syndrome, Childhood Respiratory Distress Syndrome, ischemia, reperfusion injury, and glomerulonephritis), allergic conditions ( such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation, including influenza and hepatitis) and Guillian-Barre Syndrome), chronic bronchitis, xenotransplantation, tissue transplant rejection (chronic and acute), organ rejection (chronic and acute), atherosclerosis, restenosis (including, but not limited to, restenosis following balloon and/or insertion stents), infection by HIV (use of a co-receptor), and granulomatous diseases (including sarcoidosis, leprosy, and tuberculosis) and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also have utility for the prevention of cancer metastasis. Compounds in this series may also limit cytokine production at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreased cellular infiltration, providing benefit for TNF and IL-1-related diseases, including congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV3; cytomegalovirus (CMV), adenovirus, Herpes virus (Herpes zoster and Herpes simplex). They may also provide benefit for infection-associated sequelae where such infection induces the production of detrimental inflammatory cytokines such as TNF eg, fungal meningitis, junctional injury, hyperplasia, synovial pannus formation and bone resorption, psoriatic arthropathy, insufficiency liver disease, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, Lyme disease, septic shock, cancer, trauma, and malaria, etc

MIP-la and RANTES are soluble chemotactic peptides (chemokines) that are produced by a variety of cell types, including inflammatory cells, such as CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs), and macrophages, J.Biol. Chem., 270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of patients with rheumatoid arthritis, chronic tissue rejection by transplant patients, and in the nasal secretions of patients with allergic rhinitis following allergic exposure (Teran, et. al. Immunol., 1806-1812 (1996), and Kuna et.a/._J. Allerqy Clin. Immunol. 321(1994)). Antibodies that interfere with the chemokine/receptor interaction by neutralizing MIP-1a or RANTES have provided indirect evidence for the role of CCR1 in cell infiltration and disease. (Smith et.al. J Immunol. 153 4704 (1994) and Cook et.al, Science, 269, 1583 (1995), Belperio et.al. J. Immunol.

165, 461(2000). A more direct role for CCR1 has been demonstrated in transgenic mice lacking this receptor that have shown decreased inflammation responses, prolonged survival of allogeneic tissue transplants (Gao et.al. J. Clin. Invest. 105;35 (2000 )), and diminished disease in a multiple sclerosis model (Rottman et.al. Eur. J. Imm. 30; 2372 (2000). Taken together, these data demonstrate that CCR1 receptor antagonists would be an effective treatment of several immune diseases. The compounds described herein are potent and selective CCR1 receptor antagonists.

Various piperazine derivatives have recently been described as anti-inflammatory agents in US Patent No. 6,207,665, which is incorporated herein in its entirety for all purposes. These agents are also described as inhibitors of the activity of the chemokines, MIP-Ια and RANTES.

Summary of the Invention

In one aspect, the present invention relates to compounds of formula I

AND/

Y(R)⁵)^

<img file="ECSP045073A_D0001.tif" />

and pharmaceutically acceptable forms thereof; wherein a is 0,1,2, 3, 4, or 5;

b is 0,1, or 2;

ces 0, 1, or 2;

d is 0, 1,2, 3, or 4;

X is -O-, -S-, -CH₂-, or -NR⁶-;

Y is aryl (C₆-C₁₀) or heteroaryl (C₂-Cg)¡ each R¹ is independently H-, HO-, halo-, alkyl(Ci-C₈)-, alkyl (CrC₈)-O-, HO-alkyl(CrCs)-, NC-, H₂N-,H₂N-alkyl(Ci-C₈)-, HO-(C=O)-, alkyl (CrC₈)-(C=O)-, alkyl (Ci-C₈)-(C=O)alkyl (CrCs)-, H₂N-(C=O)-, or H₂N-(C=O)-alkyl (Ci-C₈)-, each R² and R³ are independently H-, oxo, alkyl (CrC₈)-, cycloalkyl (C₃-C₈)-alkyl(C_rC.₈)-, aryl(C₆-Cio)-, aryl(C₆-C₁₀)-alkyl (Ci-C₈)-, HO-alkyl (C_rC.₈)-, alkyl (C_rC.₈)-O-alkyl (CrCs)-, H₂N-alkyl(CrCs)-, alkyl(CrC₈)-NH-alkyl(CrC₈)-, [alkyl (C-|-C₈)]₂N-alkyl(C_rC.₈)-, heterocyclyl (C₂-C₉)-alkyl (Ci-C₈)-, cycloalkyl (C₃-C₈)-NH-alkyl(CrC₈)-, alkyl (Ci-C₈)-(C=O)-NH-alkyl (C_rC.₈)-, alkyl (Ci-C₈)-O-(C=O)-NH-alkyl (CrC₈)-, H₂N-(C=O)-NH-alkyl(CrCs)-, alkyl(CrC₈)-SW₂NH alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-alkyl(CrC₈)-, H₂N-(C=O)-, or H₂N-(C=O)-alkyl (CrC₈)-¡

R.⁴ is [HO-(C=O)-][H₂N-]-alkyl(CrC₈)-, [HO-(C=O)-][alkyl (C_rC.₈)NH-]alkyl(C_rC.₈)-, [HO-(C=O)-][(alkyl (Ci-C₈))₂N-]-alkyl(CrC₈)-, HO-(C=O)-alkyl (CrC₈)-NH-, HO-(C=O)-alkyl(CrCs)-NH-alkyl(C_rC.₈)-, [HO-(C=O)-alkyl (Ci-C₈)][alkyl(CrC₈)]N-,[HO-(C=O)-alkyl(C_rC.₈)][alkyl(Ci-C₈)]N-alkyl(C_rC.₈)-, [HO-(C=O)-alkyl (Ci-C₈)][alkyl(Ci-C₈)-SW₂]N-,[HO-(C=O)alkyl (Ci-C₈)][alkyl(CyC₈)-SW₂]N-alkyl(CrC₈)-,[HO-(C=O)-alkyl (Ci-C₈)][alkyl(Ci-C₈)-(C=O)]N-, [HO-(C=O)-alkyl (Ci-C₈)][alkyl(Ci-C₈)-(C=O)-]N-alkyl(CrC₈)-, [HO-(C=O)-alkyl (Ci-C₈)][ alkyl(CrC₈)-O-(C=O)-]N-, [HO-(C=O)-alkyl (Ci-C₈)][alkyl(Ci-C₈)-O-(C=O)-]N-alkyl(CrC₈)-, [HO-(C=O)-alkyl (CrC₈)][alkyl(CrC₈)N-(C=O)-]N-, [HO-(C=O)-alkyl (C-|-C₈)][ alkyl(CrC₈)-NH(C=O)-]N-alkyl(CrC₈)-, HO-(C=O alkyl (CrC₈)-ON=alkyl (C_rC.₈)-, HO-(C=O)-alkyl (C_rC.₈)SW₂-, HO-(C=O)-alkyl (CrC₈)-SW₂-alkyl(CrC₈)-, HO-(C=O)-alkyl (CrC₈)-SW₂-NH-, HO-(C=O)alkyl (CrC₈)-SW₂-NH-alkyl(C_rC.₈)-, HO-(C=O)-alkyl (C_rC.₈)-NH-SO₂-, HO-(C=O)-alkyl (C_rC.₈)NH-SO₂-alkyl(Ci-C₈)-, HO-(C=O)-(C=O)-NH-SO₂-, HO-(C=O)-(C=O)-NH-SO₂-alkyl(CrC₈)-, HO-(C=O)-alkyl (CrC₈)-NH-(C=O)-NH-, HO-(CO)-alkyl (Ci-C₈)-NH-(C=O)-NH-alkyl (Ci-C₈)-, HO-(C=O)-alkyl (CrC₈)-O-, HO-(C=O)-alkyl (CiC₈)-O-alkyl(C_rC.₈)-, HO-(C=O)-alkyl ( C_rC.₈) substituted with hydroxy, HO-(C=O)- alkenyl (C₂-C₈)-, heterocyclyl (Ci-C₉)-alkyl(CrC₈)-O-, heterocyclyl(CrCg)-alkyl(CrC₈)-O-alkyl(CrC₈)-, heteroaryl (CrC₉)-alkyl(CrC₈)-O-,heteroaryl(CrCg)-alkyl(CrC₈)-O-alkyl(CrC₈)-, heterocyclyl (CrC₉)-O-, heterocyclyl(CrC₉)-O-alkyl(CrC₈) , heteroaryl(CrCg)-O-, heteroaryl(Ci-C₉)-O-alkyl (Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)-S-, HO-(C=O)alkyl(Oi-Cs)-S-alkyl(CrCs)-, heterocyclyl(CrCg)-alkyl(Ci-C₈)-S-, heterocyclyl (Ci-C₉)-alkyl(CyC₈)-S-alkyl (Ci-C₈)-, heteroaryl(CrCg)-alkyl(Ci-C₈)-S-, heteroaryl(CrCg)-alkyl(Ci-C₈)-S-alkyl(Ci-Cs)-, heterocyclyl(Ci-Cg)-S-, heterocyclyl(Ci-C₉)-S-alkyl (Ci-C₈)-, heteroaryl (Ci-C₉)-S-, heteroaryl(C_rC.₉)-S-alkyl (CrC₈)-, HO-(C=O)-alkyl (Ci-C₈)-NH-SO₂-NH-, HO-(C=O)-alkyl (C_rC.₈)-NH-SO₂-NH-alkyl(CrC₈)-, HO-(C=O)-alkyl (C_rC.₈)-SW₂-NH-(C=O)-, HO-(C=O)-alkyl (C_rC.₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-,HO-(C=O)-alkyl (Ci-C₈)-(C=O)-NH-SO₂-, HO-(C=O)-alkyl (C_rC.₈)-(C=O)-NH-SO₂-alkyl(CrC₈)-, HO-(C=O)-(C=O)-, HO-(C=O)-(C=O)-alkyl (CrC₈)-, HO(C=O)-alkyl (Ci-C₈)-(C=O)-, HO-(G=O)-alkyl (Ci-C₈)-(C=O)-alkyl (CrC₈)-, HO-(C=0)-heterocyclyl (CrC₉)-(C=O)-, HO-(C=0)-heteroaryl (Ci-C₉)-(C=O)-, NC-NH-(C=O)-, NC-NH-(C=O)-alkyl (C_rC.₈), [alkyl (Ci-C₈)-SW₂-NH-(C=O)-][H₂N-]alkyl(Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-, alkyl (C_rC.₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-NH-, alkyl (Ci-C₈)SW₂-NH-(C=O)-alkyl (Ci-C₈)-NH-alkyl (Ci-C₈)-, [alkyl (CrC₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)][ alkyl (Ci-C₈)]N-, [alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)][ alkyl (Ci-C_yes)]N-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl(CrC₈)-NH-SO₂-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)NH-SO₂-alkyl(CrC₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-SW₂-NH-, alkyl (Ci-C₈)-SW₂NH-(C=O)-alkyl (C₁-C₈)-SW₂-NH-alkyl (C-|-C₈)-₅ alkyl(CrC₈)-SW₂-NH-(C=O)-alkyl(CrC₈)-SW₂-, alkyl(CrC₈)-SW₂-NH-(C=O)-alkyl(CrC₈)-SW₂-alkyl(CrC₈)-, alkyl (C₁-C₈)-SW₂-NH-(C=O)(C=O)-, alkyl (C₁-C₈)-SW₂-NH-(C=O)-(C=O)-alkyl (CrC₈)-, alkyl (CrC₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-(C=O)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-(C=O)-alkyl (Ci-C_yes)-,NC-alqu¡l (C_rC.₈)-SW₂-NH-(C=O)-, NC-alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl(CrCs)-, HO-alkyl(Ci-C₈)-SW₂-NH(C=O)-, HO-alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl(CrCs)-, alkyl(CrC₈)-SW₂-NH-(C=O)-alkyenyl (C₂-C₈)-, heterocyclyl (CrC₉)-SW₂-NH-(C=O)-, heterocyclyl (CrC₉)-SW₂-NH-(C=O)-alkyl(CrC₈)-, heterocyclyl(CrCg)-alkyl(CrC₈)-SW₂-NH-(C=O)-, heterocyclyl(CrCg)-alkyl(CrC₈)-SW₂-NH(C=O)-alkyl(CrC₈)-, aryl(C₆-C₁₀)-SW₂-NH-(C=O)-, aryl(C₆-C₁₀)-SW₂-NH-(C=O)-alkyl(CrC₈)-, heteroaryl (CrC₉)-SW₂-NH-(C=O)-, heteroaryl (CrC₉)-SW₂-NH-(C=O)-alkyl(CrC₈)-, H₂N-SW₂-NH(C=0)-, H₂N-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-NH-SO₂-NH-(C=O)-, alkyl (Ci-C₈)-NHSO₂-NH-(C=O)-alkyl (Ci-C₈)-, [alkyl (Ci-C₈)]₂N-SW₂-NH-(C=O)-, [alkyl (Ci-C₈)]₂N-SW₂-NH(C=O)-alkyl(CrC₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-O-, alkyl (Ci-C₈)SW₂-NH(C=O)-alkyl (Ci-C₈)-O-alkyl(C_rC.₈)-, alkyl (CrC₈)-(C=O)-NH-SO₂-,H₂N-SW₂-alkyl(CrC₈)-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-alkyl(C)_rC.₈)-, NC-alkyl (Ci-C₈)-(C=O)-NH-SO₂-alkyl(C)_rC.₈)-, HOalkyl (Ci-C₈)-(C=O)-NH-SO₂-alkyl(C)_rC.₈)-, aryl(C₆-C₁₀)-(C=O)-NH-SO₂-, aryl(C₆-C₁₀)-(C=O)-NHSO₂-alkyl(Ci-C₈)-, heteroaryl (Ci-C_g)-(C=O)-NH-SO₂-, heteroaryl (Ci-C₉)-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, heterocyclyl (Ci-C₉)-(C=O)-NH-SO₂-, heterocyclyl (Ci-C₉)-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, H₂N-(C=O)-NH-SO₂-,H₂N-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-NH-(C=O)-NH-SO₂-, alkyl(CrC₈)-NH-(C=O)-NH-SO₂-alkyl(C)_rC.₈)-, [alkyl (Ci-C₈)]₂-N-(C=O)-NH-SO₂-,[alkyl(CrC₈)]₂-N(C=O)-NH-SO₂-alkyl(Ci-C₈)-, aryl(C₆-ci₀)-NH-(C=O)-NH-SO₂-, aryl(C₆-ci₀)-NH-(C=O)-NH-SO₂alkyl(CrC₈)-, heteroaryl (Ci-C₉)-NH-(C=O)-NH-SO₂-, heteroaryl (Ci-C₉)-NH-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-O-(C=O)-NH-SO₂-, alkyl (Ci-C₈)-O-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, aryl(C₆Cio)-ox¡-(C=0)-NH-S0₂-, aryl(C₆-C₁₀)-oxy-(C=O)-NH-SO₂-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH(C=O)-O-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-O-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-NH-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-NH-alkyl (Ci-C₈)-, aryl(C₆-Cio)-S0₂-NH-(C=0)-0-, aryl(C₆-ci₀)-SW₂-NH(C=O)-O-alkyl(CrCg)-, aryl(C₆-C₁₀)-SW₂-NH-(C=O)-NH-, aryl (C₆-C₁₀)-SW₂-NH-(C=O)-NH-alkyl (Ci-Cg)-, heteroaryl (Ο·|-ΰ₉)-δΟ₂-ΝΙ-Ι-(ΰ=Ο)-Ο-, heteroaryl (CrCgj-SO^NH-jC^-O-alkyl (C-|-C₈)-, NH₂-SW₂-NH-(C=O)-O-, NH₂-SW₂-NH-(C=O)-O-alkyl (CrC₈)-, heteroaryl (C₁-C₉)-SW₂-NH-(C=O)NH-, heteroaryl (Ci-C₉)-SW₂-NH-(C=O)-NH-alkyl (Ci-C₈)-, NH₂-SW₂-NH-(C=O)-NH-, NH₂-SW₂-NH(C=O)-NH-alkyl (CrC₈)-, HO-(C=O)-alkyl (Ci-C₈)-NH-(C=O)-O-, HO-(C=O)-alkyl (CrC₈)-NH(C=O)-O-alkyl (Ci-C₈)-, HO-(C=O)-alkyl (CrC₈)-O-(C=O)-NH-, HO-(C=O)-alkyl (C_rC.₈)-O(C=O)-NH-alkyl (C_rC.₈)-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-NH-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-NHalkyl(Ci-C₈), aryl (C₆-Cio)-(C=0)-NH-S0₂-NH-, aryl(C₆-ci₀)-(C=O)-NH-SO₂-NH-alkyl (Ci-C₈), heteroaryl (CrCgj-^Oj-NH-SCVNH-, heteroaryl (CrCgHC^-NH-SOs-NH-alkyl (ΰ_Γo₈), NH₂(C=O)-NH-SO₂-NH-, NH₂-(C=O)-NH-SO₂-NH-alkyl(CrCg), heteroaryl(CrCgj-alkyl(C_VC.₈) (C=0)-, heterocyclyl (Ci-C₉)-alkyl (Ci-C₈)-(C=O)-, heteroaryl (Ci-C₉)-alkyl (Ci-C₈)-(C=O)-alkyl (Cr C₈)-, heterocyclyl (Ci-C₉)-alkyl (Ci-C₈)-(C=O)-alkyl (CrC₈)-, heteroaryl (Ci-C₉)-(C=O)-alkyl (CiC₈)-, heterocyclyl (Ci-C₉)-(C=O)-alkyl (CrC₈), HO-( C=O)-alkyl (Ci-C₈)-, heteroaryl(C1-C9)-, heterocyclyl(C1-C9)-, heteroaryl(Ci-C₉)-alkyl(CrC₈), or heterocyclyl (Ci-C₉)-alkyl(CyC₈);

each R⁵ is independently Η-, HO-, halo-, NC-, HO-(C=O)-, H₂N-,alkyl(C_rC.₈)-NH-, [alkyl (C_rC.₈)]₂N-,alkyl(C_rC.₈)-, alkyl (CrCsJ-O-, HO-alkyl (C-|-C₈)-, alkyl (C-|-C₈)-O-alkyl (C-iC₈)-, H₂N-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-NH-alkyl (Ci-C₈)-, [alkyl(C_rC.₈) ]₂N-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-(C=O)-, alkyl (Ci-C₈)-(C=O)-alkyl (CrC₈)-, aryl(C₆-ci₀)-, heteroaryl (C₂-C₉)-, aryl(C₆-C₁₀)oxy-, H₂N-(C=O)-, H₂N-(C=O)-alkyl (CrC₈)-, alkyl (Ci-C₈)-NH-(C=O)-, alkyl (C_rC.₈)-NH-(C=O)alkyl (Ci-C₈)-, [alkyl (Ci-C₈)]₂N-(C=O)-, [alkyl (Ci-C₈)]₂-N-(C=O)-alkyl(CrC₈)-, cycloalkyl (C₃C.₈)-, alkyl (CrC₈)-SW₂-, NC-alkyl(C_rC.₈)-, alkyl (Ci-C₈)-(C=O)-NH-, H₂N-(C=O)-NH-, or H₂N(C=O)-NH-alkyl (C_rC.₈)-;and

R.⁶ is H, alkyl (Ci-C₈)-, alkyl (Ci-C₈)-(C=O)-, aryl(C₆-ci₀)-(C=O)-, heteroaryl (C₂-C₉)(C=O)-, H₂N-(C=O)-, alkyl (Ci-C₈)-NH-(C=O)-, [alkyl (C_rC.₈) ]₂N-(C=O)-, alkyl (Ci-C₈)-O-(C=O)-, or alkyl (Ci-C₈)-SW₂-.

In one embodiment, R⁴ is [HO-(C=O)-][H₂N-]alkyl(Ci-C₈)-, [HO-(C=O)-][ alkyl (C_rC.₈))NH-] alkyl {C_rC.₈)-, [HO-(C=O)-][( alkyl (CrC^N-] alkyl (CrCs)-, HO-(C=O)-alkyl (CrCs)NH-, HO-(C=O) -alkyl(CrC₈)-NH-alkyl (C₁-C₈)-,[HO-(C=O)-alkyl (C_rC.₈)][ alkyl (CrC^N-JHO(C=O)-alkyl (C_rC.₈)][ alkyl(CrCgJJN-alkyl(C_rC.₈)-, [HO-(C=O)-alkyl (C_rC.₈)][ alkyl(C_rC.₈)SW₂]N-, [HO-(C=O)-alkyl (C_rC.₈)][ alkyl (Ci-C₈)-SW₂]N-alkyl (Ci-C₈)-,[HO-(C=O)-alkyl (C_rC.₈)][ alkyl(CrC₈)-(C=O)-]N-, [HO-(C=O)-alkyl (CrC₈)][ alkyl(CrC₈)-(C=O)-]N-alkyl(CrC₈)-, [HO(C=O)-alkyl (C_rC.₈)][ alkyl (Ci-C₈)-O-(C=O)-]N-,[HO-(C=O)-alkyl (Ci-C₈)][ alkyl(C_rC.₈)-O(C=O)-]N-alkyl (Ci-C₈), [HO-(C=O)-alkyl (CrC₈)][ alkyl(C_rC.₈)N-(C=O)-]N-, [HO-(C=O)-alkyl (Ci-C₈)][ alkyl (Ci-C₈)-NH-(C=O)-]N-alkyl (C_rC.₈)-, HO-(C=O)-alkyl (Ci-C_yes)-ON=alkyl (C_rC.₈)-, HO-(C=O)-alkyl (CrC^-SO;,-, HO-(C=O)-alkyl (CrCsj-SO^alkyl (CrCs)-, HO-(C=O)-alkyl (C)_rC.₈)-SW₂-NH-, HO-(C=O)-alkyl (C_rC.₈)-SW₂-NH-alkyl (CrCs)-, HO-(C=O)-alkyl (CrC^-NH-SOs-,

HO-(C=O)-alkyl (Ci-C₈)-NH-SO₂-alkyl(CrC₈)-, HO-(C=O)-(C=O)-NH-SO₂-, HO-(C=O)-(C=O)NH-SO₂, -alkyl(Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)-NH-(C=O)-NH-,HO-(C=O)-alkyl (Ci-C₈)-NH(C=O)-NH-alkyl (Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)-O-,HO-(C=O)-alkyl (CrC₈)-O-alkyl (Ci-C₈)-, HO-(C=O)- alkenyl (C₂-C₈)-, heterocyclyl (C₂-C₉)-alkyl(CrC₈)-O-, heterocyclyl(C₂-C₉)-alkyl(C_rC.₈)-O-alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-alkyl(CrC₈)-O-, heteroaryl(C₂-C₉)-alkyl(CrC₈)-O-alkyl(Ci-Cs)-, heterocyclyl(C₂-C₉)-O-, heterocyclyl(C₂-C₉)-O-alkyl(CrCs)-, heteroaryl(C₂-C₉)-O-, heteroaryl(C₂-C₉)-O-alkyl(CrC₈)-, HO-(C=O)-alkyl (Ci-C₈)-S-. HO-(C=O)-alkyl (Ci-C₈)-S-alkyl (Ci-C₈)-, heterocyclyl (C₂-C₉)-alkyl (Ci-C₈)-S-, heterocyclyl(C₂-C₉)-alkyl (Ci-C₈)-S-alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-alkyl (Ci-G₈)-S-, heteroaryl(C₂-C₉)-alkyl (Ci-C₈)-S-alkyl (Ci-C₈)-, (C₂C.₉)heterocyclyl-S-, heterocyclyl(C₂-C₉)-S-alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-S-, heteroaryl(C₂-C₉)-Salkyl (CrC₈)-, HO-(C=O)-alkyl (Ci-C₈)-NH-SO₂-NH-, HO-(C=O)-alkyl (Ci-C₈)-NH-SO₂-NH-alkyl(CrC₈)-, HO-(C=O)-alkyl (CrC₈)-SW₂-NH-(C=O)-, HO-(C=O)-alkyl(0(-08)-502, -NH-(C=O)alkyl(Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)-(C=O)-NH-SO₂- HO-(C=O)-alkyl (Ci-C₈)-(C=O)-NH-SO₂alkyl (Ci-C₈)-, H0-(C=0)-(C=0)-, HO-(C=O)-(C=O)-alkyl (Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)(0=0)-, HO-(C=O)-alkyl (Ci-C₈)-(C=O)-alkyl (Ci-C₈)-, HO-(C=0)-heterocyclyl (C₂-C₉)-(C=O)-, HO(C=0)-heteroar¡l (C₂-C₉)-(C=O)-, NC-NH-(C=O)-, NC-NH-(C=O)-alkyl (C(-C₈), [alkyl (Ci-C₈)-SW₂NH-(C=O)-][H₂N-] alkyl (CrCs)-, alkyl (CrCsj-SO^NH-^O)-, alkyl (C₁-C₈)-SW₂-NH-(C=O)alkyl(CrOg)-, alkyl(0(-0₈)-50₂-ΝΗ-(0=0)-3ψίΙ (CrCgJ-NH-, alkyl (C₁-C₈)-SW₂-NH-(C=O)alkyl (C(-C₈)-NH-alkyl(ΟγΟ₈)-, [alkyl (CrCsJ-SOs-NH-^Oj-alkyl (C(-C₈)][ alkyl (C(-C₈)]N-, [alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)][ alkyl (Ci-C₈)]N-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂.NH-(C=O)-alkyl (Ci-C₈)-NH-SO₂-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-NH-SO₂-alkyl(CrC₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-SW₂-NH-, alkyl (Ci-C₈)-SW₂NH-(C=O)-alkyl (Cr C₈)-SW₂-NH-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-SW₂, alkyl (Ci-C₈)-SW₂NH-(C=O)-alkyl (Ci-C₈)- SO₂-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-(C=O)-, alkyl (Ci-C₈)SW₂-NH-(C=O)-(C=O)-alkyl (C(-C₈)-, alkyl (C(-C₈)-SW₂-NH-(C=O)-alkyl (0(-0^-(0=0)-, alkyl (C(-C₈)-SW₂-NH-(C=O)-alkyl (C(-C₈)-(C=O)-alkyl (C_rC.₈)-. NC-alkyl (C(-C₈)-SW₂-NH-(C=O)-,

NC-alkyl(Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, HO-alkyl (Ci-C₈)-SW₂-NH-(C=O)-, HO-alkyl (C_rC.₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alken¡l (C₂-C₈)-, heterocyclyl (0₂C.₉)-SW₂-NH-(C=O)-. heterocyclyl(C)₂-C₉)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, heterocyclyl (C₂-Cg)-alkyl(CrC₈)-SW₂-NH-(C=O)-, heterocyclyl (C₂-C₉)-alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, aryl(C₆Ci₀)-SW₂-NH-(C=O)-, aryl(C₆-ci₀)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-. heteroaryl(C)₂-C₉)-SW₂-NH(C=O)-> heteroaryl (C₂-C₉)-SW₂-NH-(C=O)-alkyl (C_rC.₈)-, H₂N-SW₂-NH-(C=O)-, H₂N-SW₂-NH(C=O)-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-NH-SO₂-NH-(C=O)-, alkyl (Ci-C₈)-NH-SO₂-NH-(C=O)-alkyl (Ci-C₈)-, [alkyl (Ci-C₈)]₂N-SW₂-NH-(C=O)-, [alkyl (Ci-C₈)]₂N-SW₂-NH-(C=O)-alkyl (Ci-C₈)-, alkyl (Gi-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-O-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-Oalkyl (Ci-C₈)-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-,H₂N-SW₂-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-(C=O)-NHSO₂-alkyl(Ci-C₈)-, NC-alkyl (Ci-C₈)-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, HO-alkyl (Ci-C₈)-(C=O)-NHSO₂-alkyl(C^Cg)-, aryl(C₆-ci₀)-(C=O)-NH-SO₂-, aryl (C6-C₁₀)-(C=O)-NH-SO2-alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-(C=O)-NH-SO₂-, heteroaryl (C2-C₉)-(C=O)-NH-SO2-alkyl (Ci-C₈)-, heterocyclyl (C₂-C₉)-(C=O)-NH-SO₂-, heterocyclyl (C₂-C₉)-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, H₂N-(C=O)-NH-SO₂-,H₂N-(C=O)-NH-SO₂-alkyl(Ci-C₈)-, alkyl (Ci-C₈)-NH-(C=O)-NH-SO₂-, alkyl (Ci-C₈)-NH-(C=O)NH-SO₂-alkyl(Ci-C₈)-, [alkyl (Ci-C₈)]₂-N-(C=O)-NH-SO₂-, [alkyl (Ci-C₈)]₂ -N-(C=O)-NH-SO₂alkyl(CrCs)-, aryl(C₆-C₁₀)-NH-(C=O)-NH-SO₂-, aryl(C₆-C₁₀)-NH-(C=O)-NH-SO₂-alkyl(CrCg)-, heteroaryl(C₂-C₉)-NH-(C=O)-NH-SO2-, heteroaryl (C₂-C₉)-NH-(C=O)-NH-SO₂-alkyl(CrCs)-, alkyl(CrCgj-O-^OJ-NH- SO₂-, alkyl (CrCsj-O-^OJ-NH-SOz-alkyl (ΟγΟ₈)-, aryl(C₆-C₁₀)-ox¡(C=O)-NH-SO₂-, aryl(C₆-ci₀)-ox¡-(C=O)-NH-SO₂-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-O-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-O-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-NH-, alkyl (Ci-C₈)SW₂-NH-(C=O)-NH-alkyl (Ci-C₈)-, aryl(C₆-Cio)-S0₂-NH-(C=0)-0-, aryl(C₆-Cio)-S0₂-NH-(C=0)-0alkyl(Ci-C₈)-, aryl(C₆-Cio)-S0₂-NH-(C=0)-NH-, aryl(C₆-C₁₀)-SW₂-NH-(C=O)-NH-alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-SW₂-NH-(C=O)-O-, heteroaryl (C₂-C₉)-SW₂-NH-(C=O)-O-alkyl (Ci-C₈)-, NH₂SW₂-NH-(C=O)-O-, NH₂-SW₂-NH-(C=O)-O-alkyl (C_rC.₈)-, heteroaryl (C₂-C₉)-SW₂-NH-(C=O)-NH-, heteroaryl (C₂-C₉)-SW₂-NH-(C=O)-NH-alkyl(CrCg)-, NH₂-SW₂-NH-(C=O)-NH-, NH₂-SW₂-NH (C=O)-NH-alkyl (Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)-NH-(C=O)-O-, HO-(G=O)-alkyl (Ci-C₈)-NH(C=O)-O-alkyl (CrC₈)-, HO-(C=O)-alkyl (CrC₈)-O-(C=O)-NH-, HO-(C=O)-alkyl (OrC₈)-0(C=O)-NH-alkyl (C_rC.₈)-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-NH-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-NHalkyl(C_rC.₈), aryl (C₆-ci₀)-(C=O)-NH-SO₂-NH-, aryl(C₆-Cio)-(C=0)-NH-S0₂-NH-alkyl(C_rC.₈), heteroaryl (C₂-C_g)-(C=O)-NH-SO₂-NH-, heteroaryl(C₂-C₉)-(C=0)-NH-S0₂-NH-alkyl(C_rC.₈), NH₂(C=O)-NH-SO₂-NH-, or NH₂-(C=0)-NH-S0₂-NH-alkyl(C_rC.₈);

or, if Y is a heteroaryl group (C₂-C₉), then R⁴ can also be HO-(C=O)-alkyl (Ci-C₈)-, heteroaryl (C₂-C₉)-, heterocyclyl (C₂-C₉)-, heteroaryl (C₂-C₉)-alkyl(CrC₈), or heterocyclyl (C₂-C₉)-alkyl (Ci-C₈).

In another embodiment, the present invention includes compounds of formula I or pharmaceutically acceptable salts or prodrugs thereof.

Preferred compounds of formula I include those in which each R¹ is independently Η-, HO-, halo, NC-, alkyl(C_rC.₈), or alkyl (Ci-C₈)-EITHER-.

Other preferred compounds of formula I include those in which each R² and R³ are each independently H-, alkyl (Ci-C₈)-, cycloalkyl (C₃-C₈)-, cycloalkyl (C₃-C₈)-alkyl(C_rC.₈)-, aryl(Ce-Cio)-, aryl(C₆-ci₀)-alkyl (Ci-C₈)-, HO-alkyl (Ci-C₈)-, H₂N-alkyl(Ci-C₈)-, heterocyclyl(CrCgj-alkyl(CrCs)-, alkyl(CrC₈)-O-(C=O)-NH-alkyl (C-|-C₈)-, H₂N-(C=O)-NH-alkyl (CrC₈)-, alkyl(CrCsj-SOrNH-alkyl(Ci-C₈)-, heteroaryl (Ci-C₉)-alkyl(CrC₈)-, H₂N-(C=O)-, or H₂N-(C=O)alkyl(CrCs)-.

Other preferred compounds of formula I include those in which X is -O- and Y is a phenyl ring.

Other preferred compounds of formula I include those in which X is -O- and Y is a pyridyl ring.

Other preferred compounds of formula I include those in which -NR⁶- and Y is a pyridyl ring.

Other preferred compounds of formula I include those in which R⁴ is [HO-(C=O) ][H₂N-]-alkyl (Ci-C₈)-, [HO-(C=O)-](alkyl(CrC₈))NH-]-alkyl (Ci-C₈)-, [HO-(C=O)-][(alkyl (C_rC.₈))₂N-]alkyl(Oi-C₈)-, H0-(0=0)-alkyl (CrC₈)-NH-, H0-(C=0)-alkyl (CrC₈)-NH-alkyl(C_rC.₈),[H0-(C=0)-alkyl (Ci-C₈)][alkyl(CrC₈)-]N-, [HO-(C=O)-alkyl (Ci-C₈)][alkyl(Ci-C₈)]N-alkyl(C_rC.₈)-, alkyl (C_rC.₈)-SW₂-NH-(C=O)-alkyl (C_rC.₈)-, NC-alkyl (Ci-C₈)-S0₂-NH-(C=0)-alkyl (C_rC.₈)-, HO-alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (C_rC.₈)-, heterocyclyl (Ci-C₉)-SW₂-NH-(C=O)-alkyl (C_rC.₈), heterocyclyl (C^Cgj-phalkyl (C-|-C3)-SO₂-NH-(C=O)-alkyl(CrCs)-, heteroaryl(Ci-C₉)-SW₂-NH(C=O)-alkyl(CrC₈)-, H₂N-SW₂-NH-(C=O)-alkyl(CrC₈)-, alkyl (Ci-C₈)-NH-SO₂-NH-(C=O)-, alkyl (Ci-C₈)-SW₂-NH-(C=O)-alkyl (Ci-C₈)-O-, alkyl (CrC₈)-S0₂-NH-(C=0)-alkyl (Ci-C₈)-O-alkyl(C_rC.₈)-, H₂N-SW₂-alkyl(CrC₈)-, alkyl (Ci-C₈)-(C=O)-NH-SO₂-alkyl(Ci-C₈)-NC-alkyl(C_rC.₈)(C=O)-NH-SO₂, -alkyl(C_rC.₈)-,HO-alkyl (Ci-C₈)-(C=O)-NH-SO₂-alkyl(C)_rC.₈)-, heteroaryl (C_rC.₉)-(C=O)-NH-SO₂-alkyl(C)_rC.₈)-, heterocyclyl (C_rC.₉)-(C=O)-NH-SO₂-alkyl(CrC₈)-, H₂N(C=O)-NH-SO₂-alkyl(CrC₈)-, alkyl (Ci-C₈)-NH-(C=O)-NH-SO₂,-alkyl(CrC₈)-, alkyl (C_rC.₈)SW₂-NH-(C=O)-NH-alkyl (Ci-C₈)-, alkyl (Ci-C₈)-(C=O)-NH-SO₂,-NH-alkyl (Ci-C₈)-, HO-(C=O)alkyl (CrC₈)-O-, HO-(C=O)-alkyl (Ci-C₈)-O-alkyl(C_rC.₈), alkyl (CrC₈)-S0₂-NH-(C=0)-alkyl (Ci-C₈)-O-, heterocyclyl(CrCg)-alkyl(Ci-C₈)-O-, heterocyclyl(Ci-Cg)-alkyl(Ci-C₈)-O-alkyl (Ci-C₈), heteroaryl (0i-C₉)-alkyl(CrC₈)-O-, heteroaryl(CrCg)-alkyl(Ci-C₈)-O-alkyl(CrC₈)-, heterocyclyl(Ci-Cgj-O-, heterocyclyl(Ci-Cgj-O-alkyl(CrCe)-, heteroaryl(CrC₉)-O-, heteroaryl (Ci-C₉)-O-alkyl (C-|-C₈)-, HO-(C=O)-alkyl (CrC₈)-S-, HO-(alkyl (C-|-C₈)-S-alkyl (CrC₈)-, heterocyclyl (CrC₉)alkyl (C-|-C₈)-S-, heterocyclyl(CrCg)-alkyl(C-|-C₈)-S-alkyl(CrC₈)-, heterocyclyl (C-|-C₉)-alkyl(C_rC.₈)-S-, heterocyclyl(CrCg)-alkyl(Ci-C₈)-S-alkyl (Ci-C₈)-, heteroaryl (CrC₉)-S-, heterocyclyl(CiCgj-S-alkyl(Ci-C₈)-, heteroaryl (Ci-C₉)-S-, heterocyclyl(Ci-Cg)-S-alkyl(Ci-C₈)-, heteroaryl(C1-C9)S-, heteroaryl(Ci-Cg)-S-alkyl(Ci-C₈)-, HO-(C=O)-alkyl (Ci-C₈)-SW₂-, HO-(C=O)-alkyl (CrC₈)SW₂-alkyl(Ci-C₈)-,HO-(C=O)-(G=O)-alkyl(CrCs)-, HO-(C=O)-alkyl(Ci-C₈)-(C=O)-, HO-(C=O)alkyl (Ci-C₈)-(C=O)-alkyl (Ci-C₈)-, heteroaryl(CrCg)-alkyl(Ci-C₈)-(C=O)-, or heterocyclyl (CrC₉)alkyl (CrC₈)-(C=O)-.

Other preferred compounds of formula I include those in which R⁵ is independently H-, HO-, NC-, alkyl(Ci-C₈)-, alkyl (CrC₈)-O-, alkyl (CrC₈)-(C=O)-, or halo.

Other preferred compounds of formula I include those in which R⁶ is H-, alkyl (Gr

C.₈)-, H₂N-(C=O)- or alkyl (Ci-C₈)-SW₂-.

Other preferred compounds of formula I include those in which a is 1; X is -O-; Y is aryl (C₆-cio); R.¹ it is halo; R.² and R³ are each independently H- or alkyl(C_rC.₈)-; and R⁵ it's halo.

Other preferred compounds of formula I include those with the absolute stereoisomerism as represented by formula I a where b and c are each 1.

<img file="ECSP045073A_D0002.tif" />

Examples of specific compounds of formula I are as follows:

(2{2-[(2R)-2-carbamoylmethyl-4-(4-ylfluoro-benzyl)-piperazin-l-yl]-2-oxo-ethoxy)-5-chloro-phenoxy)acetic acid;

(2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-5-methyl-phenyl)-acetic acid;

(2-{2-[4-(4-Fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy¡}-5-methyl-phenyl)acetic acid;

(2-{2-[4-(4-Fluoro-benz¡l)-(2R)-2-methyl-piperaz¡n-1 -¡l]-2-oxo-ethoxy¡}-5-trifluoromethyl -phenyl)methanesulfonamide;

(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-4-methoxyphenyl)-acetic acid ;

Acid (2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl]-2-oxo-ethoxy}-5- methylbenzylideneaminooxyj-acetic acid;

(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}-5-methyl-phenyl acid )acetic;

(2-{2-[4-(4-Fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-5 -trifluoromethylphenyl)-methanesulfonamide;

Acid (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-5-methoxyphenoxy) -acetic;

Acid (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-3-oxo-propyl}-5- methylphenoxy)-acetic;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy (2-Methylbenzenesulfonyl)-carbamic acid }-benzyl ester;

(2R)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}phenoxy)-propionic;

(2R)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -ylJ-2- acid οχοethoxy}-benzyloxy)-propion¡co;

Acid (2R)-2-am¡no-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- p¡peraz¡n-1-yl]-2oxo-ethoxy}-phenoxy)-butyric acid;

(2S)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxy)-propion¡co;

Acid (2S)-2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1- ¡l]-2-oxoethoxy}-benzyloxy)-propion¡c;

Acid (2S)-2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperaz¡n- 1-¡l]-2-oxoethoxy}-phenoxy)-propionic;

(2S)-2-am¡no-4-(5-bromo-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl¡lp¡ acid peraz¡n-1 -il]2-oxo-ethox¡}-f en ox i)-but ir i co;

(2S)-2-amino-4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxoethoxy acid }-phenoxy)-butyric;

(2S)-2-amino-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1- acid ylJ-2oxo-ethoxy}-phenoxy)-butyric;

(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)acetic acid;

(4-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy acid }-phenyl)acetic;

(4S)-4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}phenoxy acid )-pyrrolidine-(2S)-2-carboxylic;

(4S)-4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxoethoxy}-phenoxy)-pyrrolidine-(2S)-2-carboxylic;

Acid (4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n- 1-¡l]-2-oxoethoxy}-phenoxy)-1-methyl-pyrrolidine-(2S)-2-carboxylic;

Acid (4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - ¡l]-2-oxoethoxy}-phenoxy)-1-pyrrolidine-(2S)-2-carboxylic;

Acid (4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n- 1 -ylJ-2-οχοethoxy}-phenoxy)-pyrrolidine-2-carboxylic;

(5-Bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy¡}-phenyl acid )-acetic;

(5-Bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl )methanesulfonamide;

(5-Bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methylp¡peraz¡n-1-¡l]-2-oxoethoxy}phenyl)methanesulfonamide ;

(5-Bromo-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-d¡methyl-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)methanesulfonamide;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)acetic acid;

Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenoxy) difluoro-acetic

Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phen¡ l) acetic;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl )methanesulfonamide;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}benzylideneaminoox acid ¡)-acetic;

Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo -ethoxy¡}phenoxy)-acetic;

Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}phenoxy) -difluoro-acetic acid;

Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2-oxo -ethoxy¡}phenyl)-acetic;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)methanesulfonamide ;

(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)acetic acid;

Acid (5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl) -acetic;

(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl)methanesulfonamide ;

Acid (5-chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl) acetic;

(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl )methanesulfonamide;

Acid (5-chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl] -2-oxo-ethoxy¡}phenyl)-acetic;

(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl )methanesulfonamide;

(5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acetic acid ;

(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -¡l]-2-oxo-ethoxy¡}-phen ¡l) methanesulfonamide;

(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl) acid acetic;

(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)methanesulfonamide;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazinl-yl]-2-oxo-ethoxy}-phenyl) oxo-acetic;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)acetic acid;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)difluoro-acetic acid;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)acetic acid;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)methanesulfonamide ;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperaz¡n-1 -yl]-2-oxo-ethoxy¡}phenylmethanesulfonylamine) -oxo-acetic;

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2-oxo acid -ethoxy}benzenesulfonylamino)-acetic;

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}benzenesulfonylamino) acid -oxo-acetic;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy} -benz¡lox¡)acetyl methanesulfonamide;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo -ethoxy¡} benzylsulfamoyl)-acetic;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡rnet¡lp¡perazin-1 -yl]-2-oxo-ethox ¡}phenoxy)-acetic;

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethox acid ¡}phenoxy)-difluoro-acetic;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo -ethoxy¡}phenylmethanesulfonyl)-acetic;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}phenylmethanesulfonylam¡ acid no)-oxo-acetic acid;

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}phenylsulfamoyl) acid -acetic;

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}pyr¡ acid d¡n-3-¡lam¡no)-acetic;

Acid (5-chloro-2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -¡l]-3-oxo-propyl}phenoxy) -acetic;

[(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2-oxo -ethoxy¡}-phenyl)]-N-cyanoacetamide;

Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy¡}benz¡l)-methyl-am¡no]-acetic;

Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy¡}phenyl)-phenyl-methyleneaminoox¡]-acetic;

Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo-ethoxy} pyridin-3-ylmethyl)-amino]-acetic acid;

Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy¡pyridine-3-carbonyl)-amino]-acetic;

Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R_]5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethylamino} pyr¡d¡na-3-carbonyl)-am¡no]-acetic;

Acid [1 -(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy¡}phenyl)-ethylidenam¡nooxy]-acetic;

Acid [1 -(5-chloro-2-{2-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dirnet¡lp¡peraz¡n-1 -yl]-2- oxo-ethoxy¡}phenyl)-ethylidenam¡nooxy]-acetic;

Acid [3-(4-chloro-2-{2-(4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]- 2-oxo-ethoxy¡}phenyl)-ureido]-acetic;

Acid [3-(5-chloro-2-{2-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo- ethoxy}phenyl)-ureido]-acet¡co¡

-(5-Chloro-2-{2-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2-oxo -ethoxy}-benzyl)-3(2-methylbenzenesulfonyl)-urea;

-(5-Chloro-2-{2-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy }-benzyl)-3(methylsulfonyl)-urea;

-(5-Chloro-2-{2-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl) -2(1H-tetrazol-5-yl)-ethanone;

-(5-Chloro-2-{2-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)-3(1H-tetrazol-5-yl)-propan-1-one;

1-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-piperaz¡n-1-¡l] -2-oxo-ethoxy¡}-phenyl)-3(methylsulfonyl)-urea;

-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)-3(2-methylbenzoyl)sulfamide;

-Acet¡l-3-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n- 1-¡l]-2-oxo-ethoxy¡}benzyl)sulfamide;

2-(5-bromo-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methyl-p¡peraz¡n-1-¡l]-2-oxo- ethoxy¡}-phenoxy¡)-2-methyl-propionic;

2-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}phenoxy)-2-methyl-propion¡c;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}- acid phenoxy¡)-2-methyl-propionic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}benzenesulfonyl)-2-methyl-prop¡ónico;

2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}benzyloxy)-2-methyl-prop¡onic acid;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}benzylsulfamoyl)-propionic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}phenoxy)-2-methyl-propionic;

2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1 -yl] acid -2-oxo-ethoxy¡}phenox¡)-4-methyl-thiazole-5-carboxylic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo-ethoxy acid }phenoxy)-6-methyl-pyrimidine-4-carboxylic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡perazin-1-yl]-2-oxo acid -ethoxy¡}phenoxy)-nicotinic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡}phenoxy)-propionic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}phenoxymethyl)-furan-3-carboxylic acid;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo-ethoxy acid }phenoxymethyl)-n¡cotin¡co;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}phenoxymethyl)-thiazole-4-carboxylic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡}phenylsulfanyl)-2-methyl-propion¡c;

2-[4-Bromo-2-(2H-tetrazol-5-yloxy¡)-phenox¡]-1 -[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n -1 -I]ethanone;

2-[4-Chloro-2-(2H-tetrazol-5-¡lmethoxy¡)-phenox¡)-1-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5- dimethylpiperazin-1-yl]-ethanone;

2-(4-Chloro-2-(2H-tetrazol-5-yloxy)-phenoxy]-1 -[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl ]ethanone;

2-(4-Chloro-2-(2H-tetrazol-5-¡loxy)-phenox¡]-1-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d ¡methylp¡peraz¡n1 -ylj-ethanone;

2-[4-Chloro-2-(5-hydroxy-furan-2-¡l)-phenoxy¡)-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d ¡methylpiperazin-1-yl]-ethanone;

2-Amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxoethoxy acid } -phenyl)-propionic;

2-Amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-ylJ-2-οχοethoxy} acid -pyr¡d¡n-3-¡l)-propionic;

2-Chloro-N-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2_J5-dimethyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy¡}phenyl)-acetyl]-benzenesulfonamide

3-(2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-5-methyl-phenyl)propionic acid;

3-(2-{2-[4-(4-Fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-5-methyl-phenyl)propionic acid;

3-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy¡}-5-methylphenyl acid )-acrylic;

3-(2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}- acid 5-methylphenyl)-propionic;

3-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}- acid phenyl) acrylic;

3-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy}- acid phenyl)propionic;

3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo-ethoxy acid }phenyl)-acrylic;

3-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡}phenyl)-propionic;

3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)furan-2-carboxylic acid;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperaz¡n-1 -yl]-2-oxo-ethoxy¡}phenoxymethyl) acid -furan-2-carboxylic;

3-(5-Chloro-2-(2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)acrylic acid;

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)propionic acid;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡perazin-1-yl]-2-oxo acid -ethoxy¡}benzylamino)-prop¡ónico;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡}phenoxy)-2,2-dimethyl-prop¡ónico;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}phenoxymethyl)-furan-2-carboxylic acid;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxymethyl)-thiophene-2-carboxylic;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}phenyl)-acrylic;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡} pyr¡din-3-¡l)-acrylic;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}pyridin-3-yl)-propion¡co;

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}pyrid acid n-3-yl)-propionic;

[(5-chloro-2-{2-(4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 3,5-dimethyl-isoxazole-4-sulfonic acid -oxo-ethoxy}-phenyl)acetylj-amide;

3-[3-(4-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-yl acid ]-2-oxo-ethoxy¡}phenyl)-ureido]-prop¡ónico;

3-[3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo- acid ethoxy}-phenyl)ureidoj-propionic;

3-[3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 acid -yl]-2-oxo-ethoxy¡}phenyl)-ureido]-prop¡ónico;

4-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4oxo acid -butyric;

4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡dmethylp¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}phenyl)-4-oxo-butyric;

4-(5-chloro-2-(2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}- acid phenoxy)butyric;

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4oxo acid -butyric;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxy)-butyric;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}phenoxy)-pyridine-2-carboxylic;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡}phenyl)-4-hydroxy-but-3-eno¡co;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡rnet¡lp¡perazin-1 -yl]-2-oxo acid -ethoxy¡}phenyl)-4-oxo-butyric;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}phenyl)-4-hydroxy-butyric;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy¡}phenyl)-4-but-3- enoic;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid pindin-3-yl)-4-oxo-butyric;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}pyridin-3-ylamino)-butyric acid;

4-[2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy }-phenyl)2-oxo-ethyl]-isoxazolidine-3,5-dione;

4-[2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo -ethoxy}-phenyl)-2oxo-ethyl]-pyrazolidine-3,5-dione;

5- (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡l]-2 -oxo-ethoxy¡}-phenox¡)-5(2-methoxy-ethyl)-pyrimidine-2,4,6-trione;

5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo- ethoxy}-phenoxy)-5-ethyl-pyrimidine-2,4,6-trione;

5-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenoxy)-5-methyl-pyrimidine-2,4,6-trione;

5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxymethyl)-furan-2-carboxylic acid;

5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo acid -ethoxy¡}phenoxymethyl)-thiophene-2-carboxylic;

5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2- oxo-ethoxy}-phenyl)-5-hydroxy-dihydro-furan-2-one;

5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyllppiperazin-1-yl]-2-oxo-ethox acid ¡}phenyl)-5-oxo-pentanoic acid;

5-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5dimethylp¡peraz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)dihydro-furan-2-one;

5-[2-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl] -2-oxo-ethoxy}-phenyl)2-oxo-ethyl]-2-thioxo-dihydro-pyrimidine-4,6-dione;

5-[2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-p¡peraz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)-2oxo-ethyl]-pyrimidine-2,4,6-trione;

5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl)-2-oxo-ethoxy}benzyl acid denoam¡noox¡)-acetic;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy }-N-(2-hydroxy2-methyl-propionyl)-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluorobenzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-N-(2 -methyl phenylam¡no)-carbon¡l]-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy }-N-(4-fluorophenylamino)-carbon¡l]-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-p¡peraz¡n-1-¡l]-2- oxo-ethoxy¡}-N[ethoxycarbonylj-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡m¡l-piperaz¡n-1-¡l]-2- oxo-ethoxy¡}-N[(ethylamino)carbon¡l]-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-N[methoxycarbonylj- benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}- N[(phenylam¡no)carbon¡l]-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy }-N-[(2-propylamino)carbonyl]-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy }-N-hydroxyacetyl-benzenesulfonamide;

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}-N -isobutyrlbenzenesulfonamide;

5-Chloro-N-(2,2-dimethyl-prop¡on¡l)-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2, 5-dimethyl-piperazin-1-yl]2-oxo-ethoxy}-benzenesulfonamide;

5-Chloro-N-cyclopentanecarbon¡l-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡perazin-1 -yl] 2-oxo-ethoxy¡}-benzenesulfonamide¡de

5-Chloro-N-cyclopropanecarbonyl-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyllpperazin-1-yl] 2-oxo-ethoxy¡}-benzenesulfonamide;

6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxy)-nicotin¡co;

6-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy acid }phenoxy)-pyridine-2-carboxylic;

6-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡l-piperaz¡n-1 -yl]-2 acid -oxo-ethoxy¡}phenoxymethyl)-nicotin¡co;

6-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 acid -oxo-ethoxy¡}pyrid¡n-3-ylamino)-methyl]-nicotinic;

C-(2-{2-[4-(4-Fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-5-trifluoromethyl -phenyl)-N(2-hydroxy-2-methyl-propionyl)-methanesulfonamide;

C-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-5-trifluoromethylphenyl)- N-(2-hydroxy-2-methyl-propionyl)-methanesulfonamide;

C-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-5 -trifluoromethylphenyl)-Nh¡drox¡acetyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)-N-cyclopropanecarbonyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl ]-2-oxo-ethoxy}-phenyl)N-(2-hydroxy-2-methyl-propionyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl ]-2-oxo-ethoxy}-phenyl)N-(methoxycarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1 -yl ]-2-oxo-ethoxy}-phenyl)N-cyclopropanecarbonyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1 -yl ]-2-oxo-ethoxy}-phenyl)N-hydroxyacetyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl )-N-trifluoroacetyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1 -yl]- 2-oxo-ethoxy}-phenyl)-N(2-hydrox¡-2-methyl-propion¡l)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy} -phenyl)-N(methoxycarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-N-cyclopropanecarbonyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy} -phenyl)-N-hydroxyacetyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-N-trifluoroacetyl-methanesulfonamide;

C-(5-Chloro-2-{2-(4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N- (1 hydroxy-cyclopropanecarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl )-N-(2hydroxy¡-2-methyl-propion¡l)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phen ¡l)-N-(3-hydroxy¡-3-methyl-butyryl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phen ¡l)-N(methoxycarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl )-N-hydroxyacetyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]- 2-oxo-ethoxy}-phenyl)-N(1-hydroxy¡-cyclopropanecarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)-N(2,2-dimethyl-prop¡on¡l)-methanesulfonam¡da¡

C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡m¡l-piperaz¡n-1 -yl]- 2-oxo-ethoxy}-phenyl)-N(2-hydroxy¡-2-methyl-prop¡on¡l)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-N(3-hydrox¡-3-methyl-butyryl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl )-N(ethylamnecarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-N(methoxycarbonyl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl )-N-hydroxyacetyl-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R, 55)-2,5-dimethylpiperazin-1 -yl]-2-oxo-ethoxy} -phenyl)-N-methoxyacetyl-methanesulfonamide;

[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl)-2-oxo-ethoxy}-phenyl) ethanesulfonic acid acetylj-amide;

Methylsulfonyl acid 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}benzyl ester -carbamic;

N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-benzo ¡l) methanesulfonamide;

N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}- acid p¡r¡d¡n-3yl)-2,2-dimethyl-succinamic;

N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3¡ acid l)-succinamic;

N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2- oxo-ethoxy}-benzoyl)methanesulfonamide;

N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -¡l]- acid 2-oxo-ethoxy}pindin-3-yl)-succinamic;

N-[(2-{2-[(2R)-2-Ethyl-4-(4-fluoro-benz¡l)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-5- methyl-phenyl)-acet¡l]methanesulfonamide;

N-[(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-4- methoxy-phenyl)acetylj-methanesulfonamide;

N-[(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl ]methanesulfonamide;

N-[(2-{3-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-3-oxo-propyl }-5-methoxyphenoxy)-acetyl]-methanesulfonamide;

N-[(2-{3-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-3-oxo-propyl}-5- methyl-phenoxy¡)acetylj-methanesulfonamide;

N-[(2R)-2-Amino-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- p¡peraz¡n-1-yl]-2oxo-ethoxy}-phenoxy)-butyryl]-methanesulfonamide;

N-[(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl ]methanesulfonamide;

N-[(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}- phenyl)acetylj-methanesulfonamide;

N-[(4S)-4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - yl]-2-oxo-ethoxy} phenox¡)-pyrrolid¡na-(2S)-2-carbon¡l]-methanesulfonamide;

N-[(5-Bromo-2-{(2R)-2-[2-ethyl-4-(4-fluoroiO-benz¡l)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy }-phenyl)-acetyl]methanesulfonamide;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}- phenoxy)-acetyl]methanesulfonamide;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}- phenoxy)-acetyl]methanesulfonamide;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)acetylj-methanesulfonamide;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-piperaz¡n-1-¡l ]-2oxo-ethoxy¡}-phenyl)acetylj-methanesulfonamide;

N-[(5-Bromo-2-(2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]methanesulfonamide;

N-[(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetyl ]methanesulfonamide;

N-[(5-Gloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl ]methanesulfonamide;

N-[(5-Gloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl) -acetyl]methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethox ¡}phenyl)-acetyl]-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl) -acetyl]methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}- phenyl)acetylj-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2-oxo-ethoxy¡}-phenoxy)- acetyl]methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}- phenyl)-acetyl]methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenoxy})acetylj-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡m¡l-piperaz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acetyl]-2-fluoro-benzenesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡m¡l-piperaz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acet¡l]-2-methyl-benzenesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡m¡l-piperaz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acetyl]-4-fluoro-benzenesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dirriethyl¡lp¡peraz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)acetyl]-4-methoxy-benzenesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acetyl]-4-methyl-benzenesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡m¡l-piperaz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acetylj-benzenesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acetyl]-C,C,C-trifluoro-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acet¡l]-C-phenyl-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)acetylj-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)acetylj-sulfamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-pyridin-3¡l)-acetyl]-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-piperaz¡n-1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]methanesulfonamide ;

N-[3-(2-(2-[(2R)-2-Ethyl-4-(4-fluoro-benz¡l)-p¡peraz¡n-1 -yl]-2-oxo-ethoxy¡} -5-methyl-phenyl)-propion¡l]methanesulfonamide;

N-[3-(2-{2-[4-(4-Fluoro-benz¡l)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy¡} -5-methyl-phenyl)propionylj-methanesulfonamide;

N-[3-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy }-5-methyl-phenyl)propionylj-methanesulfonamide;

N-[3-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy }-phenyl)propionylj-methanesulfonamide;

N-[3-(3-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy }-6-methyl-pyridin-

2- ¡l)-propion¡l]-methanesulfonamide;

N-[3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl) propionylj-methanesulfonamide;

N-[3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methyl-p¡peraz¡n-1 -yl] -2-oxo-ethoxy}-phenyl)propionylj-methanesulfonamide;

N-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy }-phenyl)propionylj-methanesulfonamide;

N-[3-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl] -2-oxo-ethoxy}-phenyl)propionylj-methanesulfonamide;

N-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy }-pyridin-

3- yl)-propionyl]-methanesulfonamide;

N-Acetyl-5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡perazin-1 -¡l]- 2-oxo-ethoxy¡}benzenesulfonamide;

N-Acetyl-C-(2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-5 -trifluoromethyl phenyl)-methanesulfonamide;

N-Acetyl-C-(2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]- 2-oxo-ethoxy¡}-5-trifluoromethyl-phenyl)-methanesulfonamide;

N-Acetyl-C-(5-bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benz¡l)-p¡peraz¡n-1 -¡l]-2 -oxo-ethoxy¡}-phenyl)methanesulfonamide;

N-Acet¡lC-(5-bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)methanesulfonamide;

N-Acetyl-C-(5-bromo-2-(2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-p¡perazin-1 -yl]- 2-oxo-ethoxy¡}phenyl)-methanesulfonamide¡

N-Acet¡lC-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)methanesulfonamide;

N-Acetyl-C-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -ylJ-2-οχοethoxy}- phenyl)-methanesulfonamide;

N-Acetyl-C-(5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl )methanesulfonamide;

N-Acet¡lC-(5-chloro-2-2-[{4-(3,4-difluoro-benz¡l)-(2R)-2-methylp¡peraz¡n-1 -yl]- 2-oxo-ethoxy¡}phenyl)-methanesulfonamide;

N-Acet¡lC-(5-chloro-2-2-[{4-(3,4-d¡fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n -1-¡l]-2-oxoethoxy}-phenyl)-methanesulfonamide;

N-Acet¡lC-(5-chloro-2-2-[{4-(4-chloro-benz¡l)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)methanesulfonamide;

N-Acetyl-C-(5-chloro-2-2-[{4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo- ethoxy}phenyl)-methanesulfonamide;

N-Acetyl-C-(5-chloro-2-2-[{4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]-2-oxo- ethoxy}-phenyl)methanesulfonamide;

N-Acetyl-C-(5-chloro-2-2-[{4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -¡l]-2-oxo-ethoxy¡}phenyl)-methanesulfonamide;

[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo-ethoxy Propane-1-sulfonic acid }-phenyl)acetyl]-amide;

[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}- phenyl)acetyl]-amide of propane-2-sulfonic acid.

In one embodiment, the compound of formula I is:

(2-{2-[4-(4-Fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy¡}-5-trifluoromethyl-phenyl)methanesulfonamide;

Acid (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methyl-p¡peraz¡n-1 -yl]-3-oxo-propyl}- 5-methylphenoxy)-acetic;

(4-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyllpperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid ; (5-Bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)methanesulfonamide;

(5-Bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxoethoxy}phenyl)methanesulfonamide;

(5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benz¡l)-piperaz¡n-1 -yl]-2-oxo-ethoxy¡}-phenyl acid )-acetic;

Acid (5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-2-oxo-ethoxy}- phenyl)acetic;

(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-benzyloxy¡)acetyl methanesulfonamide;

Acid [(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethylamino}pyridine-3-carbonyl)-amino]-acetic;

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}phenoxy acid )-4-methyl-thiazole-5-carboxylic;

3-(2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -¡l]-2-oxo-ethoxy}-5 acid -methyl-phenyl)propionic;

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)acrylic acid;

3-[3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo- acid ethoxy}-phenyl)ureidoj-propionic;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4 acid -oxobutyric;

5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy} -phenoxy¡)-5-methyl-pyrimidine-2,4,6-trione;

6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -¡l]- acid 2-oxo-ethoxy¡}phenoxymethyl)-nicotinic;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl )-N-(3-hydroxy-3-methyl-butyryl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-N-hydroxyacetyl-methanesulfonamide;

N-[(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-4-methoxy¡ -phenyl)acetylj-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo -ethoxy}-phenyl)acetyl]-4-fluoro-benzenesulfonamide

In another embodiment, the compound of formula I is:

Acid (2S)-2-amino-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylpiperazine- 1-yl]-2-oxo-ethoxy}-phenoxy)-butyric acid;

(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo acid -ethoxy¡}phenoxy)-pyrrolidine-(2S)-2-carboxylic;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}benzylidenam¡ acid noox¡)-acetic;

Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo -ethoxy¡}phenoxy)-acetic;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethox ¡}benzylamino)-acetic;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}benzylsulfamoyl)- acid acetic;

1-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡l] -2oxo-ethoxy}-phenyl)-2-(1 H-tetrazol-5-yl)-ethanone;

3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methylp¡perazin-1-¡l]-2oxo- acid ethoxy}-phenyl)-acrylic

3-[3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-yl acid ]-2-oxo-ethoxy¡}phenyl)-ureido]-propion¡c;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxy)-pyridine-2-carboxylic;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}- acid phenyl)-

4-oxo-butyric;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡perazin-1-yl]-2-oxo acid -ethoxy}pyridin-3-ylamno)-butyric acid;

5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}- acid phenyl)-

5- oxo-pentanoic;

5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyllp¡peraz¡n-1 -yl]-2-oxo-ethoxy¡ acid } benzyldeneaminooxy)-acetic;

6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡} acid phenoxy)-nicotin¡co;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡l]-2oxo -ethoxy¡}-phenyl)-N-hydroxy¡acet¡l-methanesulfonamide;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1-¡l]-2-oxoethoxy¡}- phenyl)-acetyl]-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy }-phenyl)-acetyl]methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-¡l ]-2oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide; either

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine-1 -¡l]-2oxo-ethoxy¡ }-pyridin-3-yl)-acetyl]-methanesulfonamide;

In yet another embodiment, the compound of formula I is:

(2R)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-acid phenoxy)propionic;

(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo acid -ethoxy¡}phenoxy)-pyrrolidine-2-carboxylic;

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phen¡ l)-acetic acid;

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}phenylsulfamoyl) acid -acetic;

Acid 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡l]- 2-oxo-ethoxy¡}-phenyl)4-h id roxy-but-3-enó¡ co;

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}- acid phenyl)4-hydroxy-butyric acid,

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡perazin-1-yl]-2-oxo acid -ethoxy}-phenyl)but-3-enoic acid;

4-[2-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2 -oxo-ethoxy}-phenyl)-2oxo-ethyl]-isoxazolidine-3,5-dione;

4-[2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)-2-oxo-ethyl]-1,1-dioxo-[1,2,6]thiadiaz¡nano-3,5-dione;

5-[2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl] -2-oxo-ethoxy}-phenyl)-2-oxo-ethyl]-2-thioxo-dihydro-pyrimidine-4,6-dione;

5-[2-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl] -2-oxo-ethoxy}-phenyl)-2oxo-ethyl]-pyrimidine-2,4,6-trione;

5-[2-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 - yl]-2-oxo-ethoxy}-phenyl)-2oxo-ethyl]-2-imino-dihydro-pyrimidine-4,6-dione;

6- [2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 -oxo-ethoxy}-phenyl)-2oxo-ethyl]-[1,4]-diazepane-2,5,7-trione;

N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy acid }pindin-3-yl)-succinamic;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2oxo-ethoxy}-phenyl) -acet¡l]-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1 -yl]-2oxo -ethoxy}-phenyl)-acet¡l]-sulfamida;

N-Acetyl-C-(5-bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phen ¡l) methanesulfonamide;

N-Acetyl-C-(5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl )methanesulfonamide;

N-Acetyl-C-(5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin1 -¡l]-2-oxo-ethoxy }-phenyl)-methanesulfonamide; either

[(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡perazin-1 -yl]-2-oxo Propane-1-sulfonic acid -ethoxy}-phenyl)-acetyl]amide;

In another aspect, the present invention also relates to pharmaceutical compositions comprising an amount of a compound of formula I or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier.

Furthermore, another aspect of the present invention relates to the use of the aforementioned compounds of formula I wherein the use comprises administration of a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable form thereof, to a mammal for treating or preventing a disorder or condition selected from autoimmune diseases, lupus, acute and chronic inflammatory conditions, allergic conditions, inflammation associated with infection, viral, chronic bronchitis, xenotransplantation, rejection of transplanted tissue, atherosclerosis; restenosis, HIV infection, and granulomatous diseases.

In another aspect, the present invention relates to the use of compounds according to formula I, wherein the use comprises administration of a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable form thereof to a mammal. to treat or prevent a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal.

Furthermore, another aspect of the present invention relates to the use of compositions comprising compounds of Formula I or pharmaceutically acceptable forms thereof, wherein the use comprises administration of a pharmaceutically effective amount of the composition to a mammal to treat or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal.

It is to be understood that both the foregoing general description and the following detailed description are illustrative and explanatory only and are not restrictive of the invention, as claimed.

Detailed description of the invention

The present invention may be more readily understood by reference to the following detailed description of illustrative embodiments of the invention and the examples included therein.

Before the present compounds, compositions and methods are described, it is to be understood that this invention is not limited to specific and synthetic methods of carrying out which may of course vary. It is also to be understood that the terminology used in this document is solely for the utility of describing particular embodiments and is not intended to be limiting.

The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula I. The acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds in this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the salts Hydrochloride, Hydrobromide, Hydroiodide, Nitrate, Sulfate, Bisulfate, Phosphate, Acid Phosphate, Acetate, Lactate, Citrate, Acid Citrate, Tartrate, Bitartrate, Succinate, Maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (ie, 1,1'-methylene-bis-(2-hydroxy¡-3-naphthoate) salts).

The invention also relates to base addition salts of formula I. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds of formula I that are acidic in nature are those that form salts of non-toxic base with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (eg potassium and sodium) and alkaline earth metal cations (eg calcium and magnesium), ammonium or water soluble amino addition salts such as N-methylglucamine (meglumine), and lower alkanolammonium and other pharmaceutically acceptable organic amine base salts.

The compounds of this invention may contain olefin-type double bonds. When such linkages are present, the compounds of the invention exist as cis and after configurations and as mixtures thereof.

This invention also includes isotopically labeled compounds, which are identical to those described by Formula I, except that one or more atoms are changed to one or more atoms having specific atomic masses or mass numbers. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, and fluorine,

3 Ρ 14 15 18 17 18 such as Η, H, C, C, N, O, O, and F, respectively. Within the scope of this invention are the compounds of the present invention, prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs containing the aforementioned isotopes and/or other isotopes of other atoms. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes are incorporated such as³h and¹⁴C, are useful in drug and/or substrate tissue distribution assays. Particularly preferred for their ease of preparation and detectability isotopes of tritium (i.e.,³H), and carbon-14 (i.e.,¹⁴C). Also, substitution with heavier isotopes such as deuterium (i.e.,²H), may provide certain therapeutic advantages resulting from increased metabolic stability, eg increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. The isotopically labeled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures described in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a labeled reagent. not isotopically.

In this specification and in the claims that follow, reference will be made to a number of terms which will be defined to have the following meanings:

Unless otherwise indicated, alkyl as referred to herein can be linear or branched, and can also be cyclic (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) or bicyclic (for example, norbomannyl, bicyclo [3.2.1]octane) or contain cyclic groups. Alkyl includes alkyl radicals, generally known as alkylenes, including, but not limited to, methylene, ethylene, propylene, and the like. They may also contain zero to two levels of unsaturation and may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of, but not limited to: halo-, HO-, NC-, H₂N-, alkyl(Cj-Cr)-NH-, [alkyl(Cj-Cr)]N-, HO-(C=O)-, H₂N-(C=O)-.

As referred to herein, Alkenyl can be linear or branched, and can also be cyclic (eg cyclobutenyl, cyclopentenyl, cyclohexenyl) or bicyclic or contain cyclic groups. It contains carbon-carbon1-3 double bonds, which can be cis or trans. Alkenyl includes alkenyl radicals, generally known as alkylidienes, including, but not limited to, ethylidene, propylidene, and the like. Alkenyl groups can be optionally substituted by 1,2 or 3 substituents independently selected from the group consisting of, without limitation: halo-, HO-, NC-, H₂N-,alkyl(Ci-C₈)-, alkyl (C_rC.₈)-NH-, [alkyl (C_rC.₈)]N-, ΗΟ(C=O)-> H₂N-(C=O)-.

Aryl refers to phenyl or naphthyl which may be optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of but not limited to H-, HO-, halo-, alkyl (Ci-C₈)-, alkyl (Ci-C₈)-O-, HO- alkyl (Ci-C₈)-, NC-, H₂N-,alkyl(CrC₈)-NH-, [alkyl (CrC₈)]N-,H₂N-alkyl(C_rC.₈)-, HO-(C=O)-, HO-(C=O)-alkyl (C_rC.₈)-, alkyl (C_rC.₈)-(C=O), alkyl (Ci-C₈)-(C=O)-alkyl (CrC₈)-, H₂N-(C=O)-, H₂N-(C=O)- alkyl (C_rC.₈)-, H₂NSO₂-, or alkyl (Ci-C₈)-SW₂-NH-,

Unless otherwise indicated, halo or halogen includes fluoro, chloro, bromo, and iodo.

Heterocyclyl refers to but is not limited to lactone, lactam, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxy, chromenyl, barbituryl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, 1 ,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, l,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl , morpholinyl, l,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-lyl, tetrahydroazepinyl, piperazinyl, and chromanding. Said heterocyclyl group has at least one carbon atom, wherein the heteroatoms can be any combination of N, O, or S. Preferably, the heterocyclyl group is attached via a carbon or nitrogen atom and can be optionally substituted with 1 to 4 substituents independently selected from the group consisting of but not limited to Η-, HO, halo-, oxo-, HN=, alkyl (C_rC.₈)-, alkyl (C_rC.₈)-O-, HO-alkyl (C_rC.₈)-, NC-, H₂N-,alkyl(C_rC.₈)-NH-, [alkyl (Ci-C₈₎]N-,H₂N-alkyl(C_rC.₈)-, H0-(C=0)-, HO-(C=O)-alkyl (C_rC.₈)-, alkyl (C_rC.₈)-(C=O)-, alkyl (Ci-C₈)-(C=O)-alkyl (C_rC._g)-, H₂N-(C=0)-,H₂N-(C=O)-alkyl (C_rC.₈)-, H₂N-SW₂-, or alkyl (C_rC.₈)S02-NH-.

"Heteroaryl" refers to but is not limited to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4oxadiazolyl, 1,2,3-oxadiazolyl , 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1 ,3,5-triazinyl, pyrazolo[3,4bjpyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazollo, isoquinolyl, quinolyl , phthalazinyl, quinoxalinyl, quinazolinyl, and benzoxazinyl. Said heteroaryl group contains at least one carbon atom, in which the heteroatoms can be any combination of N, O, or S. Preferably, the heteroaryl group is attached through a carbon or nitrogen atom and can be optionally substituted with 1 to 4 substituents independently selected from the group consisting of but not limited to: H-, HO-, halo-, oxo-, HN= , alkyl (Ci-C₈)-, alkyl (Ci-C₈)-O-, HO-alkyl (Ci-C₈)-, NC-, H₂N-,alkyl(C_rC.₈)-NH-, [alkyl (0i-C₈)]N-,H₂N-alkyl(Ci-C₈)-, HO-(C=O)-, HO-(G=O)-alkyl (Ci-C₈)-, alkyl(CrC₈)-(C=O)-, alkyl (C-|-C₈)-(C=O)-alkyl(CrCs)-, H₂N-(C=O)-, H₂N-(C=O)-(C₁-C₈)alkyl-, H₂N-SW₂-, (CrCgjalkyl-SOs-NH-.

By pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, that is, the material can be administered to an individual without causing any substantially undesirable biological effect or interacting in a deleterious manner with any of the other components of a pharmaceutical composition. in which it can be contained.

Pharmaceutically acceptable forms as used herein refers to any pharmaceutically acceptable derivative or variation, including conformational isomers (for example, cis and trans isomers) and all optical (for example, enantiomers and diastereomers), racemic, diastereomeric, and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. By tautomers is meant chemical compounds that can exist in two or more different structural forms (isomers) in equilibrium, forms that differ, usually, in the position of a hydrogen atom. Several types of tautomerism can occur, including keto-enol, ring-chain, and ring-ring tautomerism.

The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise noted a, b, c, d, and R¹ through R⁶ and structural formula I in the Reaction Schemes and the discussion that follows are defined as above. R.⁷ refers to an amino radical which can be unsubstituted, monosubstituted, disubstituted, cyclic or acyclic.

The reactions in the Preparations and Schemes are described in co-pending, commonly assigned US patent application No.^Q. 09/821322, filed March 29, 2001, and co-pending provisional patent application No.^Q. 60/241804 filed October 19, 2000, the disclosures of which are incorporated herein by reference in their entirety for all purposes.

PREPARATION A

<img file="ECSP045073A_D0003.tif" />

<img file="ECSP045073A_D0004.tif" />

IV.

<img file="ECSP045073A_D0005.tif" />

<img file="ECSP045073A_D0006.tif" />

<img file="ECSP045073A_D0007.tif" />

<img file="ECSP045073A_D0008.tif" />

PREPARATION Β (R⁵)dh₃co-y' X

SW₂IC

V(R=)dh₃co—y' so₂r⁷

XI(R)⁵)d

Today'

SW₂R.⁷

twelfth

PREPARATION Ch₃co—(R)⁵)d

<img file="ECSP045073A_D0009.tif" />

thirteenth hour₃co(R)⁵)d

<img file="ECSP045073A_D0010.tif" />

fourteenth hour₃co&lt;R⁵)d

<img file="ECSP045073A_D0011.tif" />

fifteenth h₃co3(R®)d

<img file="ECSP045073A_D0012.tif" />

16th

H&lt;R^yes)d

<img file="ECSP045073A_D0013.tif" />

seventeenth

PREPARATION D h₃co

XVIII co₂ch₃ h₃co-

<img file="ECSP045073A_D0014.tif" />

XIX

ooh

XXIII

HjCO----'

<img file="ECSP045073A_D0015.tif" />

XX

CN

<img file="ECSP045073A_D0016.tif" />

h₃CO----'

<img file="ECSP045073A_D0017.tif" />

co₂h

XXI

Scheme 1

<img file="ECSP045073A_D0018.tif" />

<img file="ECSP045073A_D0019.tif" />

Scheme 2

<img file="ECSP045073A_D0020.tif" />

Scheme 3

<img file="ECSP045073A_D0021.tif" />

<img file="ECSP045073A_D0022.tif" />

χχνι

<img file="ECSP045073A_D0023.tif" />

Scheme 4

<img file="ECSP045073A_D0024.tif" />

<img file="ECSP045073A_D0025.tif" />

<img file="ECSP045073A_D0026.tif" />

<img file="ECSP045073A_D0027.tif" />

<img file="ECSP045073A_D0028.tif" />

Scheme 5

<img file="ECSP045073A_D0029.tif" />

<img file="ECSP045073A_D0030.tif" />

χχιχ (R^yes)d

<img file="ECSP045073A_D0031.tif" />

Yo

Scheme 6

<img file="ECSP045073A_D0032.tif" />

<img file="ECSP045073A_D0033.tif" />

Scheme 7

<img file="ECSP045073A_D0034.tif" />

v

<img file="ECSP045073A_D0035.tif" />

In reaction 1 of Preparation A, the compound of formula II in which b is 0,1 or 2, is converted to the corresponding compound of formula III by reaction of II with a benzaldehyde compound of formula:

<img file="ECSP045073A_D0036.tif" />

H in the presence of a base, such as triethylamine, and a reducing agent, such as sodium triacetoxyborohydride, in an aprotic solvent, such as 1,2-dichloroethane. The reaction mixture is stirred at room temperature for a period of from about 1 hour to about 4 hours, preferably about 2 hours.

In reaction 2 of preparation A, the compound of formula III is converted to the corresponding compound of formula IV by first reacting a compound of formula:

EITHER

<img file="ECSP045073A_D0037.tif" />

wherein c is 0, 1 or 2, with 4-methyl morpholine and isobutylchloroformate in the presence of a polar aprotic solvent, such as tetrahydrofuran, followed by reaction of the intermediate so formed with the compound of formula III. The reaction mixture thus formed is stirred overnight at room temperature.

In reaction 3 of preparation A, the compound of formula IV is converted to the corresponding piperizine-2,5-dione compound of formula V by treating IV with trifluoroacetic acid in the presence of a polar aprotic solvent, such as methylene chloride. The reaction is stirred, at room temperature, for a period of time from about 1 hour to about 4 hours, preferably about 2 hours.

In reaction 4 of preparation A, the compound of formula V is converted to the corresponding compound of formula VI by reducing V with a reducing agent, such as lithium aluminum hydride. The reaction is carried out at a temperature between about -10°C to about 10°C, preferably about 0°C, for a period of time between about 10 minutes to about 90 minutes, preferably about 40 minutes.

In reaction 5 of the preparation the compound of formula VI is converted to the corresponding compound of formula VI by reacting VI with chloroacetyl chloride in the presence of a base, such as triethylamine, in a polar aprotic solvent, such as methylene chloride, to room temperature for a period of time between 15 minutes and 3 hours, preferably about 30 minutes.

In reaction 6 of preparation A, the compound of formula VI is converted to the corresponding compound of formula VIII by reacting VI with acetoxy acetyl chloride in the presence of a base, such as triethylamine, in a polar aprotic solvent, such as sodium chloride. methylene, at room temperature for a period of time between 15 minutes and 4 hours, preferably about 1 hour. The resulting acetyl protected alcohol is reacted with lithium hydroxide hydrate in a mixed solvent including water, tetrahydrofuran and methanol, at room temperature for a period of between 1 hour and 8 hours, preferably about 2 hours.

In reaction 7 of the preparation the compound of formula VI is converted to the corresponding compound of formula IX by reacting VI with N-(-t-butoxycarbonyl)glycine in the presence of a base, such as dimethylaminopyridine and a coupling reagent, such as 1(3-dimethylaminopropyl)-3-ethylcarbodiimine, in a polar aprotic solvent, such as methylene chloride, at room temperature for a period of time between 4 hours and 18 hours, preferably about 12 hours. The resulting N-(t-butoxycarbonyl) protecting group-containing compound is reacted with trifluoroacetic acid in a polar aprotic solvent, such as methylene chloride, at room temperature for a period of between 30 minutes and 6 hours, preferably of approximately 2 hours.

One skilled in the art will recognize that Preparation A allows access to the various isomers, diastereomers and enantiomers of formula VI. In particular, Preparation A can be used to prepare compounds with the preferred stereochemistry as described in the formula:

<img file="ECSP045073A_D0038.tif" />

Via

In reaction 1 of the preparation the compound of formula X is converted to the corresponding compound of formula XI by reacting X with an appropriate amino in the presence of a polar aprotic solvent, such as tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of from about 1 hour to about 24 hours, preferably about 12 hours.

In reaction 2 of preparation B, the compound of formula XI is converted to the corresponding compound of formula XII by reacting XI with thiophenol in the presence of a base, such as sodium hydride, and a polar aprotic solvent, such as dimethylformamide. The reaction is refluxed for a period of time from about 1 hour to about 10 hours, preferably about 4 hours.

In Reaction 1 of Preparation C the compound of formula XIII, where e is 1-4, is converted to the corresponding compound of formula XIV by first converting the hydroxyl group to a chloro group by reacting XIII with thionyl chloride, in the presence of a aprotic solvent, such as methylene chloride. The reaction is heated to reflux, for a period of time from about 1 hour to about 10 hours, preferably about 3 hours. The resulting alkyl chloride is then treated with thioacetic acid in the presence of a base, such as cesium carbonate, in a polar aprotic solvent, such as dimethylformamide at room temperature for a period of time between 6 hours and 24 hours, preferably from about 12 hours.

In reaction 2 of Preparation C, the compound of formula XIV is converted to the corresponding compound of formula XV by reacting XIV with hydrogen peroxide (aqueous solution) in acetic acid at room temperature for a period of between 6 hours and 24 hours, preferably about 12 hours.

In reaction 3 of Preparation C, the compound of formula XV is converted to the corresponding compound of formula XVI by first reacting XV with phosphorus pentachloride in an aprotic solvent, such as toluene, at room temperature to reflux, preferably at reflux. for a period of time between 1 hour and 8 hours, preferably 3 hours to give the corresponding sulfonyl chloride. The sulfonyl chloride is then reacted with an appropriate amino in a polar aprotic solvent, such as tetrahydrofuran, at room temperature for a period of between 3 hours and 24 hours, preferably 12 hours.

In reaction 4 of preparation C the compound of formula XVI is converted to the corresponding compound of formula XVII according to the procedure described in reaction 2 of preparation B.

In reaction 1 of preparation D, the compound of formula XVIII is converted to the corresponding compound of formula XIX by treating XVIII with a reducing agent, such as lithium aluminum hydride, in an aprotic solvent, such as tetrahydrofuran. The reaction mixture is heated under reflux for a period of between 1 hour and 6 hours, preferably approximately 2 hours.

In reaction 2 of preparation D, the compound of formula XIX is converted to the corresponding compound of formula XX by first converting the hydroxyl group to a chloro group by reacting XIX with thionyl chloride, in the presence of an aprotic solvent, such as sodium chloride. methylene. The reaction is heated to reflux, for a period of time from about 1 hour to about 10 hours, preferably about 3 hours. The resulting alkyl chloride is then treated with a cyanide source, such as potassium cyanide, in the presence of an aprotic solvent, such as acetonitrile and a crown ether, such as 18-crown-6. The reaction mixture is stirred at room temperature for a period of from about 1 hour to about 10 hours, preferably about 3 hours.

In reaction 3 of preparation D, the compound of formula XX is converted to the compound of formula XXI by treating XX with a hydroxide source, such as potassium hydroxide in a mixture of ethanol and water. The reaction mixture is heated under reflux for a period of time from about 1 hour to about 10 hours, preferably about 8 hours.

In reaction 4 of preparation D, the compound of formula XXI is converted to the compound of formula XXII, where f is 1, by first demethylating the methyl ether by treatment with acid, such as 47% aqueous hydrogen bromide. . The reaction mixture is heated under reflux for a period of from about 10 hours to about 30 hours, preferably about 24 hours. The phenolic acid is finally converted to the corresponding compound of formula XXII, where f is 1, by treatment with ethanol in the presence of an acid, such as hydrochloric acid, at room temperature for a period of time of from about 8 hours to about 16 hours, preferably about 12 hours.

In reaction 5 of Preparation D, the compound of formula XIX is converted to the corresponding compound of formula XXIII by treating XIX with an oxidizing agent, such as Dess-Martin periodinan, in the presence of an aprotic solvent, such as tetrahydrofuran at room temperature for a period of time from about 1 hour to about 16 hours, preferably about 4 hours.

In reaction 6 of preparation D, the compound of formula XXIII is converted to the corresponding compound of formula XXII where f is 2-8, by treating XXIII with a phosphonium ylide derivative derived from the phosphonium salt of formula:

either.

crphgP^ γ o

where g is 1-7, in the presence of an aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between -78^QC and reflux, the preferred temperature depends on the phosphonium iylide being used, for a period of time from about 4 hours to about 16 hours, preferably about 10 hours (for similar transformations, see: J. Am. Chem. Soc. 1985, 107, 217). The resulting olefin ester is then hydrogenated by stirring under positive hydrogen pressure in the presence of a catalyst, such as platinum dioxide, in the presence of an aprotic solvent such as ethyl acetate. The methyl ether is then deprotected according to the procedure described in reaction 2 of preparation B.

In reaction 1 of Scheme L the compound of formula VI is converted to the corresponding compound of formula I by reacting VI with a compound of formula HO-(C=O)-CH₂-XY[(R⁵)d](R⁴), in the presence of a base, such as 4-dimethylaminopyridine, and a coupling reagent, such as 1 -(3-dimethylaminopropyl)-3-ethylcarbodimine, in a polar aprotic solvent, such as methylene chloride. The reaction is stirred at room temperature for a period of time between 4 hours and 24 hours, preferably about 12 hours. Alternatively, the compound of formula VI is converted to the corresponding compound of formula I by first reacting VI with a compound of formula:

<img file="ECSP045073A_D0039.tif" />

in the presence of an aprotic solvent, such as toluene, at a temperature between room temperature and reflux, preferably reflux, for a period of time between about 4 hours to 18 hours, preferably about 12 hours. The phenol thus formed can then be converted into compounds of formula I by usual reactions for those skilled in the art.

In reaction 1 of Scheme 2^ the compound of formula Vil is converted to the corresponding compound of formula XXIV by reacting Vil with a compound of formula, H-XY[(R⁵)_d](NO₂) wherein X is -0-, -S-, or -NH- in the presence of potassium carbonate, potassium iodide and an aprotic solvent, such as butanone. The reaction is heated at reflux for a period of time from about 4 hours to about 8 hours, preferably about 6 hours.

In reaction 2 of Scheme the compound of formula XXIV is converted to the corresponding compound of formula XXV by hydrogenating XXIV in the presence of a catalyst, such as platinum or carbon, and a polar protic solvent, such as ethanol. The reaction is carried out under a pressure between approximately 30 psi (2.1 kg/cm²) at approximately 40 psi (2.8 kg/cm²), preferably about 35 psi (2.45 kg/cm²), for a period of time from about 5 minutes to about 1 hour, preferably 30 minutes.

In reaction 3 of Scheme the compound of formula XXV is converted to the corresponding urea of ​​formula I by first reacting XXV with 4-nitrophenyl chloroformate in the presence of a base, such as pyridine, and a polar aprotic solvent, such as sodium chloride. methylene, followed by reaction of the intermediate so formed with an appropriate amine or sulfonamide. The reaction mixture thus formed is allowed to stir overnight at room temperature. The compound of formula XXV is reacted with an appropriate sulfonyl chloride to form the corresponding sulfonamides of formula I, in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as methylene chloride. The reaction is stirred overnight at room temperature. For the formation of a secondary amine of formula I, the compound of formula XXV is reacted with an appropriate aldehyde in the presence of a base, such as triethylamine, and a reducing agent, such as sodium triacetoxyborohydride, in an aprotic solvent, such as 1,2-dichloroethane. The reaction mixture is stirred at room temperature for a period of from about 1 hour to about 12 hours, preferably about 10 hours.

In reaction 1 of Scheme the compound of formula VII is converted to the corresponding compound of formula XXVI where h is 0-3 according to the procedure described above in reaction 1 of Scheme 2.

In reaction 2 of Scheme 3 the compound of formula XXVI is converted to the corresponding amino of formula I by reacting XXVI with an appropriate amino in the presence of a 10:1 dichloroethane/acetic acid solution. The reaction mixture is stirred, at room temperature, for a period of time from about 30 minutes to about 2 hours, preferably about 1 hour. A reducing agent, such as sodium cyanoborohydride, is then added to the mixture and the reaction is allowed to stir overnight at room temperature. If the amine so formed is primary or secondary, the compound of formula I can be further reacted according to the procedure described above in reaction 3 of Scheme to provide ureas or sulfonamides. The compound of formula XXVI is converted to the corresponding oxime of formula I by reacting XXVI with an appropriate alkoxyamine in the presence of a base, such as triethylamine, and a polar protic solvent, such as methanol, at a temperature between 0^QC and reflux, preferably at room temperature, for a period of time between 1 hour and 8 hours, preferably about 3 hours.

In reaction 1 of Scheme 4 the compound of formula Vil is converted to the corresponding compound of formula XXVII by reacting Vil with a compound of the formula, H-XY[(R⁵)_d](CH₂) CO₂Et, wherein X is -0-, -S-, or -NH- and i is 0 - 3, according to the procedure described in reaction 1 of Scheme 2.

In reaction 2 of Scheme 4, the compound of formula XXVII is converted to the corresponding compound of formula XXVIII by reacting XXVII with a reducing agent, such as sodium borohydride, in a polar protic solvent, such as methanol, at room temperature for a period of time from about 1 hour to about 10 hours, preferably about 3 hours.

In reaction 3 of Scheme 4 the compound of formula XXVIII is converted to the corresponding ether of formula I by first converting XXVIII to the corresponding alkyl chloride as described in reaction 2 of preparation D. The alkyl chloride is then reacted with a appropriate alcohol that has previously reacted with a strong base, such as NaH, in a polar aprotic solvent, such as dimethylformamide at a temperature of between about -10-C to about 10^QC, preferably about 0^QC, for a period of time from about 10 minutes to about 90 minutes, preferably about 40 minutes. The alkyl chloride is stirred with the resulting alkoxide at room temperature for a period of from about 3 hours to about 24 hours, preferably about 12 hours. The compound of formula XXVIII is converted to the corresponding carbamate of formula I by reacting XXVIII with an appropriate isocyanate in the presence of a base, such as triethylamine, in an aprotic solvent, such as toluene, at room temperature for a period of between 4 hours and 24 hours, preferably about 12 hours. The compound of formula XXVIII is converted to the corresponding acylsulfamide of formula I by first reacting XXVIII with a BOC-protected sulfamide, such as tert-butoxycarbonylsulfamide in the presence of triphenylphosphine and diethylazodicarboxylate in a polar aprotic solvent, such as tetrahydrofuran. The reaction is initially carried out at a temperature between -100°C and 0°C, preferably at approximately -60°C for a period of time of approximately 15 minutes, then slowly warms to between 10°C and room temperature. ambient for a period of time between 1 hour and 8 hours, preferably about 2 hours. The resulting BCO-protected sulfonamide is reacted with an acyl chloride in the presence of a base, such as triethyl amine and/or dimethylpyridine in a polar aprotic solvent, such as dichloromethane. The reaction is stirred at a temperature between 0^Qc and 40^QC, preferably at room temperature for a period of time from 8 hours to 24 hours, preferably about 18 hours. The BOC-protected acylsulfamide so formed is treated with a strong acid, such as trifluoroacetic acid, in a polar aprotic solvent, such as dichloromethane, at room temperature for a period of time between 1 hour and 6 hours, preferably about 3 hours. hours, thus giving compounds of formula I.

In reaction 4 of Scheme 4, the compound of formula XXVII is converted to the corresponding compound of formula I by reacting XXVII with lithium hydroxide monohydrate in the presence of methanol, tetrahydrofuran and water to give the corresponding carboxylic acid. The reaction mixture is stirred at room temperature for a period of between 8 and 24 hours, preferably 12 hours. The carboxylic acid is converted to the corresponding acylsulfonamide of formula I by reacting the carboxylic acid with an appropriate sulfonamide in the presence of a base, such as 4-dimethylaminopyridine, and a coupling reagent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine. , in a polar aprotic solvent, such as methylene chloride. The reaction is stirred at room temperature for a period of time between 4 hours and 24 hours, preferably about 12 hours. The carboxylic acid is converted to the corresponding acylsulfamide of formula I by reacting the carboxylic acid with chlorosulfonyl isocyanate in a polar aprotic solvent, such as 1,2-dichloroethane, at room temperature to reflux, preferably room temperature, for a period of time. between 8 and 24 hours, preferably about 12 hours, to give a compound of the formula:

<img file="ECSP045073A_D0040.tif" />

which is then reacted with an appropriate amine in a polar aprotic solvent, such as tetrahydrofuran, at room temperature for a period of between 4 hours and 24 hours, preferably about 12 hours.

In reaction 1 of Scheme the compound of formula Vil is converted to the corresponding compound of formula XXIX by reacting Vil with a compound of formula, H-XY[(R⁵)d](CH₂)]SW₂NH₂, where X is -0-, -S-, or -NR⁶- yj is 0-4, according to the procedure described in reaction 1 of Scheme 2.

In reaction 2 of Scheme 5 the compound of formula XXIX is converted to the corresponding acyl sulfonamide of formula I by reacting XXIX with an appropriate carboxylic acid in the presence of a base, such as 4-dimethylaminopyridine, and a coupling reagent, such as 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimine, in a polar aprotic solvent, such as methylene chloride. The reaction is stirred at room temperature for a period of time between 4 hours and 24 hours, preferably about 12 hours. The compound of formula XXIX is converted to the corresponding sulfonylurea of ​​formula I by reacting XXIX with an appropriate isocyanate in the presence of a base, such as 1,8-diazobicyclo[5.4.0]undec-7-ene and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature to reflux, preferably reflux for a period of 6 hours to 24 hours, preferably about 12 hours. The compound of formula XXIX is converted to the corresponding sulfonyl carbamate of formula I by reacting XXIX with an appropriate chloroformate in the presence of a base, such as 1,8-diazobicyclo[5.4.0]undec-7-ene and a polar aprotic solvent. , such as tetrahydrofuran. The reaction is stirred at room temperature to reflux, preferably reflux for a period of 6 hours to 24 hours, preferably about 12 hours. The compound of formula XXIX is converted to the corresponding alkylated sulfonamide of formula I by first treating compound XXIX with di-t-butyl dicarbonate in the presence of a base such as triethylamine and 4-dimethylaminopyridine in a polar aprotic solvent such as dichloromethane. The resulting Nt-butyloxycarbonyl protected sulfonamide is then treated with an alkyl halide in the presence of a polar aprotic solvent, such as dimethylformamide. The Nt-butyloxycarbonyl protected secondary sulfonamide is then deprotected by treating with an acid, such as trifluoroacetic acid in the presence of a polar solvent such as dichloromethane.

In reaction 1 of Scheme 6, the compound of formula VIII is converted to the corresponding compound of formula I by reacting VIII with a strong base, such as sodium hydride, in an aprotic solvent, such as toluene, at a temperature between about -10^QC and an ambient temperature, preferably around 0²C for a period of time between 15 minutes and 90 minutes, preferably about 30 minutes. To this is added a compound of formula CI-Y[(R⁵)_d](R⁴) where Y is a (C1-C9)heteroaryl in which chlorine is attached to a carbon atom that is adjacent to a heteroatom (eg, 2-pyridyl). The reagents are stirred at room temperature to reflux, preferably at room temperature for a period of time between 8 hours and 24 hours, preferably 12 hours.

In reaction 1 of Scheme 7 the compound of formula IX is converted to the corresponding compound of formula I where R⁶ is H-, by reacting IX with a compound of formula ClY[(R⁵)d](R⁴) where Y is a heteroaryl (Cj-Cg) in which chlorine is attached to a carbon atom that is adjacent to a heteroatom (for example, 2-pyridyl). The reagents are stirred in a polar aprotic solvent, such as acetonitrile, in the presence of a base, such as triethylamine, at reflux temperature for a period of time between about 4 hours and 24 hours, preferably about 12 hours. The compound of formula I where R⁶ es bise becomes the compound of formula I where R⁶ is an alkyl group reacting the compound of formula I where R⁶ is H- with an appropriate alkyl halide in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as tetrahydrofuran at room temperature to reflux, preferably at room temperature for a period of 8 hours to 24 hours, preferably about 18 hours. The compound of formula I where R⁶is H- becomes the compound of formula I where R⁶ together with the nitrogen to which it is attached forms an amide, reacting the compound of formula I where R⁶ is H- with an appropriate carboxylic acid in the presence of a base, such as 4-dimethylaminopyridine, and a coupling reagent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine, in a polar aprotic solvent, such as methylene chloride. The reaction is stirred at room temperature for a period of time between 4 hours and 24 hours, preferably about 12 hours. The compound of formula I where R⁶ is H- becomes the compound of formula I where R⁶ together with the nitrogen to which it is attached forms a urea, reacting the compound of formula I where R⁶ is H- with an appropriate isocyanate in the presence of base, such as triethylamine, and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature to reflux, preferably reflux, for a period of 4 hours to 18 hours, preferably about 12 hours. The compound of formula I where R⁶ is H- becomes the compound of formula I where R⁶ together with the nitrogen to which it is attached forms a carbamate, reacting the compound of formula I where R⁶ is H- with an appropriate chloroformate in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature to reflux, preferably reflux, for a period of 4 hours to 18 hours, preferably about 12 hours. The compound of formula I where R⁶ is H- becomes the compound of formula I where R⁶ together with the nitrogen to which it is attached forms a sulfonamide, reacting the compound of formula I where R⁶is H- with an appropriate sulfonyl chloride in the presence of base, such as triethylamine, and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature to reflux, preferably reflux, for a period of 4 hours to 18 hours, preferably about 12 hours.

Unless otherwise indicated, the pressure of each of the above reactions is not critical. Generally, reactions will be carried out at a pressure of from about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).

Compounds of formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the compound free base by treatment with an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, a solid salt is obtained.

The acids that are used to prepare the pharmaceutically acceptable acid addition salt of the base compounds of this invention are those which form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions, such as salts of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate (ie, 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts).

These compounds of formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of formula I described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, it can also be prepared by mixing lower alkanes solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In each case, stoichiometric amounts of reagents are preferably employed to ensure completion of the reaction and maximum product yields.

The compounds of formula I and their pharmaceutically acceptable salts (also referred to hereinafter, collectively, as the "active compounds") are potent antagonists of the CCR1 receptor. The active compounds are useful in the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I (new onset) diabetes, lupus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis. ), acute and chronic inflammatory conditions (such as osteoarthritis, Adult Respiratory Distress Syndrome, Childhood Respiratory Distress Syndrome, ischemia, reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection-associated inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre Syndrome), chronic bronchitis, xenotransplantation, rejection of tissue transplantation (chronic and acute), organ rejection (chronic and acute), atherosclerosis, restenosis (including, but not limited to, restenosis following balloon and/or insertion stents), HIV infection (co-receptor use), and granulomatous diseases (including sarcoidosis, leprosy, and tuberculosis) and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also have utility for the prevention of cancer metastasis. Compounds in this series may also limit cytokine production at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreased cellular infiltration, providing benefit for TNF and IL-1-related diseases that includes congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV3; cytomegalovirus (CMV), adenovirus, Herpes virus (Herpes zoster and Herpes simplex). They may also provide benefit for infection-associated sequelae where such infection induces the production of detrimental inflammatory cytokines such as TNF eg, fungal meningitis, junctional injury, hyperplasia, synovial pannus formation and bone resorption, psoriatic arthropathy, insufficiency liver disease, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, Lyme disease, septic shock, cancer, trauma, and malaria, etc

The activity of the compounds of the invention can be ascertained according to procedures known to those of ordinary skill in the art. Examples of recognized procedures for determining induced migration of CCR1 can be found in Coligan, JE, Kruisbeek, AM, Margulies, DH, Shevach, EM, Strober, W. eds: Current Protocols In Immunology, 6.12.1-6.12.3. (John Wiley and Sons, NY, 1991). A specific example of how to determine the activity of a compound inhibiting migration is described in detail below:

Chemotaxis Assay:

The ability of compounds to inhibit chemotaxis to various chemokines can be assessed using standard 48 or 96 well Boyden Chambers with a 5 micron polycarbonate filter. All reagents and cells can be prepared in standard RPMI tissue culture medium (BioWhitikker Inc.) supplemented with 1 mg/ml bovine serum albumin. Briefly, MIP-1a (Peprotech, Inc., PO Box 275, Rocky Hill NJ) or other test agonists, are placed in the Inferior chambers of the Boyden chamber. A polycarbonate filter is then applied and fed into the upper chamber. The amount of agonist chosen is that determined to give the maximum amount of chemotaxis in this system (for example, 1 nM for

MIP-1 a should be adequate.

THP-1 cells (ATCC TIB-202), first order human monocytes, or first order lymphocytes, isolated by standard techniques can then be added to the upper chambers in triplicate along with various concentrations of test compound. Compound dilutions can be prepared using standard serological techniques and mixed with cells before adding to the chamber.

After a suitable incubation period of 37 degrees Celsius (for example,

3.5 hours for THP-1 cells, 90 minutes for first order monocytes), the chamber is removed, the cells in the upper chamber are aspirated, the top of the filter is cleaned and the number of migrating cells can be determined according to the following procedure.

For THP-1 cells, the chamber (a 96-well variety manufactured by Neuroprobe) can be centrifuged to force cells out of the lower chamber and cell number can be quantitated against a standard curve by a color change of diacetate marker. of fluorocein.

For first order human monocytes, or lymphocytes, the filter can be stained with Dif Qulk® stain (Amerlcan Scientific Products) and the number of migrating cells can be determined microscopically.

The number of cells migrating in the presence of compound is divided by the number of cells migrating in control wells (without compound). The coefficient is the % inhibition for the compound which can then be plotted using standard graphical techniques against the concentration of compound used. The 50% inhibition point is then determined using linear regression analysis for all concentrations tested. The linear fit for all data points must have a correlation coefficient (square root of R) of >90% for the assay to be considered valid.

All the compounds of the invention illustrated in the following examples had a

CI₅₀ less than 10 μΜ, in the chemotaxis assay.

The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal administration or in a form indicated for administration by inhalation or insufflation. The active compounds of the invention may also be formulated for sustained release.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared in conventional ways with pharmaceutically acceptable excipients such as binding agents (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); loads (for example_TO lactose, microcrystalline cellulose or calcium phosphate); lubricants (eg magnesium stearate, talc or silica); disintegrants (eg potato starch or sodium glycolate starch); or wetting agents (eg sodium lauryl sulfate). Tablets can be coated by procedures well known in the art. Liquid preparations for oral administration can be taken in the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product to be constituted with water or other indicated vehicle before use. Such liquid preparations can be prepared in conventional ways with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, methyl cellulose, or hydrogenated edible fats); emulsifying agents (eg lecithin or acacia); non-aqueous vehicles (eg almond oil, and oily esters or ethyl alcohol); and preservatives (eg, methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of conventionally formulated tablets or lozenges.

The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional characterization techniques, or infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. Compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and they may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder for constitution with an indicated vehicle, eg, sterile, pyrogen-free water, prior to use.

The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as coconut oil or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered as a solution or suspension from a pump spray container that is pressed or pumped by the patient or as an aerosol spray presentation from a container. pressurized or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other indicated gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a fixed amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and an indicated powder base, such as lactose or starch.

A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to an average adult human for the treatment of the conditions referred to above (for example, rheumatoid arthritis) is 0.1 to 1,000 mg of the active ingredient per dose. unit that could be administered, for example, 1 to 4 times a day.

Aerosol formulations for the treatment of the conditions referred to above (eg, rheumatoid arthritis) in the average adult human are preferably established such that each fixed dose or puff of aerosol contains from 20 µg to 1,000 gg of the compound of the invention. The general daily dose with an aerosol will be in the range of 0.1 mg to 1,000 mg. The administration can take place several times a day, eg 2, 3, 4 or 8 times giving eg 1, 2 or 3 doses each time.

Active agents can be formulated for sustained release according to procedures well known to those of ordinary skill in the art. Examples of such formulations can be found in US Patents 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397 all of which are incorporated herein in their entirety for all purposes.

The compounds of the invention can also be used in combination therapy with other therapeutic agents such as Ciclosporin A, ISAtx47, Rapamicin, Everolimus, FK.-506, Azathioprine, Mycophenolate mofetil, Mycophenolic acid, Daclizumab, Basiliximab, Muromonab, horse antithymocyte globulin , polyclonal rabbit anti-thymocyte globulin, Leflunomide, FK-778 (MNA-715), FTY720, BMS-188667 (CTLA4-Ig), RG-1046 (CTLA4-Ig), Prednisone, Prednisolone, Methylprednisolone suleptanate, Cortisone, Hydrocortisone, Methotrexate, Sulfasalazine, Etanercept, Infliximab, Adalimumab (D2E7), CDP-571, CDP-870, Anakinra, NSAIDS (aspirin, acetaminophen, naproxen, ibuprofen, ketoprofen, diclofenac, and piroxicam), COX-2 inhibitors ( Celecoxib, Valdecoxib, Rofecoxib, Parecoxib, Etoricoxib, L-745337, COX-189, BMS-347070, S-2474, JTE-522, CS-502, P-54, DFP), Anti-interleukin-receptor monoclonal antibody 6 (MRA), Glatiramer Acetate, Interferon beta 1-a, Interferon beta 1-b, Mitoxantrone, Pimecrolimus, or agents that inhibit cellular recruitment mechanisms (eg, inhibitors of integrin regulation or function) or other leukocyte trafficking.

experimental part

The following examples are set forth so as to provide those of ordinary skill in the art with a development and description of how the compounds, compositions, and processes claimed herein are made and evaluated, and are intended to be purely illustrative of the invention and they are not intended to limit the scope of the inventors with respect to their invention. Unless otherwise indicated, percentage is the percentage by weight given to the component and to the total weight of the composition, the temperature is in²C o is at room temperature, and pressure is at or near atmospheric pressure. Commercial reagents were used without further purification. Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Particle Beam Mass Spectra were acquired with a Hewlett Packard 5989®, using chemical ionization (ammonium), or a Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) platform using a 50/50 mixture of acetonite/water. Ambient or room temperature refers to 2025⁵C. All non-aqueous reactions were performed under a nitrogen atmosphere for convenience and to maximize yields. Concentration in vacuo means that a rotary evaporator was used. The names for the compounds of the invention were created with the Autonom 2.0 PC-batch version of Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4)

Example 1

N-[(2-{3-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-d¡methyl-DIderaz¡n-1-yl]-3-oxo-DroD¡ll -5-methyl-phenoxy¡)acetyl-methanesulfonamide

(S)-2-(4-Fluoro-benzylamino)-propionic acid methyl ester

To a solution of (S)-2-amino-propionic acid methyl ester hydrochloride (25 g, 179 mmol) and 4-fluorobenzaldehyde (23 mL, 215 mmol) in 1,2-dichloroethane (200 mL) is triethylamine (25 mL, 179 mmol) was added. The resulting mixture was stirred for two hours at room temperature followed by the addition of sodium triacetoxyborohydride (57 g, 268 mmol) in four portions. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with dilute aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (34.4 g).

(2S)-2-fi2R)-2-tert-Butoxycarbonylamino-propionyl)-(4-tluoiObenziDaminol-propionic acid methyl ester

To a solution of (R)-2-tert-butoxycarbonylaminopropionic acid (37 g, 195 mmol) in dry tetrahydrofuran (250 mL) at 0²C 4-methyl morpholine (21.5 mL, 195 mmol) was added followed by isobutyl chloroformate (25.3 mL, 195 mmol). The reaction was allowed to warm to room temperature and stirred for two hours. This was followed by the addition of (S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a celite pad and the filter cake washed with ethyl acetate. The filtrate was concentrated in vacuo, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (43.2 g).

(3R,6S)-l-(4-Fluoro-benz¡l)-3,6-d¡met¡lp¡peraz¡na-2,5-dione

To a solution of (2S)-2-[(2R)-(2-tert-butoxycarbonylaminopropion¡l)-(4-fluoro-benzyl)-amino]-prop¡onic acid methyl ester (43 g, 382 mmol) in dichloromethane (120 mL) at 0²C trifluoroacetic acid (60 ml) was added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was cooled to 0²C and slowly quenched by addition of 3N sodium hydroxide to basic pH. The resulting mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (22g).

(2R-5S)-1-(4-Fluoro-benzyl)-2_he5-d¡me¡lp¡oeraz¡na

To a solution of (3R,6S)-1 -(4-fluoro-benzyl)-3,6-dimethyl-piperazine-2,5-dione (22 g, 87.9 mmol) in dry tetrahydrofuran (160 mL) at 0²C A solution of lithium aluminum hydride (1M in tetrahydrofuran, 373 mL, 373 mmol) was added dropwise over 40 minutes. The reaction mixture was then heated at reflux for 4 hours, cooled to room temperature, and slowly quenched with water. The resulting mixture was filtered through a celite pad and the filter cake washed with ethyl acetate. The filtrate was then concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (17.7g).

l-[4-(4-Fluoro-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-l-ill-3-(2-hidiOxy-4-methyl-phenyl)-propan-l-one

To a solution of (2R,5S)-1-(4-fluoro-benz¡l)-2,5-dimethylp¡peraz¡na (0.25 g, 1.12 mmol) in toluene (10 ml) 7-methyl-chroman-2-one (0.25 g, 1.54 mmol) was added and the resulting solution was heated under reflux for 48 hours. The reaction was cooled, concentrated in vacuo and purified by silica gel chromatography to give the title compound (0.34g).

(2-|3-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-3-oxopropi1)-5-methyl1-phenoxy) acid methyl ester -acetic

To a solution of 1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 -yl]-3-(2-hydroxy¡-4methyl-phenyl) -propan-1-one (0.15 g, 0.38 mmol) in tetrahydrofuran (2 mL) at 0-C was added sodium hydride (0.023 g, 0.57 mmol). The reaction was stirred for 5 minutes, then bromoacetic acid methyl ester (0.043 mL, 0.45 mmol) was added and the reaction stirred at room temperature overnight. The reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and concentrated in vacuo to give the title compound (0.18g).

(2-{3-[4-(4-Fluoro-benzyl)-(2R-5S)-2,5-dimethyl-piperazin-l-yl]-3-oxo-propyl]-5-methyl-phenoxy) acid acetic

To a solution of methyl ester of the acid (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl]-3-oxo-propyl} -5-methyl-phenoxy)-acetic acid (0.18 g, 0.40 mmol) in 2:2:1 tetrahydrofuran:methanol:water (5 mL) was added lithium hydroxide hydrate (0.026 g, 0.62 mmol ) and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with 0.2M hydrochloric acid, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration from methylene chloride/diethyl ether to give the title compound (0.16 g).

N-[(2-{3-r4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-3-oxo-propyl|-5-methyl-phenoxy )acetyl]-methanesulfonamide

To a solution of acid (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-3-oxopropyl}-5-methyl- phenoxy)-acetic acid (0.052 g, 0.12 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.032 g, 0.17 mmol), methanesulfonamide (0.015 g, 0.16 mmol) and triethylamine (0.035 mL, 0.25 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration from methylene chloride/diethyl ether/hexanes to give the title compound (0.050 g, LRMS: 520.3).

Example 2 N-5[(-Chloro-2-{2-[4-(4-fluoro-benz¡l-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡ l]-2-oxo-ethoxy¡)-phenoxy¡)acetyl-methanesulfonamide

(4-chloro-2-methoxy-phenox¡)-acetic acid

To a solution of sodium hydroxide (6.6 g, 160 mmol) in water (45 mL) was added 4-chloro2-methoxy-phenol (2.0 mL, 16 mmol) and chloroacetic acid (7.7 g, 81 mmol). The resulting mixture was heated to 95^QC and stirred for three hours. The reaction was allowed to cool to room temperature and slowly acidified with concentrated hydrochloric acid (10 mL) until the mixture became a solution, then extracted with diethyl ether. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (4.16g).

7-Chloro-benzo[1,4]diox¡n-2-one

To a 48% aqueous hydrogen bromide solution (20 mL) was added (4-chloro-2-methoxy-phenoxy)-acetic acid (2.1 g, 9.7 mmol). The resulting mixture was refluxed overnight. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give (4-chloro-2-hydroxy-phenoxy)acetic acid. The crude product was added to a solution of ptoluenepyridinium sulfonate (0.10 g, 0.40 mmol) in toluene (100 mL). The resulting mixture was heated under reflux for 5 hours. The reaction was allowed to cool to room temperature and was concentrated in vacuo. Silica gel chromatography gave the title compound (0.97 g).

2-(4-Chloro-2-hydroxy-phenoxy)-1-14-(4-fluoro-benzyl)-(2R.5S)-2,5-dimethyl-piperazin-1-yl1-ethanone

To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.48 g, 2.6 mmol) in toluene (5 mL) was added 1-(4-fluoro-benzyl)-(2R ,5S)-2,5-dimethyl-piperazine (0.59 g, 2.6 mmol). The resulting mixture was heated to 95^QC for one night. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel chromatography gave the title compound (0.67 g).

(5-Chloro-2-(2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-pwerazin-l-yl1-2-oxoethoxy} -phenoxyj- acetic

To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1 -[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylpiperazin-1 -yl ]-ethanone (0.30 g, 0.75 mmol) and bromoacetic acid methyl ester (0.14 ml, 1.5 mmol) in dloxane (3 ml) was added cesium carbonate (0.50 g, 1.5mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (0.61 g).

(5-chloro-2-{2-í4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy)-phenoxy)acetic acid

To a solution of acid methyl ester (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2-oxo- ethoxy}-phenoxy)-acetic acid (0.21 g, 0.46 mmol) in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.039 g, 0.93 mmol). The resulting mixture was stirred at room temperature for three hours. The reaction was acidified to pH 4 with 0.2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/diethyl ether to give the title compound (0.16 g).

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2fí-5S)-2,5-dimethyl-piperazin-1-yl]-2-oxoethoxy}-phenoxy) -acetyl]-methanesulfonamide

To a solution of acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡perazin-1 -yl]2- oxo-ethoxy}-phenoxy)-acetic acid (0.051 g, 0.10 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)prop hydrochloride ¡l)ethyl carbodiimide (0.033 g, 0.17 mmol), methanesulfonamide (0.016 g, 0.17 mmol) and triethylamine (0.040 mL, 0.29 mmol). The reaction was stirred at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated in vacuo. Chromatography on silica gel followed by trituration with methylene chloride/hydrogen chloride in diethyl ether gave the title compound as the hydrochloride salt (0.015 g, LRMS: 542.1.544.1).

Example 3

Acid 2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R-5S)-2,5-d¡m¡l-piperaz¡n-1-ill- 2-oxo-ethoxy¡}phenoxD-propionic

2-(5-Chloro-2-{2-f4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethyl-piperazin-l-yl]-2oxo-ethoxyj-phenoxy acid ethyl ester )- propionic

To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl]- ethanone (0.076 g, 0.18 mmol), triphenylphosphine (0.076 g, 0.29 mmol) and (2S)-2-hydroxy-propionic acid ethyl ester (0.036 g, 0.31 mmol) in tetrahydrofuran (1 mL) Diethyl azodicarboxylate (0.049 g, 0.29 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo. Silica gel chromatography gave the title compound (0.078 g)

Acid_______(2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxylphenoxy) - propionic

To a solution of 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy¡}-phenoxy¡)-propion¡co (0.075 g, 0.15 mmol) in methanol (0.4 mL), tetrahydrofuran (0.4 mL) and water (0.2 mL) was added lithium hydroxide (0.010 g, 0.24 mmol). The resulting mixture was stirred at room temperature for three hours. The reaction was acidified to pH 4 with 0.2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/diethyl ether to give the title compound (0.066 g, LRMS: 479.2, 481.2).

Example 4

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethyl-piperazin-1-yl1-2-oxo-ethoxy}phenyl) acid -4oxo)-butyric

4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyric acid

To a solution of 1-chloro-4-methoxy-benzene (1.1 g, 8.1 mmol) in 1,2-dichloroethane (8.0 mL) was added succinic anhydride (0.9 g, 9.0 mmol ) and anhydrous aluminum chloride (2.4 g, 18.3 mmol). The resulting mixture was stirred at room temperature for 4 days. The reaction was poured onto ice and diluted with ethyl acetate and 18% aqueous hydrochloric acid. The aqueous layer was washed with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a brown solid. The solid was triturated with hexanes and filtered to give the title compound (1.4g).

4-(5-Chloro-2-hydroxy-phenyl)-4-oxo-butyric acid ethyl ester

A solution of 4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyric acid (0.25 g, 1.09 mmol) in ethanol (10 mL) saturated with sodium chloride was stirred at room temperature for 12 hours. hydrogen (g). The reaction was concentrated in vacuo, dissolved in diethyl ether, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (0.259g).

4-(5-Chloro-2-{2-r4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethyl-piperazin-l-yl1-2oxo-ethoxy}-phenoxy acid ethyl ester )-4-oxo-butyric

A solution of 2-chloro-1-[4-(4-fluorobenzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.11 g, 0.36 mmol), 4-(5-Chloro-2-hydroxy-phenyl)-4-oxo-butyric acid ethyl ester (0.11 g, 0.43 mmol) 1,5,7-triazabicyclo [4,4,0]dec-5-ene linked to 2% DVB crosslinked polystyrene (0.21 g, 0.54 mmol) in acetonitrile (1.8 mL). The reaction mixture was filtered through a glass frit, concentrated in vacuo and purified by flash chromatography on silica gel to give the title compound (0.084 g).

4-(5-chloro-2-(2-r4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethyl1-piperazin-1-yl1-2-oxo-ethoxy}-phenyl1) acid 4-oxo-butyric

To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy}-phenyl)-4-oxo-butyric acid (0.082 g, 0.16 mmol) in 2:2:1 tetrahydrofuranomethanekwater (1.5 mL) was added lithium hydroxide monohydrate (0.34 g, 0.79 mmol). The resulting solution was stirred 12 hours at room temperature, then concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with 1M hydrochloric acid. The organic extracts were dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (0.072g, LRMS: 489.4, 491.4).

Example 5

3-[3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methylp¡perazin-1-¡l1-2-oxo- acid ethox¡|-phenyl)ureidol-propionic (3R)-1-(4-Fluoro-benzyl)-3-methyl-piperazine

4-Fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol) were added to a solution of (2R)-2-methyl-piperizine (4, 5 g, 45 mmol) in ethanol (80 mL). The reaction was refluxed overnight, cooled, and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Silica gel chromatography gave the title compound (5.0 g).

2-Chloro-1-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1-¡l1-ethanone

Triethylamine (2.0 mL, 14.4 mmol) was added to a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3g, 14.4 mmol) in dichloromethane (40 mL). The reaction was cooled to 0²C and chloroacetyl chloride (1.1 mL, 14.4 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane and washed with 10% citric acid. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (3.9 g).

2-(4-Chloro-2-nitro-phenoxy)-1-f4-(4-fluoro-benzi1)-(2R)-2-methyl-piperazin-1-ylj-ethanone

4-Chloro-2-nitro-phenol (0.25 g, 1.4 mmol), potassium carbonate (0.39 g, 2.8 mmol) and potassium iodide (233 mg, 1.4 mmol) were added to a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R)-2-methylpiperazin-1 -ylj-ethanone (0.40 g, 1.4 mmol) in 2-butanone ( 14 my). The reaction was refluxed overnight, cooled, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.56 g).

2-(2-Amino-4-chloro-phenoxy)-1-14-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone

Platinum dioxide on carbon (0.50 g, 5% on carbon) was added to a solution of 2-(4-chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl) -(2R)-2-methyl-piperazin-1-ylj-ethanone (0.55 g, 1.3 mmol) in ethanol (25 mL). The reaction was subjected to hydrogen gas at 35 psi (2.45 Kg/cm²) during 20 minutes. The reaction was then filtered through celite and the filtrate concentrated to give the title compound (0.42g).

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1-¡l]-2oxo acid 4-Nitro-phenyl ester -ethox¡)-fen¡l)-carbam¡co

Pyridine (0.032 mL, 0.39 mmol) and 4-nitrophenyl chloroformate (0.079 g, 0.39 mmol) were added to a solution of 2-(2-amino-4-chloro-phenoxy¡)-1-[4 -(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-ylj-ethanone (0.14 g, 0.36 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature for one hour and concentrated in vacuo to give the title compound (0.20g).

3-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-ill-2oxo-ethoxy¡}-acid methyl ester fen¡l)-ure¡dol-prop¡on

β-Alanine methyl ester hydrochloride (0.038 g, 0.27 mmol) and triethylamine (0.038 mL, 0.27 mmol) were added to a solution of the acid 4-nitro-phenyl ester (5-chloro-2-{ 2-[4-(4-fluorobenzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenyl)-carbamic acid (0.10 g, 0.18 mmol) in methanol. The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel chromatography to give the title compound (0.075 g).

3-[3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methylp¡perazin-1-¡ll-2-oxo- etox¡}-fen¡l)ureido-propionic

To a solution of 3-[3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2methyl-piperazin-1-yl]-2-oxo acid methyl ester -ethoxy}-phenyl)-ureido]-propionic acid (0.057 g, 0.11 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.023 g, 0. 55mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo, taken up in methanol, passed through an ion exchange column, then treated with hydrogen chloride gas to give the title compound as its salt. of hydrochloride (0.035 g, LRMS: 507.2).

Example 6

Acid (5-chloro-2-(2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-¡l1-2-oxoethoxyl -phenylsulfamoiD-acetic

2-Chloro-1-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡ll-ethanone

To a solution of (2R,5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine (2.5 g, 11.2 mmol) in dry dichloromethane (11 mL) at 0°C is added triethylamine (1.57 mL, 11.2 mmol) followed by chloroacetyl chloride (0.86 mL, 11.2 mmol). The resulting reaction mixture was stirred for 30 minutes. The reaction was then filtered through a pad of celite, washed with dichloromethane, and the resulting filtrate concentrated. Silica gel chromatography gave the title compound (2.84 g).

2-(4-Chloro-2-n¡tro-fenox¡)-1-r4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -l-ethanone

To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-¡l]-ethanone (1 0 g, 3.35 mmol) in butanone (35 mL) was added 2-nitro-4-chlorophenol (0.64 g, 3.69 mmol), potassium carbonate (0.93 g, 6.7 mmol) and potassium iodide (0.56 g, 3.35 mmol). The reaction mixture was refluxed overnight. The reaction mixture was then cooled, diluted with water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an orange oil. Silica gel chromatography gave the title compound (1.35g).

2-(2-Amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R-5S)-2,5-dimethylp¡perazin-1-ill -ethanone

To a solution of 2-(4-chloro-2-nitro-phenox¡)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1-ylj-ethanone ( 2.2 g, 5.05 mmol) in ethanol (50 mL) to an equivalent bottle was added 5% platinum on carbon (2.2 g). The reaction mixture was subjected to hydrogen gas [35 psi (2.45 Kg/cm²)] for 30 min. The reaction mixture was filtered through celite and the filter cake was washed with ethanol. The filtrate was concentrated in vacuo. Silica gel chromatography gave the title compound (1.42g).

Acid (5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-¡l]- 2-oxo-ethoxy¡}phenylsulfamoiD-acetic acid

To a solution of 2-(2-amino-4-chloro-phenox¡)-1-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylpiperazine-1- ilj-ethanone (0.030 g, 0.074 mmol) in dimethylformamide (0.5 mL) was added potassium carbonate (0.030 g 0.239 mmol), chlorosulfonyl-acetic acid ethyl ester (0.02 g, 0.12 mmol) (for preparation , see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) in dimethylformamide (0.5 ml) and finally catalytic dimethylaminopyridine. After 23 hours the reaction was diluted with ethyl acetate and washed with phosphate buffer pH 7.0 (0.05M). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude ester was then dissolved in 1:1 tetrahydrofuran:water (0.5 mL) and lithium hydroxide hydrate (0.004 g, 0.095 mmol) added. After 19 hours the reaction was concentrated and the title compound was purified by chromatography on silica gel (0.006 g, LRMS: 528.3).

Example 7

Acid 3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2.5-d¡methylp¡oerazin-1-ill-2-oxo- ethoxy¡}benzylaminoj-propionic acid

5-chloro-2-{2-r4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy}-benzaldehyde

To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡l]-ethanone (2 0.87 g, 9.6 mmol) in dimethylformamide (20 mL) was added 5-chlorosalicylaldehyde (1.65 g, 10.5 mmol), potassium carbonate (2.64 g, 19.2 mmol) and potassium iodide ( 1.59 g, 9.6 mmol). The resulting mixture was heated at 100-C for 12 hours. The reaction was cooled, diluted with saturated aqueous brine, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the crude product. Purification by silica gel chromatography gave the title compound (3.40 g).

3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl¡Deraz¡n-¡ acid methyl ester l12-oxo-ethoxy¡l-benzylam¡no)-prop¡on

To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡perazin-1 -ylj-2-οχοethoxyj-benzaldehyde ( 0.075 g, 018 mmol) in methanol (2 mL) was added 3-amino-propionic acid methyl ester hydrochloride salt (0.063 g, 0.45 mmol) and the pH of the solution was adjusted to 5-6 with triethylamine and acetic acid. The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.023 g, 0.36 mmol) was added to the resulting reaction mixture, and the pH of the solution was adjusted to pH 5 again with acetic acid and triethylamine. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with saturated aqueous acidic sodium carbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (0.035 g).

Acid________3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l-(2R₁5S)-2₁5-dimethyl-p¡perazin-¡1-2-oxo-ethoxy}benzylaminoj-propionic

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid methyl ester -oxo-ethoxy¡}-benz¡lamino)-prop¡ónico (0.035 g, 0.069 mmol) in tetrahydrofuran (0.2 ml), methanol (0.2 ml) and water (0.1 ml) was added lithium hydroxide monohydrate (0.015 g, 0.35 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in dichloromethane and treated with hydrogen chloride gas. The resulting white solid was washed with acetonitrile. The acetonitrile wash was concentrated to give the title compound as its hydrochloride salt (0.010 g, LRMS: 490.3).

Example 8 1-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡ l]-2-oxo-ethoxy¡lbenzyl)-3(2-methylbenzenesulfon¡l)-urea

2-(5-Chloro-2-hydroxy-benc¡l)-¡so¡ndol-1,3-d¡one

To 4-chlorophenol (2.0 g, 15.5 mmol) and chloromethylphthalamide (2.62 g, 13.4 mmol) was added zinc chloride (3 mL, 0.5 M in tetrahydrofuran, 1.5 mmol). The reaction was stirred at 90⁵C for 48 hours. After cooling the reaction was diluted with methanol (15 mL) and brought to reflux. After 30 minutes the hot slurry was filtered through a medium glass frit and concentrated to an off-white solid. Methanol (50 mL) was added again and the reaction was brought to reflux. After 3 hours the hot slurry was filtered through a medium glass frit and concentrated to an off-white solid. The crude product was purified by silica gel chromatography to give the title compound (3.86 g).

2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡Derazin-¡ll-2-oxo- ethox¡}-benz¡l)iso¡ndol-1-3-dione

To a solution of 2-chloro-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -ylj-ethanone (0.75 g, 2.50 mmol ) in dry dimethylformamide (25 mL) was added potassium iodide (0.40 g, 2.39 mmol), 2-(5-chloro-2-hydroxy-benzyl)-isoindole-1,3-dione (0.80 g, 2.76 mmol) and potassium carbonate (0.70 g, 5.10 mmol). The resulting mixture was heated at 70°C for 23 hours. The reaction was cooled to room temperature, diluted with water, and extracted with 1:1 diethyl ether/hexanes (3X). The organic layers were combined, washed with water, brine, dried over magnesium sulphate, filtered and evaporated to give the title compound (0.87g).

2-(2-Aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-illetanone

A 2-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -¡l]- 2-oxo-ethoxy¡}-benz¡l)isoindole-1,3-dione (0.87 g, 1.59 mmol) in ethanol (20 mL) was added 35% hydrazine (3 mL, 33.1 mmol ). After 17 hours, the reaction was filtered and concentrated to a brown solid. This solid was triturated with methylene chloride and the title compound was obtained after filtration, dried over magnesium sulphate and concentrated in vacuo (0.62g).

Ester________5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylo¡perazin-1-¡l1-2-oxo-ethox (2-methylbenzenesulfon¡l)-carbamic acid ¡}benzyl

To a solution of 2-(2-aminomethyl-4-chloro-phenox¡)-1-[4-(4-fluoro-benz¡l)-(2R, 5S)-2,5dimethyl-piperazin-1 -ylj- ethanone (0.050 g, 0.12 mmol) in dry toluene (2 ml) was added otoluenesulfonylisocyanate (0.05 ml, 0.36 mmol). The reaction was concentrated to dryness and purified by silica gel chromatography to give the title compound (0.048 g, LRMS: 617.2).

Example 9

Acid 2-(5-chloro-2-{244-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡ll-2- oxoethoxyl-benzylsulfamoiD-propionic

To a solution of 2-(2-aminomethyl-4-chloro-phenoxy)-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡lpiperazin-1-ylj -ethanone (0.05 g, 0.119 mmol) in tetrahydrofuran (1 mL) at -40°C t-ethylamine (0.021 mL, 0.151 mmol) was added, catalytic dimethylaminopyridine and finally 2-chlorosulfonyl-propionic acid ethyl ester solution ( for preparation, see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) (0.029 g, 0.145 mmol) in tetrahydrofuran (0.25 mL), added over 5 minutes. The reaction was allowed to warm to room temperature. After 23 hours the reaction was diluted with ethyl acetate and washed with phosphate buffer pH 7 (0.5M). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The desired product was isolated by chromatography on silica gel (0.047 g). This ester (0.07 mmol) was dissolved in 1:1 tetrahydrofuranorwater (1 mL) and lithium hydroxide hydrate (5.8 mg, 0.138 mmol) was added. After 21 hours the reaction was concentrated and the title compound was obtained after chromatography on silica gel (0.039 g, LRMS: 556.1).

Example 10 (5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡l1- 2-oxo-ethoxy¡}-benz¡lox¡)acetyl methanesulfonamide

2-(4-Chloro-2-hydroxymethyl-phenoxy)-l-f4-(4-fluoro-benzyl)-(2R.5S)-2,5-dnnetyl-piperaziii-l-yl1-ethanone

To a solution of 5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-piperaz¡n-1 -ilj- 2-οχοethoxyj-benzaldehyde (0.99 g, 2.36 mmol) in dry methanol (25 mL) was added sodium borohydride (0.19 g, 4.92 mmol). After 1 hour the reaction was acidified to pH 2 by the addition of 1N hydrochloric acid. After 5 minutes the reaction was quenched with 1N sodium hydroxide and the methanol was removed by evaporation. The resulting aqueous suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound (0.98g).

(5-Chloro-2-{2-f4-(4-fluoro-benzyl)-(2R.5S)-2.5-dimethyl-piperazin-l-yl1-2oxo-ethoxyl-benzyloxy)-acetic acid tert-butyl ester

To a solution to 0^yesC of sodium hydride (0.025 g, 60% dispersion, 1.0 mmol) in tetrahydrofuran (2 mL) was added a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[ 4-(4-fluorobenzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-ylj-ethanone (0.17 g, 0.40 mmol) and terebutyl bromoacetate (0.23 g, 3.0 mmol) in tetrahydrofuran (2 mL). The reaction mixture was warmed to room temperature overnight, quenched with water, and diluted with ethyl acetate.

The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (0.14 g).

Acid________5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-piperaz¡n-1-¡l1-2-oxo -ethoxy¡}benzyloxy)-acetic

To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid tert-butyl ester oxo-ethoxy}-benzyloxy)-acetic acid (0.14 g, 0.25 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature overnight, diluted with dichloromethane, and treated with excess hydrogen chloride gas. The mixture was concentrated in vacuo to give the title compound as its hydrochloride salt (0.14 g).

(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡ll-2-oxo- ethoxy}-benzyloxy)acetyl methanesulfonamide

To a solution of acid (5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl] 2-oxo-ethoxy}-benzyloxy)-acetic acid (0.11 g, 0.22 mmol) in dichloromethane (10 mL) was added 4-dimethylaminopyridine (0.04 g, 0.33 mmol) and 1,3-dicyclohexylcarbodiimide (0.049 g, 0.24mmol). The resulting reaction mixture was stirred at room temperature for 20 minutes, then treated with methanesulfonamide (0.025 g, 0.26 mmol). The reaction was stirred at room temperature for 18 hours, filtered through a pad of celite, and the resulting filter cake washed with dichloromethane. The combined organic extracts were concentrated in vacuo and purified by silica gel chromatography to give the title compound (0.045 g, LRMS: 556.2).

Example 11 1-Acetyl-3-(5-chloro-2-{2-r4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-11-2 -oxo-ethoxy}benzyl)sulfamide

1-(tert-Butoxy¡carbon¡l)-1-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R_he5S)-2_he5-d¡methylp¡peraz¡n-1-¡l12-oxo-ethoxyl-benc¡l)sulfam¡da

To a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1 -[4-(4-fluoro-benzyl)-2,5-dimethylpiperazin-1-yl)-ethanone (0.2 g , 0.48 mmol) in tetrahydrofuran (2 mL) was added tert-butoxycarbonylsulfamide (for preparation see: EP 557122A1) (0.14 g, 0.71 mmol) and triphenylphosphine (0.16 g, 0.62 mmol) . The reaction mixture was cooled to -60^QC and diethyl azodicarboxylate (0.10 mL, 0.64 mmol) was added dropwise. The reaction was heated to 10^QC for 2 hours and then allowed to warm to room temperature. The reaction was diluted with ethyl acetate and washed with pH 7 phosphate buffer (0.5M) and brine, then dried over magnesium sulfate. The reaction was concentrated to dryness and purified by silica gel chromatography to give the title compound (0.28g).

1-Acet¡l-3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylD¡perazin-1-¡ ll-2-oxo-ethoxy)benziDsulfamide

To a solution of 1-(tert-butoxycarbonyl)-1-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5dimethyl-piperazine-1 -yl]-2-oxo-ethoxy}-benzyl)sulfamide (0.05 g, 0.08 mmol) in methylene chloride (1 mL) was added triethylamine (0.01 mL, 0.09 mmol), acetyl (0.007 mL, 0.098 mmol) and catalytic dimethylaminopyridine. After 18 hours, the reaction was diluted with methanol, concentrated to dryness, and purified by chromatography on silica gel (0.041 g). This material (0.064 mmol) was dissolved in methylene chloride (1 ml) and trifluoroacetic acid (1 ml). After 3 hours at room temperature the reaction was diluted with methylene chloride and quenched with 5% sodium carbonate. The layers were separated and the aqueous layer was washed twice with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated to dryness. The title compound was obtained after chromatography on silica gel (0.035 g, LRMS: 541.3).

Example 12

Acid________5-chloro-2-{2-í4-(4-fluoro-benz¡l)-(2R,5S)-2.5-d¡methyl-piperaz¡n-1-¡l1-2-oxo-ethox¡ }benzylideneaminooxyj-acetic acid

To a solution of 5-chloro-2-(2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxoethoxyj-benzaldehyde (0.050 g, 0.12 mmol) in methanol (1 mL) was added triethylamine (excess) and carboxymethoxylamine hemihydrochloride (0.030 g, 0.24 mmol).After 3 hours at room temperature the reaction was concentrated and the desired product was purified by silica gel chromatography (0.045 g, LRMS: 492.1)

Example 13

5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R) ester₁5S)-2,5-d¡lp¡peraz¡n-1-¡l1-2-oxo-ethoxy¡l-benzyl of (2-methylbenzenesulfon¡0-carbamic) acid

To a solution of 2-(4-chloro-2-hidrox¡methyl-phenox¡)-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazine-1 - ilj-ethanone (0.050 g, 0.12 mmol) in dry toluene (2 mL) was added triethylamine (0.05 mL, 0.36 mmol) followed by o-toluenesulfonylisocyanate (0.05 mL, 0.36 mmol) and Catalytic 4-dimethylaminopyridine. After 23 hours the reaction was warmed to 55^andC for 2 hours. After cooling the reaction was evaporated to dryness and the title compound was purified by chromatography on silica gel (0.074 g, LRMS: 618.1).

Example 14 N-[(5-Chloro-2-[2-í4-(4-fluoro-benz¡l-(2R.5S)-2.5-d¡methylp¡peraz¡n-1-¡l1-2 -oxo-ethoxy¡}-phenyl)acetyl-methanesulfonamide (5-Chloro-2-methoxy-phenyl)-methanol

To a solution of 5-chloro-2-methoxy-benzoic acid methyl ester (20 g, 9.97 mmol) in THF (100 mL) at 0°C was added dropwise a solution of lithium aluminum hydride ( 210 ml, 210 mmol, 1 M solution in THF). The solution was then heated under reflux for 2 hours. The reaction was cooled to 0²C and carefully quenched by adding cold water. The mixture was filtered through celite and the filter cake washed with diethyl ether. The filtrate was washed with saturated aqueous acidic sodium carbonate and then dried over magnesium sulfate. Concentration in vacuo gave the title compound (17.2 g).

(5-Chloro-2-methox¡-phenyl)-acetonitrile

To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1 mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5 mL, 198 mmol). . The reaction was stirred at reflux for 3 hours, cooled to room temperature, and concentrated in vacuo. The crude product was dissolved in methylene chloride and washed with saturated aqueous acidic sodium carbonate then dried over magnesium sulfate. Concentration in vacuo gave 4-chloro-2-chloromethyl-1-methoxybenzene (18.4 g). To a solution of 4-chloro-2-chloromethyl-1-methoxybenzene (18.4 g, 96.4 mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193 mmol) and 18-crown- 6 (2.54g, 9.64mmol). The reaction was stirred 12 hours at room temperature, diluted with ethyl acetate and washed with aqueous acidic sodium carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by passing through a pad of silica gel, diluting with methylene chloride to give the title compound (17.2 g).

(5-chloro-2-methoxy-phenyl)-acetic acid

To a solution of (5-chloro-2-methoxy-phenyl)-acetonitrile (17.2 g, 96.3 mmol) in ethanol (200 ml) and water (20 ml) was added potassium hydroxide ( 27g, 481mmol). The reaction was refluxed for 12 hours, cooled, and the ethanol removed by concentration in vacuo. The remaining solution was acidified with aqueous hydrochloric acid (3M) and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound (15.6 g).

(5-Chloro-2-hydroxy-phenyl)-acetic acid ethyl ester

A solution of (5-chloro-2-methoxy-phenyl)-acetic acid (15.5 g, 77.5 mmol) in 48% aqueous hydrogen bromide was heated under reflux for 20 hours. The solution was cooled, diluted with water, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by trituration from 2:1 methylene chloride:hexanes to give (5-chloro-2-hydroxy-phenyl)-acetic acid (12.8 g). This was dissolved in a solution of ethanol saturated with hydrochloric acid and stirred for 12 hours. The reaction was concentrated in vacuo, then the crude product was dissolved in diethyl ether and washed with saturated aqueous acidic sodium carbonate. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (12.7g).

Acid (5-chloro-2-(2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl¡loeraz¡n-1-¡ acid ethyl ester l1-2oxo-ethoxyj-phenyll-acetic acid

To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxyphenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22 0.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hours. The solution was cooled, diluted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).

Acid (5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R_he5S)-2₁5-d¡met¡l-piperaz¡n-1-¡l1-2-oxo-ethox¡|-fen¡l)acetic

To a solution of ethyl ester of the acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2-oxo- ethoxy}-phenyl)-acetic acid (5.1 g, 10.7 mmol) in tetrahydrofuran (30 mL), methanol (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (2.2 g, 53, 5mmol). The reaction was stirred for 18 hours at room temperature. The reaction was then concentrated in vacuo and the remaining solution acidified with 1M aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was diluted with a minimum of dichloromethane and diethyl ether was added. A white precipitate was collected by filtration to give the title compound (3.93g).

N-[(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡Deraz¡n-1-ill- 2-oxo-ethoxy¡}-phenyl)acetyl-methanesulfonamide

To a solution of acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡l ]2-oxo-ethoxy}-phenyl)-acetic acid (0.70 g, 1.44 mmol) was added 4-dimethylaminopyridine (0.26 g, 2.16 mmol), (3-(dimethylamino)propyl) hydrochloride ethyl carbodiimide (0.42 g, 2.16 mmol), methanesulfonamide (0.15 g, 1.58 mmol) and triethylamine (0.40 mL, 2.88 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 1M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (0.34 g, LRMS: 526.2).

Example 15 Nf(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡l ]-2-oxo-ethoxy}-phenyl)acetyl-sulfamide

A solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-lyl]-2-oxo-ethoxy} acid was stirred -phenyl)-acetic acid (0.10 g, 0.21 mmol) in thionyl chloride (2 mL) at room temperature for two hours. The reaction was concentrated to dryness and the crude acid chloride dissolved in 1.4-dioxane (4 mL) followed by addition of sulfonamide (0.022 g, 0.23 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated and chromatographed on silica gel to give the title compound (0.014 g, LRMS: 525.1).

Example 16 N-[3-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n- 1-¡l]-2-oxo-ethox¡Men¡Dpropionill-methanesulfonamide

3-(5-Chloro-2-{2-|~4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2oxo-ethoxyl acid ethyl ester -phenyl)-acrylic

To a solution of 5-chloro-2-{2-[4-(fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxoethoxyj-benzaldehyde (0.50 g, 1.19 mmol) in ethanol (10 mL) at 0^yesC was added potassium carbonate (0.4 mL, 2.4 mmol, 6 M soln in water) and triethylphosphonoacetate (0.47 mL, 2.4 mmol). The reaction was stirred at 0°C for 2 hours, then at room temperature for 12 hours. The reaction was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was then washed with saturated aqueous acidic sodium carbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (0.51 g).

3-(5-Chloro-2-{2-í4-(4-fluoro-benz¡l)-(2R,5S)-2.5-dimethylD¡Derazin-1-¡l12-oxo acid ethyl ester -ethox¡l-fen¡l)-prop¡on

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy}-phenyl)-acrylic acid (0.50 g, 1.0 mmol) in ethyl acetate (15 mL) In a Parr bottle platinum dioxide on carbon (0.25 g, 5% on carbon) was added. . The mixture was stirred under a positive pressure of hydrogen at 30 psi (2.1 kg/cm²) for 15 min at room temperature. The mixture was filtered through a celite pad and concentrated to give the title compound (0.47g).

3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2 acid₁5-dimethyl-p¡peraz¡n-1-¡l1-2-oxo-ethox¡|pheniD-propionic

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy}-phenyl)-propionic acid (1.3 g, 2.7 mmol) in tetrahydrofuran (10 mL), methanol (10 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.57 g, 13.3mmol). The reaction was stirred at room temperature for 12 hours, then made acidic by the addition of 1M hydrochloric acid. The solution was then extracted with methylene chloride and the organic layer was dried over magnesium sulfate. Concentration in vacuo gave the title compound (1.0 g).

N-[3-(5-chloro-2-[2-[4-(4-fluoro-benz¡P-(2R,5S)-2₁5-dimethylp¡peraz¡n-1-¡ll-2-oxo-ethoxy}-phen¡P propionyl-methanesulfonamide

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo- ethoxy}-phenyl)-propionic acid (0.20 g, 0.40 mmol) was added 4-dimethylaminopinedine (0.075 g, 0.60 mmol), (3-(dimethylamino)propyl)ethylcarbodimide hydrochloride (0.12 g , 0.60 mmol), methanesulfonamide (0.045 g, 0.48 mmol) and triethylamine (0.12 mL, 0.84 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (0.10 g, LRMS: 540.2).

Example 17

3-(5-chloro-2-{2-í4-(4-fluoro-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-1-yl1-2-oxo-ethoxy¡} acid feniD-acrylic

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid methyl ester oxo-ethoxy}-phenyl)-acrylic acid (0.060 g, 0.13 mmol) in tetrahydrofuran, methanol and water (1 mL each) was added lithium hydroxide hydrate (0.020 g, 0.51 mmol). After 1 hour at 50²C The reaction was concentrated and the title compound was isolated by chromatography on silica gel (0.032 g, LRMS: 461.1).

Example 18

Acid_______(5-chloro-2-(2-[4-(4-fluoro-benz¡l)-(2R,5S)-2.5-d¡methylp¡peraz¡n-1-¡ll-2-oxo -ethoxy¡)benzenesulfonylaminoj-acetic acid

5-Chloro-2-methoxy-benzenesulfonamide

To a solution of 5-chloro-2-methoxybenzene sulfonyl chloride (1.0 g, 4.15 mmol) in tetrahydrofuran (10 mL) was bubbled ammonia gas until saturated. The reaction was stirred overnight. The white solid that precipitated out of solution was collected by filtration and washed with dichloromethane to give the title compound (0.52g).

5-Chloro-2-hydroxy-benzenesulfonamide

To a suspension of 5-chloro-2-methoxy-benzenesulfonamide (0.52 g, 2.33 mmol) in dichloromethane (25 mL) at -78^QC Boron tribromide (1 M dichloromethane soln, 3.5 mL, 3.5 mmol) was added. The reaction was stirred at -78^QC for 30 minutes and then warmed to room temperature and stirred overnight. The reaction was quenched with water (0.30 ml) and the precipitate formed was removed by filtration. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel to give the title compound (0.32 g).

5-Chloro-2-{2-í4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyllp¡Derazin-1-¡ll-2-oxo-ethox¡ }benzenesulfonamide

To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.29 g, 0.96 mmol) in 2-butanone (10 mL) was added 5-chloro-2-hydroxy-benzenesulfonamide (0.20 g, 0.96 mmol), potassium carbonate (0.27 g, 1.92 mmol) and ¡ potassium odide (0.16 g, 0.96 mmol). The reaction was refluxed for 4 hours, cooled, diluted with ethyl acetate, and washed with brine. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.32 g).

AZ-tert-butyl carbonate (5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R_he5S)-2,5-d¡methylp¡peraz¡n-1 -ill-2oxo-ethoxyl-benzenesulfonylamino

To a solution of 5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]-2 -oxoethoxyj-benzenesulfonamide (0.10 g, 0.21 mmol) in dichloromethane (1.0 mL) was added 4-dimethylaminopyridine (0.010 g, 0.08 mmol), triethylamine (0.045 mL, 0.31 mmol), and dicarbonate Butyl dithero (0.056 g, 0.25 mmol). The reaction mixture was stirred at room temperature for 1 hour and washed with water and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (0.14g).

(5-Chloro-2-{2-[4-(4-Fluoro-benzyl)(2R) ΛΖ-tert-butyl carbonate tert-butyl ester₁5S)-2_he5-dimethylp¡peraz¡n-1-¡ll-2-oxo-ethoxy}-benzenesulfon¡lam¡no)-acet¡co

To a solution of N-tert-butyl carbonate (5-chloro-2-{2-[4-(4-fluoro-benzyl)(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2-oxo- ethoxy}-benzenesulfonylamino (0.13 g, 0.22 mmol) in dimethylformamide (1.0 mL) was added bromoacetic acid tert-butyl ester (0.049 g, 0.25 mmol) and potassium carbonate (0.15 g, 1.10 mmol) The resulting reaction mixture was stirred at room temperature overnight, washed with brine, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography provided the title compound (0.045 g).

Acid (5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperazin-1-yl1-2-oxo-ethoxy¡ }benzenesulfonylaminoj-acetic acid

A solution of N-tert-butyl carbonate (5-chloro-2-{2-[4-(4fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 acid tert-butyl ester -yl]-2-oxo-ethoxy}-benzenesulfonylamino)-acetic acid (0.044 g, 0.064 mmol) in dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL), stirred at room temperature overnight, concentrated in vacuo and treated with diethyl ether saturated with hydrochloric acid to give the hydrochloride salt of the title compound (0.040 g, LRMS: 528.3).

Example 19

5-Chloro-2-f2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-piperazine-1-¡ll-2-oxo-ethoxy¡}- N-[(2propylaminojcarbonyl-benzenesulfonamide

5-Chloro-2-|2-f4-(4-yluoiO-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-l-yl1-2-oxo-ethoxyÍ-Nf(2-propylaminojcarbonyl-benzenesulfonamide

To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxoethoxyj-benzenesulfonamide (0.07 g, 0.150 mmol) in tetrahydrofuran (1.5 mL) was added isopropyl isocyanate (0.022 mL, 0.23 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.034 mL , 0.23mmol). The reaction was stirred at 60°C overnight. The reaction was concentrated and purified by silica gel chromatography to give the title compound (0.06 g, LRMS: 555.2).

Example 20 5-Chloro-N-(2₁2-d¡methyl-prop¡on¡l)-2-{2-[4-(4-fluoro-benz¡l)-(2R₁5S)-2,5-dimethyl-piperaz¡n-1-¡l12-oxo-ethoxyl-benzenesulfonamide

To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methyl-piperazin-1 -ylj-2-οχοethoxyj-benzenesulfonamide ( 0.050 g, 0.11 mmol) in acetonitrile (1.0 mL) was added 2,2-dimethyl-propionyl chloride (0.050 g, 0.47 mmol) and 1,8-diazobicyclo[5.4.0]undec-7 -ene (0.25 mL, 1.64 mmol). The resulting reaction mixture was heated to 50⁵C for 2 hours, concentrated in vacuo and purified by silica gel chromatography to give the title compound (0.030 g, LRMS: 554.4).

Example 21 5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2₁5-d¡methylp¡peraz¡n-1-¡l1-2-oxo-ethox¡}-N-(2-h¡drox¡2-methyl-propion¡l)-benzenesulfonam¡da

2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2oxo-ethoxy}-acid ethyl ester benzenesulfonylamino)-1,1-dimethyl-2-οχο- acetic acid

To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyllp¡peraz¡n-1 -ylj-2-οχοethoxyj- benzenesulfonamide (0.10 g, 0.21 mmol) in dichloromethane (2 mL) was added triethylamine (0.033 mL, 0.23 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol) and 1-chlorocarbonyl-acid ethyl ester. 1 -Methyl-acetic acid (0.037 mL, 0.25 mmol). The resulting reaction mixture was stirred at room temperature overnight, treated with 0.2N hydrochloric acid, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude title compound ( 0.140g).

5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-¡ll-2-oxo -ethoxy)-N-(2-hydroxy¡2-methyl-propion¡l)-benzenesulfonamide

To a solution of 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy}-benzenesulfon¡lam¡no)-1,1-dimethyl-2-oxo-acetic acid (0.14 g, 0.21 mmol) in tetrahydrofuran (2 mL), methanol (0.2 mL) and added water (0.4 mL), lithium hydroxide monohydrate (0.020 g, 0.48 mmol). The resulting reaction mixture was stirred at room temperature overnight. Silica gel chromatography of the reaction mixture gave the title compound (0.104 g, LRMS: 556.3).

Example 22 N-Acet¡lC-(5-chloro-2-{2-r4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡perazine-1- ¡ll-2-oxo-ethoxylphenyl-D-methanesulfonamide

Thioacetic acid S-(5-chloro-2-methoxy-benzyl) ester

To a solution of cesium carbonate (0.55 g, 1.70 mmol) in dimethylformamide (13 mL) was added thioacetic acid (0.24 g, 3.14 mmol) followed by the addition of 4-chloro-2-chloromethyl-l- methoxybenzene (0.50 g, 2.62 mmol) in one portion. The reaction was stirred in the dark at room temperature overnight. The reaction was diluted with ethyl acetate, washed with water, 5% aqueous hydrogen carbonate, and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.58 g).

(5-chloro-2-methoxy¡-phenyl)-methanesulfonic acid

To a solution of thioacetic acid S-(5-chloro-2-methoxy-benzyl) ester (0.30 g, 1.3 mmol) in acetic acid (1.5 mL) was added a solution of hydrogen peroxide ( 1.5 mL, 30% in water) in acetic acid (3 mL). The reaction was stirred overnight at room temperature. This was followed by the addition of palladium on carbon (0.006 g, 10% on carbon) to remove excess hydrogen peroxide. The reaction was stirred for 10 minutes and filtered through a nylon filter, then azeotroped with toluene (3X) and concentrated in vacuo to give the title compound (0.32g).

(5-Chloro-2-methoxy-phen¡D-methanesulfonam¡de

To a solution of (5-chloro-2-methoxy-phenyl)-methanesulfonic acid (0.15 g, 0.63 mmol) in benzene (6 mL) was added phosphorus pentachloride (0.15 g, 0.72 mmol ). The reaction was refluxed for 2.5 hours, cooled, and concentrated in vacuo. The resulting residue was dissolved in tetrahydrofuran (1 ml) and ammonium hydroxide (1 ml) was added. The reaction was stirred for two days at room temperature. The reaction was then diluted with water and extracted with ethyl acetate (3X). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.033 g).

(5-Chloro-2-hydroxy¡-phenyl)-methanesulfonamide

To a suspension of (5-chloro-2-methoxy-phenyl)-methanesulfonamide (0.03 g, 0.13 mmol) in dichloroethane (1.5 mL) was added a solution of boron tribromide (1 M in dichloromethane, 0.26 mL, 0.26 mmol). The reaction was stirred for one hour at room temperature. The reaction was quenched with water, saturated with sodium chloride, and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and concentrated to give the title compound (0.025g).

(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡peraz¡n-1-ill-2-oxo -ethoxy¡}-phenyl)methanesulfonamide

To a solution of 2-chloro-l-[4-(4-fluoroiO-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-ethanone (0.028 g, 0.094 mmol) in dimethylformamide (1 mL) was added (5-chloro-2-hydroxy-phenyl)-methanesulfonamide (0.023 g, 0.10 mmol), potassium carbonate (0.026 g, 0.19 mmol) and potassium iodide (0.016 g, 0.094 mmol). . The reaction was heated at 60°C for 17 hours, cooled, diluted with water and extracted with ethyl acetate (3X). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.014 g).

N-Acet¡lC-(5-chloro-2-{2-í4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperaz¡n-1- ¡ll-2-ox¡-ethox¡)pheniD-methanesulfonamide

To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxoethoxy}-phenyl )-methanesulfonamide (0.05 g, 0.10 mmol) in dichloromethane (1 mL), added acetic acid (0.007 g, 0.12 mmol), (3-(dimethylamino)propyl)ethylcarbodiimide (0.030 g, 0, 16 mmol), 4-dimethylaminopyridine (0.019 g, 0.16 mmol) and triethylamine (0.023 g, 0.23 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the aqueous layer re-extracted with dichloromethane (3X). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.039 g, LRMS: 526.20).

Example 23 0-(5-0ΙθΓθ-2-{2-[4-(4-ίΙιιθΓθ-ΐ36ηάΙ)-(2Π,55)-2,5&lt;ΙίπΊ6ΐίΙ-ρίρ6Γ3ζίη-1-ίΙ1-2-οχο-6ΐοχί -Ν-(2hydroxy-2-methyl-propionyl)-methanesulfonamide

2-(5-chloro-2-|2-í4-(4-fluoro-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-l-ill-2-oxo-ethoxylphenylmethanesulfonylamino)-l,l-dimethyl Acetic acid -2-oxo-ethyl ester

A solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)- was stirred at room temperature.

2,5-dimethyl-piperaz¡n-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonam¡de (50 mg, 0.103 mmol), ethyl 1-chlorocarbonyl-1-methylacetate (19 mg , 0.016 ml, 0.114 mmol), triethylamine (13 mg, 0.018 ml, 0.129 mmol) and a catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (1 ml). After 18h the solution was directly purified using radial chromatography to give the title compound (0.033g).

C-(5-Chloro-2-{2-[4-(4-fluoroiO-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy|-phenyl )-N-(2-hydroxy-2-methyl-propionyl)-methanesulfonamide

A solution of 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo acid ethyl ester -ethoxy}-phenylmethanesulfonylamino)-1,1-dimethyl-2-oxo-acetic acid (0.030 g, 0.049 mmol) and lithium hydroxide monohydrate (0.004 g, 0.098 mmol) in tetrahydrofuran (0.5 mL), methanol (0. 25 ml) and water (0.25 ml) was stirred for 20 h. The resulting solution was concentrated and partitioned between 1M hydrochloric acid and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered, concentrated and purified using radial chromatography to give the title compound (0.022 g, LRMS: 568.2, 570.3).

Example 24

C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R.5S)-2,5-d¡methylp¡Deraz¡n-1-¡ll- 2-oxo-ethoxy¡)-phenyl)- N(ethylaminocarboniD-methanesulfonamide

A solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxyjphenyl)-methanesulfonamide (0.050 g, 0.103 mmol), ethyl isocyanate (0.011 g, 0.012 mL, 0.155 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.024 g, 0.023 mL, 0.155 mmol) in tetrahydrofuran (1 mL) heated on a shaker plate to 60°C. After 5 hours the solution was cooled to room temperature and purified using radial chromatography to give the title compound (0.034 g, LRMS: 553.4, 555.4).

Example 25

N-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methylp¡peraz¡n-1-¡l]-2-oxo- acid etox¡lp¡r¡d¡n-3¡l)-succ¡nám¡co

1-[4-(4-Fluoro-benzyl)-(2R)-2-methyl-piperaz¡n-1-ill-2-hidrox¡-ethanona

To a solution of glycolic acid (0.70 g, 9.2 mmol), 4-dimethylaminopindine (catalytic) and pyridine (1.52 mL, 18.6 mmol) in dry dichloromethane (20 mL) was added trimethylsilyl chloride dropwise. (2.39 ml, 2.05 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was then cooled to 0²C and catalytic dimethylformamide (3 drops) was added followed by the addition of oxalyl chloride. The reaction was stirred at 0⁹C for one hour and for 30 minutes at room temperature. The reaction was cooled back to 0⁹C and (3R)-1 -(4-fluorobenzyl)-3-methyl-piperazine (2.11 g, 10.12 mmol) was added as a solution in pyridine (2.45 mL, 30.4 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with 1N hydrochloric acid and extracted with dichloromethane (2X). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (1.84 g).

2-(5-Chloro-3-nitro-pyrid¡n-2-¡lox¡)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡perazin-1 -ill-ethanone

To a solution of 1 -[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -ylj-2-hydroxy-ethanone (0.77 g, 2.9 mmol) in dry toluene (30 mL) at 0°C sodium hydride (0.13 g, 3.2 mmol, 60% dispersion in mineral oil) was added. The reaction was stirred for 30 min at 0^QC followed by the addition of 2,5-dichloro-3-nitro-pyridine (0.60 g, 3.18 mmol) as a solution in toluene (5 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated and chromatographed on silica gel to give the title compound (0.96 g).

2-(3-Am¡no-5-chloro-p¡r¡d¡n-2-¡lox¡)-1-[4-(4-fluoro-benz¡l)-(2R)-2-methyl -p¡peraz¡n-1-¡ll-ethanone

To a solution of 2-(5-chloro-3-nitro-pyridin-2-yloxy)-l-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazm1-yl]-ethanone ( 0.96 g, 2.3 mmol) in ethanol (25 mL) was added platinum dioxide on carbon (0.90 mg, 5% on carbon). The reaction was subjected to a pressure of 35 psi (2.45 Kg/cm²) in hydrogen gas for 20 min. The reaction was filtered through celite, concentrated in vacuo and chromatographed on silica gel to give the title compound (0.78g).

N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-l-yl1-2-oxo-ethoxy|-pyridin-3-yl acid )succinamic

To a solution of 2-(3-amino-5-chloro-p¡ridin-2-¡lox¡)-1 -[4-(4-fluoro-benzyl)-(2R)-2-methylpiperazine-1 -yl]-ethanone (0.10 g, 0.26 mmol) in dichloromethane (3 mL) was added N-methylmorpholine (0.028 mL, 0.26 mmol) and succinic anhydride (0.026 g, 0.26 mmol). The reaction was stirred at room temperature for 3 days. The reaction was diluted with dichloromethane and washed with 1N hydrochloric acid solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.040 g, LRMS: 493.2).

Example 26 N-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R.5S)-2,5-d¡methylD¡Deraz¡n-1-¡ ll-2-oxo-ethox¡Lpir¡d¡n-3¡l)-acet¡ll-methanesulfonam¡da

4-Chloro-but-3-enpnitr¡lo

To a solution of 1,3-dichloropropene (20.0 g, 180 mmol) in acetonitrile (110 mL) was added potassium iodide (0.75 g, 4.5 mol) and potassium cyanide (70.0 g, 1080 mmol). The reaction mixture was stirred at room temperature for 72 hours, filtered through a celite pad, and the resulting filter cake washed with diethyl ether. Diethyl ether and acetonitrile were distilled under atmospheric pressure and the residue was purified by fractional distillation to give the title compound as a mixture of isomers with its regioisomers 4-chloro-but-2-enenitrile (2.2 g) -

2,5-Dichloro-pyridine-3-carbaldehyde

To a solution of 4-chloro-but-3-enonitrile (2.25 g, 22.3 mmol) in dimethylformamide (8.6 mL) was added phosphoryl chloride (10.4 mL, 111 mmol). The resulting reaction mixture was heated to 100^QC overnight, cooled to 0^QC and quenched with water. The product was extracted with dichloromethane and the organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. Recrystallization from hexanes provided the title compound (2.0 g).

(2,5-Dichloro-Diridin-3-yl)-acetic acid methyl ester

To tmethoxyorthoformate (5.47 mL, 50 mmol) was slowly added diphenylphosphine chloride (11.0 g, 50 mmol) at room temperature. After the reaction mixture solidified (about 1 hour) the solid was heated at 110°C for 2 hours. The reaction product was then cooled to room temperature and recrystallized from toluene and water to give dimethoxymethyl diphenylphosphine oxide (12 g).

To a solution at -78²To C of disopropyl amine (1.21 mL, 9.0 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (3.45 mL, 2.5M in hexanes, 9.0 mmol). The reaction mixture was stirred at -78^SC for 20 minutes and at 0°C for 15 minutes, and then cooled to -110^yesC. To the cooled reaction mixture was added dimethoxymethyl diphenyl phosphine oxide (2.18 g, 8.0 mmol) in tetrahydrofuran (120 mL) and then 2,5-dichloro-pyridine-3-carbaldehyde (1.37 g , 8.0 mmol) in tetrahydrofuran (15 mL) while keeping the reaction temperature below -100°C. The reaction mixture was stirred at -110^QC for 45 min then quenched with water (50 mL), extracted with diethyl ether and washed with brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was azeotroped with toluene and then dissolved in tetrahydrofuran (80 mL) and treated with potassium tert-butoxide (0.97 g, 9.0 mmol) at room temperature. After stirring for 2 hours the dark solution was treated with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated aqueous acidic sodium carbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.61 g).

(5-Chloro-2-{2-f4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2-oxoethoxyj-pyridin-3- il)-acetic

To a solution to 0²(2,5-Dichloro-pyridin-3-yl)-acetic acid methyl ester C (0.45 g, 2.05 mmol) 1 -[4-(4-fluoro-benzyl)- Added (2R,5S)-2,5-dimethylpiperazin-1-ylj-2-hydroxy-ethanone (0.52 g, 1.86 mmol) in toluene (5.5 mL) sodium hydride (0.082 g, 2.05 mmol, 60% dispersion in mineral oil) in toluene (9.3 mL). The reaction mixture was slowly warmed to room temperature and then refluxed overnight. The resulting reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous acidic sodium carbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.14 g) and acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- dimethylpiperazin-l-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acetic acid (0.20 g).

Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-l-piperazin-l-yl1-2-oxo-ethoxyl-pyridin3- il)- acetic

To a solution of methyl ester of the acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2-oxo- lithium hydroxide monohydrate ( 0.031 g, 0.75 mmol) at room temperature. After stirring for 4 hours the reaction mixture was filtered through a pad of silica gel diluting with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo to provide the title compound (0.061g).

N-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-1-piperazin-1-yl]-2-oxoethoxy¡} -pyridin-3-yl)-acetyl]-methanesulfonamide

To a solution of acid N-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n1 -yl]- 2-oxo-ethoxy}-pyridin-3-yl)-acetic acid (0.045 g, 0.10 mmol) in dichloromethane (2 mL) was added 4-dimethylaminopyridine (0.018 g, 0.15 mmol), and 1,3-dicyclohexylcarbodiimide ( 0.023g, 0.11mmol). The resulting reaction mixture was stirred at room temperature for 20 minutes, then treated with methanesulfonamide (0.011 g, 0.12 mmol). The reaction was stirred at room temperature for 18 hours, filtered through a pad of celite, and the resulting filter cake washed with dichloromethane. The combined organic extracts were concentrated in vacuo and purified by silica gel chromatography followed by trituration with dichloromethane to give the title compound (0.037 g, LRMS: 525.3, 527.2).

Example 27

3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R) acid₁5S)-2,5-d¡m¡l-1-piperazin-1-yl1-2-oxo-ethoxy¡l· pyrid¡n-3-¡l)-propion¡co

2,5-Dichloro-pyridine-3-carbaldehyde

To a solution of 2,5-dichloro-nicotinoyl chloride (15 g, 0.071 mol) in tetrahydrofuran was added tributylstannane (24.9 g, 0.086 mol) portionwise over 45 minutes. The resulting mixture was stirred at room temperature for 50 minutes, then treated with tetrakis(triphenylphosphine)palladium(0) (0.82 g, 0.00071 mol). The reaction mixture was stirred at room temperature for 4 hours, poured into water; the product was extracted with ethyl acetate, the combined organic extracts dried over magnesium sulphate, filtered and concentrated in vacuo. Silica gel chromatography (10% ethyl acetate/hexanes) followed by recrystallization from hexanes/ethyl acetate gave the title compound (4.3 g).

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R₁5S)-2₁5-dimethylp¡peraz¡n-1-¡l1-2-oxoethoxyl-pyridine-3-carbaldehyde

To a suspension at 0²Sodium hydride C (60% dispersion in mineral oil, 0.031 g,

0.78 mmol) in toluene (3 mL) was added 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0 0.20 g, 0.71 mmol) in toluene (2 mL). The reaction mixture was stirred at 0^yesC for 30 minutes, then treated with 2,5-dichloro-pyridine-3-carbaldehyde (0.14 g, 0.78 mmol). The resulting mixture was heated under reflux for 4 hours, cooled to room temperature, and washed with saturated aqueous acidic sodium carbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography provided the title compound (0.20 g).

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡ acid ethyl ester l12-oxo-ethoxy)-pyridin-3-l)-acrylic

To a solution to 0^Q5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-d¡methyl-piperazin-1 -ylj-2-οχοethoxyj-pyridine-3-carbaldehyde C (0.200 g, 0 0.47 mmol) in ethanol (5 ml) was added potassium carbonate (0.131 g, 0.95 mmol) in water (0.30 ml) and triethylphosphonium acetate (0.21 g, 0.19 ml). The reaction mixture is warmed to room temperature for 48 hours, filtered through celite, the filter cake washed with ethanol and concentrated in vacuo, purification by chromatography on silica gel to give the title compound (0.102 g). .

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R) ethyl ester₁5S)-2₁5-d¡methylp¡peraz¡n-1-¡l1-

2- oxo-ethox¡]-p¡r¡d¡n-3-¡l)-prop¡on

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy}-pyridin-3-yl)-acrylic acid (0.102 g, 0.21 mmol) in ethanol (20 mL) was added platinum oxide (0.010 g). The reaction mixture was stirred under positive pressure of hydrogen gas [20 psi (1.4 Kg/cm²)] during 20 minutes. The resulting mixture was filtered through a celite pad, the filter cake washed with ethanol, and the combined filtrate concentrated in vacuo to give the title compound (0.081 g).

3-(5-chloro-2-(2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy}-pyridine acid -

3- yl)-propionic

To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -¡l]- acid ethyl ester 2-oxo-ethoxy¡}-pyrid¡n-3-¡l)-prop¡ónico (0.081 g, 0.17 mmol) in tetrahydrofuran (2 ml), methanol (2 ml) and water (1 ml) lithium hydroxide monohydrate (0.013 g, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, neutralized with 0.2M hydrochloric acid and phosphate buffer (pH=7), and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by HPLC gave the title compound (0.020 g, LRMS: 464.4).

Example 28

Acid [(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2₁5-dimethyl-p¡peraz¡n-1-¡l1-2-oxo-ethylaminol p¡rid¡n-3-carbon¡l)-amino]-acet¡co

{2-f4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dmethyl-piperazin-l-yl]-2-oxo-ethyl-carbamic acid tert-butyl ester

To a solution of tert-butoxycarbonylamino-acetic acid (0.71 g, 4.05 mmol) in dichloromethane (40 mL) was added 4-dimethylaminopyridine (0.74 g, 6.07 mmol), 1-(3-dimethylaminopropyl) hydrochloride )-3-ethylcarbodiimide (1.16 g, 6.07 mmol) and 1 -(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine (0.90 g, 4.05 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (1.45 g).

2-Am¡no-1-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡met¡lD¡Deraz¡n-1-yl1-ethanona

To a solution of {2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester ( 1.45 g, 3.28 mmol) in dichloromethane (38 mL) was added trifluoroacetic acid (20 mL). The reaction was stirred at room temperature for two hours. The reaction was diluted with dichloromethane and washed with 1N sodium hydroxide. The organic layer was separated, dried over magnesium sulphate, filtered and concentrated to give the title compound (1.03g).

5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-D¡Deraz¡n-1-¡l12 acid methyl ester -oxo-ethylam¡no}-n¡cotin¡co

To a solution of 2-am¡no-1-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-¡l] -ethanone (0.27 g, 0.97 mmol) in acetonitrile (5 mL) was added 2,5-dichloro-nicotinic acid methyl ester (0.20 g, 0.97 mmol) and triethylamine (0.135 mL, 0 .97mmol). The reaction was heated at reflux for 2 hours. The reaction was concentrated and purified by silica gel chromatography to give the title compound (0.16 g).

_______5-chloro-2-|2-r4-(4-fluoro-benzyl)-(2R.5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethylamino-nicotinic acid

To a solution of 5-chloro-2-{2-[4-(fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1-¡l]-2-oxo-eth¡ acid methyl ester lamino}-n¡cotin¡co (0.16 g, 0.36 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.075 g, 1.78 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo, diluted with dichloromethane, and passed through a glass filter. The filtrate was treated with diethyl ether saturated with hydrogen chloride gas, and the white precipitate so formed was collected by filtration to give the title compound as its hydrochloride salt (0.13 g).

[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2oxo-ethylaminoj-pyridine acid methyl ester -3-carbonyl)-amino]-acetic

To a suspension of the hydrochloride salt of the acid 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-

2,5-dimethyl-piperaz¡n-1 -ylj-2-oxo-ethylaminoj-nicotinic acid (0.060 g, 0.12 mmol) in dichloromethane (2 ml) was added 1 -(3-dimethylaminopropyl)-hydrochloride 3-ethylcarbodimide (0.034 g, 0.18 mmol). The reaction was stirred at room temperature for 5 minutes. This was followed by the addition of a solution of glycine methyl ester hydrochloride (0.015 g, 0.12 mmol) and triethylamine (0.016 mL, 0.12 mmol) in dichloromethane (0.5 mL). The reaction was then stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.030 g).

r(5-chloro-2-{2-r4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethylanimo|pyridine-3- acid carbonyl)-arnino]-acetic

To a solution of [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1-yl]-2-oxo acid methyl ester -ethylamino}-pyridine-3-carbonyl)-amino]-acetic acid (0.043 g, 0.085 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.018g, 0.43mmol). The reaction was stirred overnight. The reaction was then concentrated in vacuo, diluted with dichloromethane, and passed through a frit funnel. The filtrate was treated with saturated hydrogen chloride in diethyl ether and the white precipitate formed was collected by filtration to give the title compound (0.022 g, LRMS: 492.2).

Example 29

2-(5-chloro-2-{244-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-¡ll-2-ethoxy)phen¡ acid lsulfan¡l)-2-methyl-prop¡ónico

6-Chloro-3,3-dimethyl-benzo[1,4loxathiin-2-one

2-(5-Chloro-2-methoxy-phenylsulfanyl)-2-methyl-propionic acid methyl ester (prepared from 5-chloro-2-methoxy-benzenesulfonyl chloride: Syn. Comm., (2001)) was added. , 31, 505510) (0.25 g, 0.9 mmol) to 48% hydrobromic acid (5 mL). The reaction was heated at reflux for 24 hours at which time the solvent was removed by evaporation. To the crude phenolic acid was added toluene (5 mL) and catalytic pyridinium p-toluenesulfonate. After 12 hours of heating at reflux, the reaction was concentrated and the title compound isolated by chromatography on silica gel (0.27 g).

2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2oxo-ethoxy) acid ethyl ester -phenylsulfanyl)-2-methyl-propionic

Potassium carbonate (0.015 g, 0.11 mmol) was added to 6-chloro-3,3-dimethyl-benzo[1,4]oxathiin2-one (0.050 g, 0.22 mmol) in ethanol and tetrahydrofuran (1 ml of each). After 2 hours to

50^QC, The reaction was concentrated and the phenol ethyl ester was isolated by chromatography on silica gel (0.043 g).

Diethyl azodicarboxylate (0.03 mL, 0.19 mmol) was slowly added to the above phenol (0.041 g, 0.15 mmol), triphenylphosphine (0.049 g, 0.19 mmol), and 1-[4-(4-fluoro -benzyl)-(2R,5S)-2,5dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.025 g, 0.13 mmol) in toluene (1.2 mL). After 14 hours at 50^QC, the reaction was cooled to room temperature and diluted with ethyl acetate. After washing with saturated aqueous sodium chloride, the organic layer was dried over magnesium sulfate and the title compound was isolated by chromatography on silica gel (0.056 g).

2-(5-Chloro-2-{2-f4-(4-fluoro-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-l-yl1-2-oxo-ethoxylphenylsulfanyl)-2-methyl- acid propionic

Lithium hydroxide hydrate (0.008 g, 0.19 mmol) was added to 2-(5-chloro2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-acid ethyl ester -dimethyllp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenylsulfan¡l)-2-methylpropionic acid (0.020 g, 0.4 mmol) in tetrahydrofuran, methanol and water (1 ml of each). After 1 hour at 50^QC, The reaction was concentrated and the title compound was isolated by chromatography on silica gel (0.010 g, LRMS: 509.4).

Example 30

2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-yl1-2-oxo- acid ethox¡}benzenesulfon¡l)-2-methyl-propion¡co

Oxono (0.12 g, 0.19 mmol) was added to a solution of 2-(5-chloro-2-{2-[4-(4fluoroiO-benzyl)-(2R,5S)-2 ethyl ester of acid ,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy}-phenylsulfanyl)-2-methyl-propionic acid (0.020 g, 0.04 mmol) in methanol and water (1 mL each). After 2 hours, the reaction was diluted with methylene chloride and washed with saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and the sulfone ester was isolated by chromatography on silica gel (0.014 g).

The above ester was dissolved in tetrahydrofuran and water (0.5 mL each) and lithium hydroxide hydrate (0.013 g, 0.33 mmol) added. After 4 hours the solvent was removed in vacuo and the title compound isolated by chromatography on silica gel (0.019 g, LRMS: 541.4).

Example 31

Acid________(5-chloro-2-{2[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-ill-2-oxo-ethoxy} phenylmethanesulfonylP-acetic

(5-Choro-2-(2-f4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl1-2oxo -ethoxy} -benzylsulfanyl)- acetic

Thionyl chloride (3 mL) was added to 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)(2R,5S)-2,5-dimethyl- piperazin-1-yl]-ethanone (0.50 g, 1.19 mmol). The reaction was heated at reflux for 3 hours. After concentration, the benzyl chloride was isolated by chromatography on silica gel (0.27 g).

Potassium carbonate (0.070 g, 0.51 mmol), tetrabutylammonium iodide (0.088 mg, 0.24 mmol) and finally methyl thioglycolate (0.02 mL, 0.25 mmol) were added to 2-(4-chloro-2 -chloromethyl-phenoxy)-1[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl)-ethanone (0.10 g, 0.23 mmol) in dimethyl formamide (2 ml). The reaction was stirred at 50^QC for 19 hours. The reaction was diluted with ethyl acetate and washed with pH 7 phosphate buffer (0.05M) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and the title compound was isolated by chromatography on silica gel (0.046 g).

Acid_______(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡perazin-1-¡ll-2-oxo -ethoxy¡}phenylmethanesulfonyl- acetic

Oxone (0.16 g, 0.27 mmol) was added followed by the dropwise addition of water (1 mL) to (5-chloro-2-{2-[4-(4-fluoro- benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxoethoxy}-benzylsulfanyl)-acetic acid (0.046 g, 0.9 mmol) in methanol (1 mL) at 0^QC. The reaction was allowed to warm to room temperature. After 14 hours, the reaction was diluted with methylene chloride and washed with saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and the sulfone ester was isolated by chromatography on silica gel (0.014 g).

The above ester (0.014 g, 0.03 mmol) was dissolved in tetrahydrofuran and water (0.5 mL each) and lithium hydroxide hydrate (0.003 g, 0.08 mmol) added. After 25 hours, the solvent was removed in vacuo and the title compound was isolated by chromatography on silica gel (0.007 g, LRMS: 527.1).

Example 32 Ν-[3-(3-{2-[4-(4-ΕΙίΐθΓθ-ΐ3θηύΙ)-(2Β,55)-2,5&lt;ΙϊΐΊΊ6ϋΙ-ρίρθΓ3ζ!η-1-ϋ1-2-οχο-θΐοχίΐ- 6-ΠΊθΐίΙ-ρίπυίη2-yl)-prop¡on¡ll-methanesulfonamide

3-Hydroxy-6-met¡lp¡r¡d¡na-2-carbaldehyde

Manganese dioxide (12.5 g, 143 mmol) was added to a solution of 2-hydroxymethyl-6-methyl-pyridin-3-ol (1.0 g, 7.19 mmol) in methylene chloride (30 mL) at room temperature. atmosphere. The reaction was stirred for 48 hours, then filtered through celite and concentrated to give the title compound (0.070g).

3-{2-f4-(4-Fluoro-benzyl)-(2R.5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy¡-6-methyl-pyridine-2-carbaldehyde

2-Chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methylpiperazin-1-¡l]-ethanone (0.53 g, 1.77 mmol), potassium carbonate (0.49 g, 3.5 mmol) and potassium iodide (0.29 g, 1.8 mmol) to a solution of 3-hydroxy-6-methyl-pyridine- 2-carbaldehyde (0.27 g, 1.95 mmol) in dimethylformamide (4 mL). The resulting mixture was stirred at 60^yesC overnight, then diluted with EtOAc, washed with brine, and the organic layer dried over magnesium sulfate. Filtration followed by concentration in vacuo gave the title compound (0.85 g).

3-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy}-6-methyl-pyridine-2-acid ethyl ester -yl)-acrylic

Triethylphosphonoacetate (0.65 g, 2.9 mmol) and potassium carbonate (0.4 g in 1.0 mL water) were added to a solution of 3-{2-[4-(4-fluoro-benzyl )-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]2-oxo-ethoxy}-

6-methyl-pyridine-2-carbaldehyde (0.58 g, 1.45 mmol) in EtOH (7 mL) at room temperature. The reaction was stirred for 12 hours, then filtered through celite and concentrated in vacuo. Silica gel chromatography gave the title compound (0.55 g).

3-(3-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxyl-acid ethyl ester

6-methyl-pyridin-2-yl)-propionic

To a solution of 3-(3-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1-yl]-2-oxo-ethoxy} acid ethyl ester Platinum oxide (0.050 g) was added to -6-methyl-pyridin-2-yl)-acrylic acid (0.54 g, 1.15 mmol) in EtOH (5.0 mL) and the mixture was hydrogenated at 45 psi ( 3.15 Kg/cm²) for 90 min. The mixture was filtered through celite and concentrated in vacuo to give the title compound (0.50g).

3-(3-{2-r4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy|-6-methyl-pyridin2- acid il)-propionic

Lithium hydroxide hydrate (0.089 g, 2.12 mmol) was added to a solution of 3-(3-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2, 5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-6-methyl-pyridin-2yl)-propionic acid (0.50 g, 1.06 mmol) in 2:2:1 tetrahydrofuran:methanol:water (5.0ml). The solution was stirred at room temperature for 2 hours, concentrated, diluted in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a sodium salt (0.22g).

N-f3-(3-i2-[4-(4-Fluoro-benzyl)-(2R,5S)-2.5-dinethyl-piperazin-l-yl1-2-oxo-ethoxyÍ-6-methyl-pyridin-2ill- propionill-methanesulfonamide

4-Dimethylaminopyridine (0.032 g, 0.27 mmol), (3(dimethylamino)propyl)ethylcarbodimide hydrochloride (0.051 g, 0.27 mmol), methanesulfonamide (0.025 g, 0.27 mmol) and triethylamine (0.037 mmol) were added. mL, 0.27 mmol) to a solution of 3-(3-{2-[4-(4-fluoro-benzyl)(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2 acid -oxo-ethoxy}-6-methyl-pyridin-2-yl)-propionic acid (0.10 g, 0.23 mmol) in methylene chloride (2 mL). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (0.051 g, LRMS: 521.5).

Example 33

2-Amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡perazine- acid 1-¡l]-2-oxoethoxyl-pheniD-propionic

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2.5-dinethyl-piperazin-l-ill-2oxo-ethoxy 1-phenyl' acid ethyl ester )-2-nitro -propionic

Added 2-(4-chloro-2-chloromethyl-phenox¡)-1-[4-(4-fl uoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1-yl] -ethanone (0.52 g, 1.19 mmol) to nitro-acetic acid ethyl ester (0.32 g, 2.39 mmol), sodium bicarbonate (0.10 g, 1.19 mmol) and sodium iodide tetrabutyl ammonium (0.088 g, 0.24 mmol) in dimethyl formamide (5 mL). After 1 hour of heating at 60^QC, the reaction was concentrated and then diluted with methylene chloride. After washing with saturated aqueous sodium bicarbonate and saturated sodium chloride, the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (0.30 g).

2-Amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine-lill-2-oxo acid ethyl ester -ethoxyl-phenyl)-propionic

Zinc dust (0.085 g, 1.3 mmol) was added to a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S) acid ethyl ester. -2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-2-nitropropionic acid (0.035 g, 0.065 mmol) in acetic acid (1 mL). After 2 hours of heating at 60°C, the reaction was filtered and concentrated in vacuo. Silica gel chromatography gave the title compound (0.033 g).

Acid______2-amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxoethoxy 1 -phenyl)-propionic

To a solution of 2-amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)(2R,5S)-2,5-dimethyl-p¡peraz¡ acid ethyl ester n-1 -yl]-2-oxo-ethoxy}-phenyl)-propionic acid (0.033 g, 0.065 mmol) in tetrahydrofuran, methanol and water (1 mL each) was added lithium hydroxide hydrate (0.014 g, 0. 33mmol). After 3 hours the reaction was concentrated in vacuo and the title compound isolated by chromatography on silica gel (0.031 g, LRMS 478.5).

Example 34

Acid_______[(5-chloro-2-f2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methyl-piperaz¡n-1-ill-2-oxo- ethoxyl benzyl-methyl-aminol-acetic

[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2oxo-ethoxy 1-benzyl acid methyl ester )-methyl-amino1-acetic acid

Sarcosine methyl ester hydrochloride salt (0.10 g, 0.72 mmol) followed by sodium triacetoxyborohydride (0.155 g, 0.73 mmol) was added to a solution of 5-chloro-2-{2-[4- (4-fluorobenzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.10 g, 0.24 mmol) in methanol (2.5 ml). After 15 hours the solvent was removed and the resulting solid was taken up in methylene chloride. After washing with pH 7 phosphate buffer (0.05M) and saturated aqueous sodium chloride, the organic layer was dried over magnesium sulfate. After filtration and concentration, the title compound was isolated by chromatography on silica gel (0.051 g).

r(5-chloro-2-|2-f4-(4-fluoro-benzyl)-(2R.5S)-2.5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy|-benzyl)methyl-aminol acid -acetic

[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)(2R,5S)-2,5-dimethyl-piperazin-1 -yl]- 2-oxo-ethoxy}-benzyl)-methyl-amino]-acetic acid (0.051 g, 0.10 mmol) in 1:1 tetrahydrofuran/water (1 mL) and lithium hydroxide hydrate (0.016 g, 0.38 mmol) . After

1.5 hours, the reaction was concentrated and the title compound was isolated by chromatography on silica gel (0.045 g, LRMS: 492.4).

Example 35 2-[4-Chloro-2-(2H-tetrazol-5-¡lmethox¡)-phenox¡1-1-[4-(4-fluoro-benz¡l)-(2R₁5S)-2₁5-dimethylp¡peraz¡n-1-¡l1-ethanone (5-Chloro-2-{2-[4-(4-fluoroiO-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-l-yl ]-2-oxo-ethoxyl-phenoxy)acetonitrile

Bromoacetonitrile (0.034 g, 0.28 mmol) was added to a solution of 2-(4-chloro-2-hydroxyphenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S) -2,5-dimethylp¡peraz¡n-1-yl]-ethanone (0.10 g, 0.24 mmol), and cesium carbonate (0.12 g, 0.38 mmol) in dioxane (1 mi). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (0.11 g).

2-(4-Chloro-2-(2H-tetrazol-5-ylmethoxy)-phenoxy1-l-(4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazinl-yl] -ethanone

Ammonium chloride (0.058 g, 1.1 mmol) and sodium azide (0.055 g, 0.85 mmol) were added to a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl )-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy¡}phenoxyj-acetonitrile (0.11 g, 0.25 mmol) in dimethylformamide (0.50 ml).The resulting mixture was stirred at 100⁵C for 12 hours. The reaction was cooled and diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. Trituration with diethyl ether and methylene chloride gave the title compound (0.018 g, LRMS 489.4, 491.5).

Example 36

2/5-Chloro-2d2-[4-(4-fluoro(rbenzyl)-(2R,5S)-2,5-dinethyl-piperazine-1-L1]-2-oxo-ethoxy}-phenoxy)-mcotinic acid

Potassium carbonate (0.084 g, 0.60 mmol), copper (0.0050 g, 0.078 mmol) and copper(I) iodide (0.0050 g, 0.0026 mmol) were added to a solution of 2-(4 -chloro-2-hydroxy¡-phenox¡)-1-[4-(4fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-ethanone (0.10 g , 0.25 mmol), and 2-chloronicotinic acid (0.045 g, 0.28 mmol) in dimethylformamide (0.75 mL). The resulting mixture was stirred at

145^QC for 2 hours. The reaction was cooled and diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. Chromatography on silica gel followed by trituration with methylene chloride/hydrogen chloride in diethyl ether gave the title compound as a hydrochloride salt (0.022 g, LRMS 528.4, 530.4).

Example 37

Acid (2-f2-[(2R)-2-carbamo¡lmethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1-yl1-2-oxo-ethoxy¡l-5-chlorophenoxy )-acetic

[2-(4-fluoro-benzylam¡no)-ethyl1-carbamic acid tert-butyl ester

(2-Amino-ethyl)-carbamic acid tert-butyl ester (5.95 g, 37.1 mmol), 4-fluorobenzaldehyde (5.07 g, 40.9 mmol, 4.4 mL), triethylamine were stirred (1.50 g, 14.9 mmol, 2.1 mL) and magnesium sulfate (6.71 g, 55.7 mmol) in methanol (50 mL). After 1.5 hours, the solution was cooled to 0^QC and sodium borohydride (8.4 g, 223 mmol) was added portionwise. After 2 hours, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and the desired product was extracted from the aqueous layer with 0.5M hydrochloric acid (4 x 50 mL). The combined acid wash was cooled to 0⁵C and made basic with saturated aqueous ammonium hydroxide. The aqueous layer was extracted three times with chloroform and the combined chloroform layer was washed three times with water, dried over sodium sulfate, and concentrated to give the title compound as a colorless oil (7.49 g).

4-[(2-tert-butox¡carbon¡lam¡no-ethyl)-(4-fluoro-benzyl)-am¡nol-but-2enoic acid methyl ester

[2-(4-Fluoro-benzylamino)-ethyl]-carbamic acid tert-butyl ester (7.0 g,

26.1 mmol) and potassium carbonate (7.2 g, 52.2 mmol) in acetone (150 mL). To this solution was added dropwise using an addition funnel a mixture of methyl 4-bromocrotonate (4.7 g, 26.1 mmol, 3.1 mL) in acetone (50 mL). After 18h the solution was filtered, concentrated and chromatographed on silica gel to give the title compound as a yellow oil (8.53g).

f(4R)-4-(4-fluoro-benzyl)-p¡peraz¡n-2-¡l1-acetic acid methyl ester

A solution of 4-[(2-tert-butoxycarbonylamino-ethyl)-(4-fluorobenzyl)-amino]-but-2-enoic acid methyl ester (8.5 g, 23.2 mmol) in dichloromethane ( 250 ml) and trifluoroacetic acid (25 ml) was stirred for 5 hours and then concentrated. The resulting residue was diluted with dichloromethane and the pH adjusted to 10 with saturated aqueous sodium carbonate. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 6.05 g of a pale yellow oil. The racemic mixture was separated on a chiral column using preparative HPLC to give the title compound as a white solid.

(2R)-2-[l-[(4-Chloro-2-hydroxy-phenoxy)-acetyl]-4-(4-fluoro-benzyl)-piperazin-2-yl1-acetamide

[(4R)-4-(4-fluoro-benzyl)-piperaz¡n-2-¡l]-acetic acid methyl ester (0.25 g, 0.94 mmol) was dissolved in methanol (10 mL ) and ammonia gas was bubbled into the solution for 10 min. The reaction flask was stoppered tightly and the reaction was stirred overnight. After thin layer chromatography indicated completion of the reaction, the solution was concentrated and the residue was dissolved in toluene (9 mL). 7-Chloro-benzo[1,4]dioxin-2-one (0.17 g, 0.94 mmol) was added and the solution heated to 95²C for 16h. The reaction was cooled to room temperature, concentrated in vacuo and the resulting oil chromatographed on silica gel to provide the title compound (0.19g).

(2-{2-f(2R)-2-carbamoylmethyl-4-(4-fluoroiO-benziD-piperazin-l-yl1-2-oxoethoxy)-5-chloro-phenoxy)-acetic acid tert-butyl ester

(2R)-2-[1-[(4-chloro-2-hydroxy-phenoxy¡)-acetyl]-4-(4-fluoro-benzyl)-piperazin-2-yl]acetamide (0.070 g, 0 0.16 mmol), cesium carbonate (0.078 g, 0.24 mmol) and terebutyl bromoacetate (0.038 g, 0.028 mL, 0.193 mmol) in dioxane (2 mL). After 2.5 days the solution was filtered, concentrated and chromatographed on silica gel to give the title compound as a white solid (0.077g).

Acid (2-{2[(2R)-2-carbamo¡lmethyl-4-(4-fluoro-benz¡l)-piperaz¡n-1 -¡11-2-oxoethoxy}-5-chloro-phenoxy )-acetic

A solution of (2-{2-[(2R)-2-carbamoylmethyl-4-(4-fluoro-benzyl)piperazin-l-yl]-2-oxo-ethoxy}-5-chloro acid tert-butyric ester -phenoxy)-acetic acid (0.070 g, 0.13 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.10 mL) was stirred for 3.5 hours, then concentrated. The resulting residue was diluted with dichloromethane and excess trifluoroacetic acid quenched with saturated aqueous sodium carbonate. The aqueous layer was neutralized with 0.1 N hydrochloric acid and extracted once with dichloromethane/methanol (1:1) and twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.054 g, LRMS: 492.4, 494.4).

Example 38

Acid (4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n- 1-yl]-2-oxo-ethox¡)phenox¡)-1-methylpyrrolidin-(2S)-2-carboxylic

(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl-(2R,5S)-2,5-dimethylpiperazin-1-yl] acid di-tert-butyl ester -2-oxo-ethoxy)-phenoxy)-pyrrolidine-1,2S-dicarboxylic

To a solution of 2-(4-chloro-2-hydroxy-phenox¡)-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -¡l)- ethanone (0.51 g, 1.2 mmol), triphenylphosphine (0.51 g, 1.9 mmol) and (2S,4R)-4-hydroxy-pyrrolidine-1,2-acid di-tert-butyl ester dicarboxylic acid (0.56 g, 1.9 mmol) in tetrahydrofuran (12 mL) was added diethylazodicarboxylate (0.34 g, 1.9 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo. Silica gel chromatography gave the title compound (0.76 g).

(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-acid ethoxy}phenoxy)-pyrrolidine-(2S)-2-carboxylic

(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl-(2R,5S)-2,5-dimethyl-piperazine-l-acid di-tert-butyl ester was dissolved yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidine-1,2S-dicarboxylic acid (0.76 g, 1.1 mmol) in 4N hydrogen chloride in dioxane (20 mL).The resulting mixture was stirred at room temperature for six hours The reaction was concentrated in vacuo The crude product was purified by trituration with diethyl ether to give the title compound as the bis-hydrochloride salt (0.76 g).

(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl-(2R,5S)-2,5-dimethyl-piperazin-1-yl]2-oxo-ethox acid ¡}-phenoxy)-1-methyl-pyrrolidine-(2S)-2-carboxylic

To a solution of the acid bis-hydrochloride (4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)(2R,5S)-2,5-dimethyl-piperazine -1 -yl)-2-oxo-ethoxy}-phenoxy)-pyrrolidine-(2S)-2-carboxylic acid (0.030 g, 0.051 mmol) in ethanol (6 mL) was added 37% aqueous formaldehyde (0.10 mL ), and 10% palladium on carbon (0.010 g). The resulting mixture was hydrogenated on a Parr shaker at 30 psi (2.1 kg/cm²) of hydrogen for 12 hours at room temperature. The mixture was filtered through a 0.45 pm filter and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/hydrogen chloride in diethyl ether to give the title compound as the bis-hydrochloride salt (0.030 g, LRMS 534.5, 536.5).

Example 39 C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-yl1 -2-oxo-ethox¡|-phenyl)-N(methoxycarbonlP-methanesulfonamide

(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 -ylj-2-oxo were stirred -ethoxy}phenyl)-methanesulfonamide (0.050 g, 0.103 mmol), Λ/,Λ/disopropylethylamine (0.020 g, 0.155 mmol, 0.027 mL) and methyl chloroformate (0.012 g, 0.124 mmol, 0.010 mL) in dichloromethane (1 mL ). After 3.5 hours, the solution was directly purified using radial chromatography to give the title compound (0.021 g, LRMS: 542.1, 540.2).

Example 40

6-(5-chloro-2-f2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl1-2-oxo-ethox acid ¡l· phenoxymetiD-nicotin

6-Bromomethyl-nicotinic acid methyl ester

To a solution of 6-methyl-nicotinic acid methyl ester (0.54 g, 3.57 mmol) in carbon tetrachloride (10 mL) was added 2,2'-azo-bis(2-methyl-propionitrile) ( 0.030 g, 0.18 mmol) and N-bromosuccinimide (0.703 g, 3.95 mmol). The solution was stirred at reflux for 12 hours, cooled, and concentrated in vacuo. Flash chromatography on silica gel provided the title compound (0.28 g).

6-(5-chloro-2-(2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-ill acid methyl ester -2oxo-ethoxyj-phenoxymethylj-nicotinic

To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1-ylj-ethanone (0 0.11 g, 0.27 mmol) in dioxane (1 mL) was added 6-bromomethyl-nicotinic acid methyl ester (0.075 g, 0.32 mmol) and cesium carbonate (0.15 g, 0.47 mmol). The reaction was stirred at room temperature for 6 days, then concentrated. Silica gel chromatography gave the title compound (0.13 g).

6-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡methylp¡perazin-1-¡l1-2 acid -oxo-ethoxy¡}phenoxymetiD-nicotinic

To a solution of 6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1-yl]-2- acid methyl ester oxo-ethoxy}-phenoxymethyl)-nicotinic acid (0.13 g, 0.23 mmol) in tetrahydrofuran:methanol:H₂0 2:2:1 (2 mL) lithium hydroxide hydrate (0.020 g, 0.48 mmol) was added. The reaction was stirred at room temperature for 3 hours, the pH then adjusted to 4 with 0.2M hydrochloric acid. The solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulphate, filtered and concentrated to empty. Trituration in diethyl ether provided the title compound (0.034 g, LRMS: 542.4, 544.5).

Example 41

5-(5-chloro-2-f2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-yl1-2-oxo-ethoxy}phenyl acid -5-oxo)-pentanoic

5-(5-chloro-2-hydroxy¡-phenyl)-5-oxo-pentano¡co acid ethyl ester

To a solution of 5-(5-chloro-2-hydroxy-phenyl)-5-oxo-pentanoic acid (0.38 g, 0.23 mmol), this compound was prepared by procedures described in: Eur. J. Med Chem. 1990, 25, 749) in ethanol was bubbled with hydrogen chloride (g) for 10 minutes. The resulting solution was stirred for 3 days at room temperature. Concentration gave the title compound (0.39 g).

5-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡ acid ethyl ester ll2-oxo-ethoxyl-phenyl)-5-oxo-oentanoico

To a solution of (2-chloro-1 -[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yljetanone (0.10 g, 0.35 mmol) in 2-butanone (1 mi) added potassium carbonate (0.13 g, 0.90 mmol), potassium iodide (0.065 g, 0.39 mmol) and 5-(5-chloro-2-hydroxy-phenyl)-5-acid ethyl ester -oxo-pentanoic acid (0.11 g, 0.39 mmol) The reaction was stirred at 60²C for 12 hours, then cooled and concentrated. Silica gel chromatography gave the title compound (0.089 g).

Acid 5-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-¡l1 -2-oxo-ethoxy¡}fen¡l)-5-oxo-pentano¡co

To a solution of 5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2- acid ethyl ester oxo-ethoxy}-phenyl)-5-oxo-pentanoic acid (0.089 g, 0.17 mmol) in tetrahydrofuran:methanol:H₂0 2:2:1 (2 mL) lithium hydroxide hydrate (0.025 g, 0.60 mmol) was added. The reaction was stirred at room temperature for 4 hours. The pH was then adjusted to 4 with 0.2M hydrochloric acid. The solution was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Ion exchange chromatography (MCX) provided the title compound (0.014 g, LRMS: 505.5, 507.5).

Example 42 5-(5-Chloro-2-{2-í4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-¡n-2 -oxo-ethoxy¡}-phenyl)dihydrofuran-2-one

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxyj-phenyl acid )4-hydroxy-butyric

To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl acid ]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid (0.10 g, 0.20 mmol) in methanol (4 mL) was added sodium borohydride (0.012 g, 0.32 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Trituration in diethyl ether/methylene chloride/hexanes gave the title compound (0.095 g, LRMS: 493.2, 495.3).

5-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-d¡m¡lp¡oeraz¡n-1-¡l1- 2oxo-ethoxy}-phenyl)-d¡hydrofuran-2-one

To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2oxo-ethoxyj acid -phenyl)-4-hydroxy-butyric acid (0.050 g, 0.10 mmol) in toluene (5 mL) was added p-toluene sulfonic acid (0.040 g) and the reaction stirred at reflux for 4 hours. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Trituration in diethyl ether/hexanes gave the title compound (0.052 g, LRMS: 475.2.477.3).

Example 43

4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperaz¡n-1-ill-2-oxo- acid ethox¡}p¡r¡d¡n-3-ilam¡no)-butyric

2-(5-CloiO-3-nitro-pyridin-2-yloxy)-l-[4-(4-fluoroiO-benzyl)-(2R.5S)-2.5-dimethyl-piperazin-l-yl1-ethanone

To a solution of 1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -ylj-2-hydroxy-ethanone (0.90 g, 3.2 mmol ) in toluene (20 mL) at 0^yesC Sodium hydride (0.18 g, 4.5 mmol, 60% dispersion in mineral oil) was added. The reaction was stirred for 15 minutes, then 2,5-dichloro-3-nitro-pyridine (0.65 g, 3.38 mmol) was added and the solution stirred at room temperature for 18 hours. The reaction was quenched by the slow addition of water (5 mL) and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (1.25 g).

2-(3-Amino-5-chloro-pyridin-2-yloxy)-l-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]ethanone

To a solution of 2-(5-chloro-3-nitro-pyridin-2-yloxy¡)-1 -[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazine- 1-ylj-ethanone (1.25 g, 2.86 mmol) in ethanol (50 mL) was added platinum dioxide (0.92 g). The mixture was hydrogenated on a Parr shaker at 35 psi (2.45 kg/cm²) of hydrogen for 5 minutes at room temperature. The reaction was then purged with nitrogen and filtered through celite. The filtrate was concentrated in vacuo to give the title compound (1.08 g).

4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-piperaz¡n-1 acid ethyl ester -¡l]2-oxo-ethoxy¡lp¡r¡d¡n-3-lamino)-butyric

To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1-ylj -ethanone (0.072 g, 0.18 mmol) in ethanol (1 mL) was added 4-bromo-butyric acid ethyl ester (0.030 mL, 0.21 mmol), sodium bicarbonate (0.031 g, 0.37 mmol) and potassium iodide (-0.030 g). The resulting solution was stirred at 70^QC for 18 hours. Additional bromobutyric acid ethyl ester (0.030 mL, 0.21 mmol) was added and the reaction stirred at 70^QC for 18 hours. The reaction was cooled, concentrated in vacuo and purified by flash chromatography on silica gel to give the title compound (0.034g).

4-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R5S)-2,5-dimethyl-piperaz¡n-1-¡l]- acid 2-oxo-ethoxy, pindin-3-ylaminol-butyric

To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-l-yl]-2- acid ethyl ester oxo-ethoxy}-pyridin-3-ylamino)-butyric acid (0.034 g, 0.065 mmol) in 2:2:1 methanol:tetrahydrofuran:water (1 mL) was added lithium hydroxide monohydrate (0.010 g, 0.24 mmol) . The reaction was stirred at room temperature for 3 hours. The pH of the solution was adjusted to ~4 by the addition of 0.2M hydrochloric acid, then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by ion exchange chromatography to give the title compound as its acetic acid addition salt (0.020 g, LRMS: 493.1,495.3)

Example 44

Acid_______(5-chloro-2-f2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methyl-piperaz¡n-1-ill-2-oxo-ethox ¡}p¡r¡din-3-¡lam¡no)-acetic

(5-Chloro-2-(2-[4-(4-fluoro-benzi1)-(2R,5S)-2,5-dirnethyl-piperazin-1-yl-2-oxoethoxy} -pyridin- 3-ylamino)-acetic

To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1-yl ]-ethanone (0.105 g, 0.26 mmol) in 1,2-dichloroethane (2 mL) was added ethyl glyoxylate (0.050 mL, -0.5 mmol, 50% soln in toluene), acetic acid (0.016 mL , 0.28 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol). The reaction was stirred at room temperature for 18 hours. Additional ethyl glyoxylate (0.050 mL, ~0.5 mmol, 50% soln in toluene) and acetic acid (0.016 mL, 0.28 mmol) were added and the reaction heated under reflux for 3 hours. The reaction was then cooled to room temperature, sodium cyanoborohydride (0.030 g, 0.48 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel provided the title compound (0.085 g).

(5-chloro-2-{2-í4-(4-fluoro-benzyl)-(2R.5S)-2.5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy)-pyridin-3-ylaminoj-acetic acid

To a solution of ethyl ester of the acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5dimethyl-piperazin-1 -yl]-2-oxo- ethoxy}-pyridin-3-ylamino)-acetic acid (0.080 g, 0.16 mmol) in 2:2:1 methanol:tetrahydrofuran:water (1.5 mL) was added lithium hydroxide monohydrate (0.015 g, 0.36 mmol). The reaction was stirred at room temperature for 3 hours. The pH of the solution was adjusted to ~4 by the addition of 0.2M hydrochloric acid, then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by anion exchange chromatography to give the title compound as its acetic acid addition salt (0.058 g, LRMS: 465.1, 467.2).

Example 45 2-[4-Chloro-2-(2H-tetrazol-5-¡lox¡)-fenoxy¡l-1-f4-(4-fluoro-benz¡l)-(2R)-2-methylp ¡peraz¡n-1-¡l1ethanone

2-(4-Chloro-2-hydroxy-phenoxy)-l-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-l-yl1-ethanone

To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.845 g, 4.81 mmol) in toluene (25 mL) was added (3R)-1 -(4-fluoro-benzyl)- 3-methyl-piperazine (1.003, 4.81 mmol). The resulting mixture was heated to 95^SC for one night. The reaction was cooled to room temperature, filtered, and concentrated in vacuo. Silica gel chromatography gave the title compound (~1 g).

2-(4-Chloro-2-cyanato-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-D¡Deraz¡n-1-¡ll-ethanone

To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1 -[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperaz¡n1-¡l]-ethanone (0.168 g, 0.427 mmol) in methylene chloride (2 mL) was added triethylamine (0.12 mL, 0.86 mmol). The solution was cooled to -5⁹C with an acetone/ice bath, then cyanogen bromide (0.22 mL, 0.66 mmol) was added. The reaction was stirred at -5⁵C for 30 minutes, then concentrated in vacuo to give the crude title compound which was taken directly to the next step (0.17 g).

2-f4-CloiO-2-(2H-tetrazol-5-yloxy)-phenoxy1-1-f4-('4-fluoiO-benzyl)-('2R)-2-methyl-piperazin-1-yl-1ethanone

To a solution of 2-(4-chloro-2-cyanato-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin1 -ylj-ethanone (0 0.17 g, 0.427 mmol) in acetone (2 mL) was added sodium azide (0.061 g, 0.94 mmol) and the reaction stirred at reflux for 3 hours, then cooled to room temperature and stirred for 18 hours. . The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by anion exchange chromatography to give the title compound as its acetic acid addition salt (0.073 g, LRMS: 461.2, 463.3).

Example 46

1-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡H-2- oxo-ethox¡|-phenyl)-2(1 H-tetrazol-5-yl)-ethanone

2-(4-Chloro-2-isoxazQl-5-yl-phenoxy)-l-f4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-ethanone

To a solution of (2-chloro-1 -[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yljetanone (0.30 g, 1.0 mmol) in acetonitrile (10 mL) potassium carbonate (0.207 g, 1.5 mmol), potassium iodide (0.033 g, 0.20 mmol) and 4-chloro-2-isoxazol-5-yl-phenol (0.215 g, 1.1 mmol) were added. The resulting mixture was stirred for 18 hours at room temperature.The reaction was diluted with tetrahydrofuran (10 mL), filtered, and concentrated in vacuo to give the title compound (0.465 g).

3-(5-Chloro-2-{2-f4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl1-2-oxo-ethoxy}-phenyl)- 3-oxopropionitrile

To a stirred mixture of sodium ethoxide (0.14 g, 1.0 mmol) in ethanol (2 mL) was added 2(4-chloro-2-isoxazol-5-yl-phenoxy)-1-[4-( 4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.465 g, 1.0 mmol) in ethanol (3 mL). The resulting mixture was stirred at room temperature for 3 hours. To the reaction was then added 3M hydrochloric acid (2ml) and the resulting solution was poured into water (30ml). This was extracted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (0.34 g).

1-(5-Chloro-2{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy}-phenyl) -2-(1Htetrazol-5-yl)-ethanone

To a mixture of sodium azide (0.061 g, 0.95 mmol) and aluminum trichloride (0.042 g, 0.31 mmol) was added 3-(5-chloro-2-{2-[4-(4-fluoro -benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy}-phenyl)-3oxo-propionitrile (0.035 g, 0.076 mmol) in tetrahydrofuran (2 mL). The reaction was heated to 70°C and stirred for 18 hours. To this was added saturated aqueous sodium bicarbonate (0.5ml) and dimethylsulfoxide (0.5ml) and the solution was stirred for 1 hour at room temperature. The solids were filtered off and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give the title compound which was converted to its hydrochloride salt (0.020 g, LRMS: 501.2).

Example 47

1-(5-Chloro-2-{2-(4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1-¡ll-2- oxo-ethoxy¡}-phenyl)-3(1 H-tetrazol-5-yl)-propan-1 -one

4-(5-Chloro-2-hydrox¡-phenyl)-4-oxo-but¡ronitr¡le

A solution of 1-(5-chloro-2-hydroxy-phenyl)-ethanone (1.0 g, 5.86 mmol) and magnesium methylcarbonate (13 mL, 32.5 mmol, 2.5 M soln in DMF) it was stirred at 120°C for 3 hours. The mixture was cooled to room temperature followed by the addition of bromoacetonitrile (1.22 mL, 17.6 mmol). The resulting solution was stirred at 90°C for 3 hours. The reaction was cooled to room temperature, then slowly poured into 1M hydrochloric acid (200ml). This was extracted with ethyl acetate, washed with brine, dried over magnesium sulphate, filtered and concentrated. Flash chromatography on silica gel gave the title compound (0.72 g).

4-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R₁5S)-2_he5-dimethylp¡peraz¡n-1-¡l]-2-oxo-ethoxy}-phenyl)-4oxo-butyronitrile

To a solution of 4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyronitrile (0.15 g, 0.70 mmol) in acetonitrile (4 mL) was added potassium carbonate (0.16 g, 1.16 mmol), potassium iodide (0.040 g, 0.24 mmol) and (2-chloro-1 -[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1 -yl]- ethanone (0.21 g, 0.70 mmol) The reaction was stirred for 20 hours at room temperature Tetrahydrofuran (8 mL) was added and the solids removed by filtration. The filtrate was concentrated and the crude product was purified by flash chromatography to give the title compound (0.31 g).

1-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R₁5S)-2_he5-dimethylp¡peraz¡n-1-¡H-2oxo-ethoxy}-phenyl)-3-(1 H-tetrazol-5-¡l)-Dropan-1 -one

To a mixture of sodium azide (0.061 g, 0.95 mmol) and aluminum dichloride (0.042 g, 0.31 mmol) was added 3-(5-chloro-2-{2-[4-(4-fluoro -benzyl)-(2R,5S)-2,5-dimethyl-piperazin-l-yl]-2-oxo-ethoxy}-phenyl)-3oxo-propionitrile (0.036 g, 0.076 mmol) in tetrahydrofuran (2 mL). The reaction was heated to 70°C and stirred for 18 hours. To this was added saturated aqueous sodium bicarbonate (0.5 ml) and dimethyl sulphoxide (0.5 ml) and the solution was stirred for 1 hour at room temperature. The solids were filtered off and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give the title compound which was converted to its hydrochloride salt (0.008 g, LRMS: 515.2, 517.3).

Compounds in Table 1 were prepared according to the procedures described above in Examples 1-47.

Table I: Example of compounds prepared

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 48</td><td>(2-{3-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]- acid 3-oxo-propyl} -5-methoxy-phenoxy)-acetic</td><td> 457,4</td>

<td> 49</td><td>Acid (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine-1- yl]-3-oxo-propyl}-5-methyl-phenoxy)-acetic</td><td> 441,4</td>

<td> 50</td><td>N-[(2-{3-[4-(4-Fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-p¡perazin-1-yl]- 3- oxo-propyl}-5-methoxy-phenox¡)-acet¡l]-methanesulfonamide</td><td> 536,3</td>

<td> 51</td><td>Acid (5-chloro-2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-3-oxo-propyl}-phenoxy)-acetic</td><td> 463,1, 465,1</td>

<td> 52</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-oxo-acetic</td><td> 461,2</td>

<td> 53</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic</td><td> 465,2, 467,2</td>

<td> 54</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 - yl]-2-oxo-ethoxy}-phenoxy)-acetic</td><td> 451,1, 453,2</td>

<td> 55</td><td>N-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]- 2-oxo-ethoxy}-phenox¡)-acetyl]-methanesulfonamide</td><td> 528,1, 530,1</td>

<td> 56</td><td>Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenox¡)-acetic</td><td> 509,1, 511,1</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 57</td><td>Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine- 1-yl]-2-oxo-ethoxy}-phenoxy)-acetic</td><td> 495,2, 497,2</td>

<td> 58</td><td>(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]- acid 2-oxo-ethoxy}-phenoxy)-acetic</td><td> 465,1, 467,2</td>

<td> 59</td><td>N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetyl]-methanesulfonamide</td><td> 586,0, 588,0</td>

<td> 60</td><td>N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1- yl]-2-oxo-ethoxy}-phenoxy)-acetyl]-methanesulfonamide</td><td> 572,0, 574,0</td>

<td> 61</td><td>N-[(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenoxy)-acet¡l]-methanesulfonamide</td><td> 542,1</td>

<td> 62</td><td>2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1 -yl]-2-oxo-ethoxy}-phenoxy)-2-methyl-propionic</td><td> 493,2, 495,2</td>

<td> 63</td><td>4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-¡l]-2-oxo-ethoxy}-phenoxy)-butyric</td><td> 493,2, 495,2</td>

<td> 64</td><td>6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-pyridine-2-carboxylic</td><td> 528,2, 530,2</td>

<td> 65</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-</td><td> 501,4,</td>

<td></td><td>piperazin-1 -yl]-2-oxo-ethoxy}-phenox¡)-d¡fluoro-acetic</td><td> 503,5</td>

<td> 66</td><td>(2R)-2-amino-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)- acid 2,5-dimethylp¡peraz¡n-1 -yl]-2-oxo-ethoxy}-phenox¡)-butyric</td><td> 508,4</td>

<td> 67</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 - yl]-2-oxo-ethoxy}-phenox¡)-d¡fluoro-acetic</td><td> 487,4, 489,3</td>

<td> 68</td><td>4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine-1- acid yl] -2- oxo -ethoxy} -phenoxy) -butyric</td><td> 479,5, 481,5</td>

<td> 69</td><td>2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine- acid 1 -yl]-2-oxo-ethoxy¡}-phenox¡)-2-methyl-prop¡ónico</td><td> 479,5, 481,5</td>

<td> 70</td><td>(2S)-2-amino-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)- acid 2,5-dimethyl-piperazin-l -yl]-2-oxo-ethoxy¡}-phenoxy¡)-butyric acid</td><td> 508,5</td>

<td> 71</td><td>2-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy¡}-phenoxy)-2-methyl-propionic</td><td> 537,2, 539,2</td>

<td> 72</td><td>Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-difluoro-acetic acid</td><td> 545,1, 547,1</td>

<td> 73</td><td>2-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- acid piperazin-1-yl]-2-oxo-ethoxy¡}-phenoxy)-2-methyl-propionic</td><td> 523,2, 525,2</td>

<td> 74</td><td>Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n- 1-yl]-2-oxo-ethoxy}-phenoxy¡)-difluoro-acetic acid</td><td> 531,1, 533,1</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 75</td><td>(2S)-2-amino-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2- acid methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-butyric acid</td><td> 494,4</td>

<td> 76</td><td>(2S)-2-amino-4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)- acid 2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-butyric</td><td> 550,2, 552,2</td>

<td> 77</td><td>4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid</td><td> 521,5</td>

<td></td><td>piperazine-1 -¡l]-2-oxo-ethoxy}-phenox¡)-pyr¡d¡na-2-carboxylic</td><td></td>

<td> 78</td><td>N-[(2R)-2-Amino-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)- 2.5- dimethyl-piperazin-1 -yl]-2-oxo-ethoxy¡}-phenoxy)-butyr¡l]- methanesulfonamide</td><td> 585,5, 587,5</td>

<td> 79</td><td>2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-thiazole-4-carboxylic</td><td> 548,2, 550,3</td>

<td> 80</td><td>3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-furan-2-carboxylic</td><td> 531,2, 533,2</td>

<td> 81</td><td>5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-furan-2-carboxylic</td><td> 531,3, 533,3</td>

<td> 82</td><td>3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1 -yl]-2-oxo-ethoxy}-phenoxymethyl)-thiophene-2-carboxylic</td><td> 547,2, 549,3</td>

<td> 83</td><td>2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1 -yl]-2-oxo-ethoxy}-phenoxymethyl)-furan-3-carboxylic</td><td> 531,2, 533,3</td>

<td> 84</td><td>5-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-thiophene-2-carboxylic</td><td> 547,2, 549,2</td>

<td> 85</td><td>3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine- acid 1-yl]-2-oxo-ethoxy}-phenoxymethyl)-furan-2-carboxylic</td><td> 517,1, 519,2</td>

<td> 86</td><td>3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazine-1- acid yl]-2-oxo-ethoxy¡}-phenox¡methyl)-furan-2-carboxylic</td><td> 561,1, 563,1</td>

<td> 87</td><td>5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy¡}-phenoxy)-5-(2-methoxy-ethyl)-pyrimidine- 2,4,6-thryone</td><td> 591,1, 593,3</td>

<td> 88</td><td>5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-</td><td> 547,0</td>

<td></td><td>piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-5-methyl-pyrimidine-2,4,6- triona</td><td></td>

<td> 89</td><td>5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -¡l]-2-oxo-ethoxy}-phenox¡)-5-et¡lp¡r¡mid¡na-2,4,6-tr¡one</td><td> 561,0</td>

<td> 90</td><td>(2S)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- acid dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenoxy)-propionic</td><td> 479,2, 481,2</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 91</td><td>(2R)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- Acid piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-propionic</td><td> 465,2, 467,2</td>

<td> 92</td><td>(2S)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-propionic</td><td> 465,2, 467,3</td>

<td> 93</td><td>(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- acid dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidin-2-carboxylic</td><td> 520,4</td>

<td> 94</td><td>3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-2,2-dimethyl-propionic</td><td> 507,5, 509,7</td>

<td> 95</td><td>(4S)-4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- acid dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidine-(2S)-2- carboxylic</td><td> 564,4, 566,4</td>

<td> 96</td><td>(4S)-4-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidine-(2S)-2-carboxylic</td><td> 550,4, 552,4</td>

<td> 97</td><td>(4S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- acid dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidine-(2S)-2-carboxylic</td><td> 520,4</td>

<td> 98</td><td>N-[(4S)-4-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethox¡}-phenox¡)-p¡rrol¡d¡na-(2S)-2-carbon¡l]- methanesulfonamide</td><td> 597,5</td>

<td> 99</td><td>Acid [3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-ureido]-acetic</td><td> 507,2</td>

<td> 100</td><td>3-[3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethox¡}-fen¡l)-ure¡do]-propionic</td><td> 521,2</td>

<td> 101</td><td>3-[3-(4-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -il]-2-oxo-ethox¡}-fen¡l)-ure¡do]-propion¡co</td><td> 521,2</td>

<td> 102</td><td>Acid [3-(4-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- piperazin-1 -il]-2-oxo-ethox¡}-fen¡l)-ureido]-acet¡co</td><td> 507,2</td>

<td> 103</td><td>1 -(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-3-(methylsulfonyl)-urea</td><td> 527,2</td>

<td> 104</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy¡}-benzylsulfamoyl)-acetic</td><td> 542,3</td>

<td> 105</td><td>1 -(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-3-(methylsulfonyl)-urea</td><td> 541,2</td>

<td> 106</td><td>1 -[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy¡}-benzyl)]-3-(2-methylbenzoyl)sulfamide</td><td> 617,2</td>

<td> 107</td><td>Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-benzylideneaminooxy)-acetic</td><td> 538,2</td>

<td> 108</td><td>Acid [1 -(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethylideneaminooxy]-acetic</td><td> 506,2</td>

<td> 109</td><td>[1 -(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl]-2-oxo-ethoxy}-phenyl acid )-ethylideneaminooxy]-acetic</td><td> 552,1</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 110</td><td>Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-phenyl-methyleneaminoox¡]-acetic</td><td> 568,0</td>

<td> 111</td><td>Acid (2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 - yl]-2-oxo-ethoxy}-5-methyl-benzyldenaminooxy)-acetic</td><td> 471,5</td>

<td> 112</td><td>(2S)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- acid dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-benz¡lox¡)-prop¡ónico</td><td> 493</td>

<td> 113</td><td>(2R)-2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- acid dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-benzyloxy)-prop¡onic</td><td> 493</td>

<td> 114</td><td>2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1 -yl]-2-oxo-ethoxy¡}-benz¡loxy)-2-methyl-propionic</td><td> 507,6</td>

<td> 115</td><td>5-Chloro-2-{2-[4-(4-fluoro-benzyl)- ester Methylsulfonyl-carbamic acid (2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-benzyl</td><td> 540,3, 542,2</td>

<td> 116</td><td>N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-benzoyl)-methanesulfonamide</td><td> 512,2</td>

<td> 117</td><td>N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]- 2-oxo-ethoxy}-benzoyl)-methanesulfonamide</td><td> 498,1</td>

<td> 118</td><td>N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy¡}-phenyl)-acetyl]-methanesulfonamide</td><td> 570,0, 572,1</td>

<td> 119</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-piperaz¡n-1 -yl]-2-oxo-ethoxy¡}- phenyl)-acetyl]-methanesulfonamide</td><td> 498,1</td>

<td> 120</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-</td><td> 579,3</td>

<td></td><td>piperazin-1 -yl]-2-oxo-ethox¡}-phenyl)-acet¡l]-C,C,C-trifluoro- methanesulfonamide</td><td></td>

<td> 121</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-¡l]-2-oxo-ethoxy}-phenyl)-acet¡l]-4-fluorobenzenesulfonamide</td><td> 607,1</td>

<td> 122</td><td>N-[(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]- 2-oxo-ethoxy}-4-methoxy¡-phenyl)-acetyl]-methanesulfonamide</td><td> 522,3</td>

<td> 123</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethox¡}-phenyl)-acet¡l]-benzenesulfonamide</td><td> 588,4</td>

<td> 124</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-2-methyl- benzenesulfonamide</td><td> 602,4</td>

<td> 125</td><td>[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n- Ethanesulfonic acid 1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-amide</td><td> 540,3</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 126</td><td>[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine- 3,5-Dimethyl-acid 1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-amide isoxazole-4-sulfonic acid</td><td> 607,2</td>

<td> 127</td><td>N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-piperazin-1 -yl]-2-oxo- ethoxy}-phenyl)-acetyl]-methanesulfonamide</td><td> 542,1, 544,1</td>

<td> 128</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]- 2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide</td><td> 512,0</td>

<td> 129</td><td>N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine-1- yl]-2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide</td><td> 556,2, 558,1</td>

<td> 130</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-</td><td> 618,2</td>

<td></td><td>piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-4-methoxy¡- benzenesulfonamide</td><td></td>

<td> 131</td><td>2-Chloro-N-[(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethox¡}-phenyl)-acetyl]-benzenesulfonamide</td><td> 622,1</td>

<td> 132</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-2-fluoro- benzenesulfonamide</td><td> 606,1</td>

<td> 133</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-4-methyl- benzenesulfonamide</td><td> 602,2</td>

<td> 134</td><td>[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n- propane-2- acid 1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-amide sulfonic</td><td> 544,2</td>

<td> 135</td><td>[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n- Propane-1- acid 1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-amide sulfonic</td><td> 544,2</td>

<td> 136</td><td>[(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin- 1-yl]-2-oxo-ethox¡}-phenyl)]-Nc¡anoacetamide</td><td> 473,2</td>

<td> 137</td><td>N-[(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy¡}-phenyl)-acetyl]-methanesulfonamide</td><td> 526,2</td>

<td> 138</td><td>N-[(4-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]- 2-oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td> 512,2, 510,3</td>

<td> 139</td><td>N-[(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide</td><td> 544,2</td>

<td> 140</td><td>N-[(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-dimethyl-</td><td> 542,3</td>

<td></td><td>piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td></td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 141</td><td>N-[(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 -yl]- 2-oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td> 492,2</td>

<td> 142</td><td>N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-C-phenyl- methanesulfonamide</td><td> 602,1</td>

<td> 143</td><td>N-[3-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine-1 - yl]-2-oxo-ethox¡}-phenyl)-prop¡on¡l]-methanesulfonamide</td><td> 506,5</td>

<td> 144</td><td>N-[(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -yl]- 2-oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td> 528,1</td>

<td> 145</td><td>N-[(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methylp¡peraz¡n- 1 -yl]-2-oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td> 530,2</td>

<td> 146</td><td>N-[(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡perazin-1 -yl]-2- oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td> 526,2, 528,2</td>

<td> 147</td><td>N-[(5-Bromo-2-{(2R)-2-[2-ethyl-4-(4-fluoro-benz¡l)-p¡peraz¡n-1 -yl]- 2-oxo-ethoxy}-phenyl)-acet¡l]-methanesulfonamide</td><td> 568,2, 570,2</td>

<td> 148</td><td>N-[(2-{2-[(2R)-2-Ethyl-4-(4-fluoro-benzyl)-piperazin-1 -yl]-2-oxo- ethoxy}-5-methyl-phenyl)-acetyl]-methanesulfonamide</td><td> 506,2</td>

<td> 149</td><td>N-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 - ¡l]-2-oxo-ethoxy}-phenyl)-propion¡l]-methanesulfonamide</td><td> 526,1</td>

<td> 150</td><td>N-[3-(2-{2-[4-(4-Fluoro-benz¡l)-(2R)-2-methyl-piperaz¡n-1 -yl]-2- oxo-ethox¡}-5-methyl-phenyl)-prop¡onyl]-methanesulfonamide</td><td> 506,2</td>

<td> 151</td><td>N-[3-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-d¡methylp¡perazine-1- ¡l]-2-oxo-ethoxy}-5-methyl-phenyl)-propion¡l]-methanesulfonamide</td><td> 520,2</td>

<td> 152</td><td>N-[3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 - il]-2-oxo-ethox¡}-fen¡l)-propion¡l]-methanesulfonam¡de</td><td> 570,1, 572,1</td>

<td> 153</td><td>N-[3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethox¡}-phenyl)-propionyl]-methanesulfonamide</td><td> 584,1, 586,1</td>

<td> 154</td><td>N-[3-(2-{2-[(2R)-2-Ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -ÍIJ-2-οχο- ethoxy}-5-methyl-phenyl)-propionyl]-methanesulfonamide</td><td> 520,2</td>

<td> 155</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-benzylamino)-acetic</td><td> 478,5</td>

<td> 156</td><td>Acid 3-(5-bromo-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic</td><td> 505,1</td>

<td> 157</td><td>3-(2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n- 1 -¡l]-2-oxo-ethoxy}-5-methyl-phenyl)-acrylic</td><td> 441,4</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 158</td><td>3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine- acid 1-yl]-2-oxo-ethoxy}-phenyl)-acrylic</td><td> 446,1</td>

<td> 159</td><td>3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic</td><td> 490,1</td>

<td> 160</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - yl]-2-oxo-ethoxy¡}-N-(ethylamino)carbonyl]-benzenesulfonamide</td><td> 541,2</td>

<td> 161</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1 - ¡l]-2-oxo-ethox¡}-N-(phenylam¡no)carbonyl]-benzenesulfonam¡de</td><td> 589,1</td>

<td> 162</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1- yl]-2-oxo-ethoxy¡}-N-(2-methylphenylamino)carbon¡l]- benzenesulfonamide</td><td> 603,1</td>

<td> 163</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethyl-p¡peraz¡n-1-</td><td> 607,1</td>

<td></td><td>¡l]-2-oxo-ethoxy}-N-(4-fluorofen¡lam¡no)carbon¡l]- benzenesulfonamide</td><td></td>

<td> 164</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - yl]-2-oxo-ethoxy}-N-(methoxy¡carbon¡l]-benzenesulfonamide</td><td> 470,3</td>

<td> 165</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - yl]-2-oxo-ethox¡}-N-(ethoxy¡carbon¡l]-benzenesulfonamide</td><td> 470,3</td>

<td> 166</td><td>5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - il]-2-oxo-ethox¡}-N-¡sobutyr¡l-benzenesulfonam¡de</td><td> 540,4</td>

<td> 167</td><td>5-Chloro-N-cyclopropanecarbonyl-2-{2-[4-(4-fluoro-benzyl)- (2R,5S)-2,5-dimethylp¡peraz¡n-1 -¡l]-2-oxo-ethoxy}- benzenesulfonamide</td><td> 538,4</td>

<td> 168</td><td>N-Acet¡l-5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-d¡methyl- piperazin-1-l]-2-oxo-ethox¡}-benzenesulfonamide</td><td> 512,2</td>

<td> 169</td><td>5-Chloro-N-cyclopentanecarbonyl-2-{2-[4-(4-fluoro-benzyl)- (2R,5S)- 2,5-dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-benzenesulfonamide</td><td> 566,2</td>

<td> 170</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperaz¡n-1-¡l]-2-oxo-ethox¡}-benzenesulfon¡lam¡no)-oxo-acet¡co</td><td> 542,3</td>

<td> 171</td><td>5-Gloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine-1 - ¡l]-2-oxo-ethox¡}-Nh¡drox¡acet¡l-benzenesulfonam¡da</td><td> 528,2</td>

<td> 172</td><td>N-Acet¡lC-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 510,2, 512,1</td>

<td> 173</td><td>N-Acet¡lC-(5-chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 530,2</td>

<td> 174</td><td>N-Acet¡lC-(5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-</td><td> 528,2</td>

<td></td><td>piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td></td>

<td> 175</td><td>(5-Chloro-2-{2-[4-(3,4-d¡fluoro-benzyl)-(2R)-2-methyl-piperaz¡n-1 -ylj- 2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 488,1</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 176</td><td>(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -ilj-2- oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 486,1</td>

<td> 177</td><td>(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 470,1</td>

<td> 178</td><td>C-(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 - yl]-2-oxo-ethoxy¡}-phenyl)-N-cyclopropanecarbonyl- methanesulfonamide</td><td> 556,2</td>

<td> 179</td><td>C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]-2- oxo-ethox¡}-phenyl)-N-trifluoroacetyl-methanesulfonamide</td><td> 582,1</td>

<td> 180</td><td>(5-Chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 484,1, 486,1</td>

<td> 181</td><td>(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n- 1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 528,1, 530,1</td>

<td> 182</td><td>(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 514,1, 516,1</td>

<td> 183</td><td>(5-Bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benz¡l)-piperaz¡n-1 -yl]-2- oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 528,1, 530,1</td>

<td> 184</td><td>N-Acet¡lC-(5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benz¡l)- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 526,1, 528,1</td>

<td> 185</td><td>N-Acet¡lC-(5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5- dimethyl-piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 570,1, 572,1</td>

<td> 186</td><td>N-Acet¡lC-(5-bromo-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methyl- piperazin-1 -yl]-2-oxo-ethox¡}-phenyl)-methanesulfonam¡de</td><td> 556,0, 558,0</td>

<td> 187</td><td>N-Acet¡lC-(5-bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benz¡l)- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 570,1, 572,1</td>

<td> 188</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R_:5S)-2,5-dimethyl- piperazin-1 -¡l]-2-oxo-ethoxy}-phenyl)-N-(2,2-dimethyl-propion¡l)- methanesulfonamide</td><td> 566,3, 568,2</td>

<td> 189</td><td>(5-Chloro-2-{2-[4-(3,4-d¡fluoro-benzyl)-(2R,5S)-2,5-d¡methyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 502,4</td>

<td> 190</td><td>(5-Chloro-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - ¡l]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 501,8</td>

<td> 191</td><td>N-Acet¡lC-(5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-d¡methyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 542,3</td>

<td> 192</td><td>C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N-cyclopropanecarbonyl- methanesulfonamide</td><td> 568,3</td>

<td> 193</td><td>C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy¡}-phenyl)-N-trifluoroacetyl- methanesulfonamide</td><td> 596,2</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 194</td><td>N-Acetyl-C-(5-chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R,5S)-2,5- dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 544,3</td>

<td> 195</td><td>C-(5-Chloro-2-{2-[4-(3,4-d¡fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N-cyclopropanecarbonyl- methanesulfonamide</td><td> 570,3</td>

<td> 196</td><td>(5-Bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-p¡peraz¡n-1 -¡l]-2- oxo-ethoxy}phenyl)methanesulfonamide</td><td> 530,0</td>

<td> 197</td><td>N-Acet¡lC-(5-bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 573,9</td>

<td> 198</td><td>N-Acet¡lC-(5-bromo-2-{2-[4-(4-chloro-benz¡l)-(2R,5S)-2,5- dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 586,2</td>

<td> 199</td><td>(5-Bromo-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-p¡peraz¡n- 1-¡l]-2-oxo-ethoxy}-phenyl)-methanesulfonamide</td><td> 544,2</td>

<td> 200</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenylmethanesulfon¡lam¡no)-oxo- acetic</td><td> 556,3, 554,4</td>

<td> 201</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N-(1 -hydroxy- cyclopropanecarbonylj-methanesulfonamide</td><td> 568,4, 566,3</td>

<td> 202</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine-1- ¡l]-2-oxo-ethox¡}-phen¡lmethanesulfonylam¡no)-oxo-acetic</td><td> 542,3, 540,2</td>

<td> 203</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy¡}-phenyl)-N-methoxyacetyl- methanesulfonamide</td><td> 556,4, 554,3</td>

<td> 204</td><td>N-Acet¡lC-(2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methyl-piperaz¡n-1-¡l]- 2-oxo-ethoxy}-5-trifluoromethyl-phenyl)-methanesulfonamide</td><td> 546,2</td>

<td> 205</td><td>N-Acetyl-C-(2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-5-trifluoromethyl-phenyl)- methanesulfonamide</td><td> 560,2</td>

<td> 206</td><td>(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]-2-</td><td> 518,2</td>

<td></td><td>oxo-ethox¡}-5-trifluoromethyl-phenyl)-methanesulfonamide</td><td></td>

<td> 207</td><td>(2-{2-[4-(4-Fluoro-benz¡l)-(2R)-2-methyl-piperaz¡n-1 -¡l]-2-oxo- ethoxy}-5-trifluoromethyl-phenyl)-methanesulfonamide</td><td> 504,1</td>

<td> 208</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -¡l]-2-oxo-ethoxy}-phenyl)-Nh¡drox¡acetyl- methanesulfonamide</td><td> 540,2, 542,4</td>

<td> 209</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1 -yl]-2-oxo-ethoxy} -phenyl)-N-(3-hidrox¡-3-methyl-butyryl)methanesulfonamide</td><td> 582,3, 584,4</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 210</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -ilj- 2-oxo-ethoxy}-phenyl)-N-(2-hydroxy-2-methyl-propionyl)- methanesulfonamide</td><td> 554,2, 556,4</td>

<td> 211</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -ylj- 2-oxo-ethoxy}-phenyl)-Nh¡drox¡acetyl-methanesulfonam¡de</td><td> 526,2, 528,3</td>

<td> 212</td><td>C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N-(2-hydroxy-2-methyl-propionyl)- methanesulfonamide</td><td> 588,2</td>

<td> 213</td><td>C-(5-Chloro-2-{2-[4-(3,4-d¡fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N-(2-hydroxy-2-methyl-propionyl)- methanesulfonamide</td><td> 586,2</td>

<td> 214</td><td>C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-hydroxyacetyl- methanesulfonamide</td><td> 558,1</td>

<td> 215</td><td>C-(5-Chloro-2-{2-[4-(3,4-difluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-</td><td> 560,1</td>

<td></td><td>piperazin-1 -¡l]-2-oxo-ethox¡}-fen¡l)-N-hidrox¡acet¡l- methanesulfonamide</td><td></td>

<td> 216</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methyl-p¡perazin-1 -yl]- 2-oxo-ethoxy}-phenyl)-N-(3-hydroxy¡-3-methyl-but¡ryl)- methanesulfonamide</td><td> 570,2, 568,3</td>

<td> 217</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -¡I]- 2-oxo-ethoxy}-phenyl)-N-(1-hydroxy-cyclopropanecarbonyl)- methanesulfonamide</td><td> 554,4, 552,3</td>

<td> 218</td><td>C-(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1 -yl]- 2- oxo-ethoxy}-5-t¡fluoromethyl-phenyl)-Nh¡droxiacet¡l- methanesulfonamide</td><td> 576,3</td>

<td> 219</td><td>C-(2-{2-[4-(4-Fluoro-benz¡l)-(2R,5S)-2,5-d¡methyl-p¡peraz¡ri-1 -yl]- 2- oxo-ethox¡}-5-t¡fluoromethyl-phenyl)-N-(2-hydroxy¡-2-methyl-propion¡l)methanesulfonamide</td><td> 604,1</td>

<td> 220</td><td>C-(2-{2-[4-(4-Fluoro-benzyl)-(2R)-2-methylp¡peraz¡n-1 -¡l]-2-oxoethoxy}-5-trifluoromethyl l-phenyl)-N-(2-hydroxy-2-methyl-propion¡l)methanesulfonamide</td><td> 590,2</td>

<td> 221</td><td>C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1 -yl]- 2-oxo-ethoxy}-phenyl)-N-(methoxycarbon¡l)-methanesulfonamide</td><td> 526,2, 528,3</td>

<td> 222</td><td>C-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-N-(methoxycarbon¡l)- methanesulfonamide</td><td> 558,1</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 223</td><td>C-(5-Chloro-2-{2-[4-(3,4-d¡fluoro-benz¡l)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy¡}-phenyl)-N-(methoxycarbon¡l)- methanesulfonamide</td><td> 560,1</td>

<td> 224</td><td>N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methylp¡peraz¡n- acid 1 -¡l]-2-oxo-ethoxy}-pyridin-3-¡l)-2,2-dimethyl-succinamic</td><td> 521,2</td>

<td> 225</td><td>Acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1 -yl]-2-oxo-ethoxy}-p¡r¡d¡na-3-carbonyl)-am¡no]-acetic</td><td> 493,2</td>

<td> 226</td><td>N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy¡}-pyridin-3-yl)-succinamic</td><td> 507,2</td>

<td> 227</td><td>3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy¡}-pyridin-3-yl)-acrylic</td><td> 462,2</td>

<td> 228</td><td>3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethylamino}-pyridin-3-yl)-propionic</td><td> 463,4, 461,4</td>

<td> 229</td><td>N-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-propionyl- methanesulfonamide</td><td> 541</td>

<td> 230</td><td>2-amino-3-(5-chloro-2-{2-[4-(4-fluoro-benz¡l)-(2R,5S)-2,5- acid dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-propionic</td><td> 479,4, 477,7</td>

<td> 231</td><td>Acid [(5-oloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-ylmethyl)-amino]-acetic</td><td> 479,2, 477,5</td>

<td> 232</td><td>2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1 -yl]-2-oxo-ethoxy¡}-phenoxy)-6-methyl-pyrimidine-4- carboxylic</td><td> 543,2, 545,3</td>

<td> 233</td><td>2-(5-Oloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-4-methyl-thiazole-5-carboxylic</td><td> 548,1, 550,2</td>

<td> 234</td><td>6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1 -yl]-2-oxo-ethoxy}-phenox¡)-n¡cotin¡co</td><td> 528,1, 530,2</td>

<td> 235</td><td>2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-nicotinic</td><td> 542,4, 544,5</td>

<td> 236</td><td>6-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy¡}-pyridin-3-ylamino)-methyl]-nicotinic</td><td> 542,0</td>

<td> 237</td><td>2-[4-Chloro-2-(2H-tetrazol-5-yloxy)-phenoxy]-1-[4-(4-fluoro-benzyl)- (2R,5S)-2,5-dimethyl-piperazin-1 -ylj-ethanone</td><td> 473,4, 475,4</td>

<td> 238</td><td>2-[4-Bromo-2-(2H-tetrazol-5-yloxy¡)-phenoxy¡]-1 -[4-(4-fluoro-benzyl)- (2R)-2-methyl-piperazin-1-ylj-ethanone</td><td> 505,2, 507,2</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 239</td><td>Acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine-1- yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 435</td>

<td> 240</td><td>Acid (5-bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 495,1, 493,1</td>

<td> 241</td><td>(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine- acid 1-yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 479,1</td>

<td> 242</td><td>Acid (2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine-1- yl]-2-oxo-ethoxy}-4-methoxy-phenyl)-acetic</td><td> 445,4</td>

<td> 243</td><td>3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine- acid 1-yl]-2-oxo-ethoxy}-phenyl)-propionic</td><td> 449,1, 447,3</td>

<td> 244</td><td>Acid (4-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 449,2, 447,4</td>

<td> 245</td><td>Acid (4-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazine-1- yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 435,2, 433,4</td>

<td> 246</td><td>3-(2-{2-[4-(4-fluoro-benz¡l)-(2R)-2-methylp¡perazin-1 -yl]-2- acid oxo-ethoxy}-5-methyl-phenyl)-propionic</td><td> 429,3</td>

<td> 247</td><td>3-(2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n- 1 -¡l]-2-oxo-ethoxy}-5-methyl-phenyl)-propionic</td><td> 443,3</td>

<td> 248</td><td>3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl- acid piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-prop¡onic acid</td><td> 493,1, 495,1</td>

<td> 249</td><td>3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl- acid piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic</td><td> 507,1, 509,1</td>

<td> 250</td><td>Acid (5-chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 465,2</td>

<td> 251</td><td>Acid (5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl- piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 467,2</td>

<td> 252</td><td>(5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]- acid 2-oxo-ethoxy}-phenyl)-acetic</td><td> 449,2, 451,2</td>

<td> 253</td><td>(5-Bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazine-1-acid yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 493,2, 495,2</td>

<td> 254</td><td>Acid (5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-piperazine-1- yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 451,1</td>

<td> 255</td><td>Acid (5-chloro-2-{2-[4-(3,4-difluoro-benzyl)-(2R)-2-methyl- piperazin-1 -yl]-2-oxo-ethoxy}-phenyl)-acetic</td><td> 453,1</td>

<td> 256</td><td>(2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo- acid ethoxy}-5-methyl-phenyl)-acetic</td><td> 429,2</td>

<td>Example</td><td>Name</td><td>LRMS</td>

<td> 257</td><td>Acid (2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2- oxo-</td><td> 415,2, 413,3</td>

<td></td><td>ethoxy}-5-methyl-phenyl)-acetic</td><td></td>

<td> 258</td><td>Acid (2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylp¡peraz¡n-1 - yl]-2-oxo-ethoxy}-5-methyl-phenyl)-acetic</td><td> 429,2, 427,3</td>

<td> 259</td><td>3-(2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2- acid oxo- ethoxy}-5-methyl-phenyl)-propionic</td><td> 443,2</td>

Through this request, several publications are referenced. The descriptions of these publications are incorporated herein in their entirety by reference to their application for all purposes.

It will be apparent to those skilled in the art that various modifications and variations may be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be obvious to those skilled in the art from a consideration of the specification and the practice of the invention described herein. It is intended that the specification and examples be considered by way of example only, with the true scope and spirit of the invention being indicated by the following claims.

Having described the invention as above, what is contained in the following is declared as property