[go: up one dir, main page]

AU8576098A - Cyclic amine modulators of chemokine receptor activity - Google Patents

Cyclic amine modulators of chemokine receptor activity Download PDF

Info

Publication number
AU8576098A
AU8576098A AU85760/98A AU8576098A AU8576098A AU 8576098 A AU8576098 A AU 8576098A AU 85760/98 A AU85760/98 A AU 85760/98A AU 8576098 A AU8576098 A AU 8576098A AU 8576098 A AU8576098 A AU 8576098A
Authority
AU
Australia
Prior art keywords
phenyl
methylbenzenesulfonamide
alkyl
substituted
phenylpiperidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU85760/98A
Inventor
Charles G Caldwell
Paul E. Finke
Malcolm Maccoss
Laura C. Meurer
Sander G. Mills
Bryan Oates
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9800958.2A external-priority patent/GB9800958D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of AU8576098A publication Critical patent/AU8576098A/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pain & Pain Management (AREA)
  • AIDS & HIV (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

wU YY/U4 /94 PCT/US98/1499U TITLE OF THE INVENTION CYCLIC AMINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY 5 BACKGROUND OF THE INVENTION Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cyvtokine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). 10 There are two classes of chemokines, C-X-C (a) and C-C (P), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C). The a-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for 15 neutrophils, whereas P-chemokines, such as RANTES, MIP-la, MIP-10 , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381,661-666 (1996)). The chemokines bind specific cell-surface receptors 20 belonging to the family of G-protein-coupled seven-transmembrane domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15,159-165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase 25 in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to P-chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1") [MIP-la, MIP-1, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72,415-425 (1993)); CCR 30 2A and CCR-2B (or "CKR-2A"/"CKR-2A" or "CC-CKR-2A"/"CC-CKR 2A") [MCP-1, MCP-3, MCP-4]; CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem. 270 16491-16494 (1995); CCR-4 (or "CKR-4" or "CC-CKR-4") [MIP-la, RANTES, MCP-1] (Power, et al., J. Biol. Chem. 270, 19495-19500 (1995)); 35 CCR-5 (or "CKR-5" or "CC-CKR-5") [MIP-la, RANTES, MIP-1p] -1- WU /U4 /V94 PC /UN95/14OVU (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 269, 7835-7838 (1994)). The 3-chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein") and 5 RANTES ("regulation-upon-activation, normal T expressed and secreted"). Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory 10 disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. A retrovirus designated human immunodeficiency virus 15 (HIV-1) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. 20 Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Patent No. 5,468,469). Some of these antiviral agents have been shown to act by 25 blocking the binding of gpl20, the coat protein of HIV, to its target, the CD4 gyycoprotein of the cell. Entry of HIV-1 into a target cell requires cell-surface CD4 and additional host cell cofactors. Fusin has been identified as a cofactor required for infection with virus adapted for growth in transformed T 30 cells, however, fusin does not promote entry of macrophagetropic viruses which are believed to be the key pathogenic strains of HIV in vivo. It has recently been recognized that for efficient entry into target cells, human immunodeficiency viruses require the chemokine receptors CCR-5 and CXCR-4, as well as the primary receptor CD4 35 (Levy, N. Engl. J. Med., 335(20), 1528-1530 (Nov. 14 1996). The principal -2- WU 99/U4794 FCT/US9/1499U cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the P chemokines RANTES, MIP-lx and MIP-13 (Deng, et al., Nature 381, 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a 5 region of its envelope protein, gpl20. It is believed that the CD-4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4. This brings the viral envelope closer to the cell surface and allows interaction 10 between gp41 on the viral envelope and a fusion domain on the cell surface, fusion with the cell membrane, and entry of the viral core into the cell. It has been shown that P-chemokine ligands prevent HIV-1 from fusing with the cell (Dragic, et al., Nature 381, 667-673 (1996)). It has further been demonstrated that a complex of gpl20 and soluble CD4 15 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands MIP-lac and MIP-10 (Wu, et al., Nature, 384, 179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)). Humans who are homozygous for mutant CCR-5 receptors which do not serve as co-receptors for HIV-1 in vitro apper to be 20 unusually resistant to HIV-1 infection and are not immunocompromised by the presence of this genetic variant (Nature, 382, 722-725 (1996)). Absence of CCR-5 appears to confer protection from HIV-1 infection (Nature, 382, 668-669 (1996)). Other chemokine receptors may be used by some strains of HIV-1 or may be favored by non-sexual 25 routes of transmission. Although most HIV-1 isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine, 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HIV-1 (Zhang, et al., Nature, 30 383, 768 (1996)). Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients. By focusing on the host's cellular immune response to HIV infection, better therapies towards all subtypes 35 of HIV may be provided. These results indicate that inhibition of -3- W U YY/U4 / 4V1U9~I9I chemokine receptors presents a viable method for the prevention or treatment of infection by HIV and the prevention or treatment of AIDS. The peptides eotaxin, RANTES, MIP-la, MIP-1, MCP-1, and MCP-3 are known to bind to chemokine receptors. As noted above, 5 the inhibitors of HIV-1 replication present in supernatants of CD8+ T cells have been characterized as the P-chemokines RANTES, MIP-la and MIP-1. PCT Patent Publication WO 97/10211 and EPO Patent Publication EP 0,673,928 disclose certain piperidines as tachykinin antagonists. 10 SUMMARY OF THE INVENTION The present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory 15 disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such 20 diseases in which chemokine receptors are involved. The present invention is further concerned with compounds which inhibit the entry of human immunodeficiency virus (HIV) into target cells and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the prevention and/or treatment of the 25 resulting acquired immune deficiency syndrome (AIDS). The present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV. 30 DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of formula I: -4- WU "JYU.14 / vYii F /U ibn sII49U N- R' R 3 n In wherein: 5 R 1 is selected from a group consisting of: linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from: 10 (a) hydroxy, (b) oxo, (c) cyano, (d) halogen which is selected from F, Cl, Br, and I, (e) trifluoromethyl, 15 (f) phenyl (g) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (1') phenyl, (2') hydroxy, 20 (3') C1-3alkyl, (4') cyano, (5') halogen, (6') trifluoromethyl, (7') -NR 6
COR
7 , 25 (8') -NR 6 CO2R 7 , (9') -NR 6
CONHR
7 , (10') -NR 6 S(O)jR 7 , wherein j is 1 or 2, (11') -CONR 6
R
7 , (12') -COR 6 , 30 (13') -CO2R 6 , (14') -OR 6 , -5- WU VY/14194 PCTl/US98/1499U (15') -S(O)kR 6 , wherein k is 0, 1 or 2, (h) C1-6 alkyl, unsubstituted or substituted with hydroxy, (i) -NR 6
R
7 , (j)
-NR
6
COR
7 , 5 (k) -NR 6 CO2R 7 , (1) -NR 6
CONHR
7 , (m) -NR 6 S(O)j-R 7 , (n) -CONR 6
R
7 , (o) -COR 6 , 10 (p) -CO2R 6 , (q) -OCOR 6 , (r) -CN, (s) -OR 6 , (t) -S(O)kR 6 , 15 (u) -NR 6 CO-heteroaryl, (v) -NR 6 S(O)j-heteroaryl, and (w) heteroaryl, wherein heteroaryl is selected from the group consisting of: (1') benzimidazolyl, 20 (2') benzofuranyl, (3') benzoxazolyl, (4') furanyl, (5') imidazolyl, (6') indolyl, 25 (7') isooxazolyl, (8') isothiazolyl, (9') oxadiazolyl, (10') oxazolyl, (11') pyrazinyl, 30 (12') pyrazolyl, (13') pyridyl, (14') pyrimidyl, (15') pyrrolyl, (16') quinolyl, -6- W U V9WU4 /94 PT/LUN95/149YU (17') tetrazolyl, (18') thiadiazolyl, (19') thiazolyl, (20') thienyl, and 5 (21') triazolyl, wherein the heteroaryl is unsubstituted or mono di or tri substituted, where the substituents are independently selected from: (a") phenyl, 10 (b") hydroxy, (c") oxo, (d") cyano, (e") halogen, and (f') trifluoromethyl; 15
R
2 is selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) C1-6 alkyl, 20 (4) substituted C1-6 alkyl, where the substituents are independently selected from: (a) phenyl, (b) hydroxy, (c) oxo, 25 (d) halogen, (e) trifluoromethyl, (f) -N(R 4
)(R
5 ), wherein R 4 and R 5 are independently selected from hydrogen, CI-10 linear or branched alkyl, and CO-6 alkyl substituted with C3-8 cycloalkyl, 30 (g) -N(R 4
)-CO-O-(R
5 ), and (h) -N(R 4
')-CO-N(R
4
)(R
5 ), wherein R 4 ' is selected from the definitions of R 4 , (5) -O-C1-6 alkyl, and (6) phenyl; 35 -7- WU YY/U4 194 PC/U59/499U
R
3 is selected from the group consisting of: (1) Ar, (2) -N(R 4 )-CO-O-(C1.-6 alkyl)-Ar, (3) -N(R 4
)-CO-O-R
7 , 5 (4) -(C1-6 alkyl)-Ar, (5) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar, and (6) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar; Ar is selected from the group consisting of: 10 (1) phenyl, (2) pyridyl, (3) pyrimidyl, (4) naphthyl, (5) furyl, 15 (6) pyrryl, (7) thienyl, (8) isothiazolyl, (9) imidazolyl, (10) benzimidazolyl, 20 (11) tetrazolyl, (12) pyrazinyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, 25 (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyl, 30 (21) purinyl, (22) isoxazolyl, (23) thiazolyl, (24) oxazolyl, (25) triazinyl, and -8- WO 99/U4794 PCT/US98/1499U (26) benzthiazolyl, (27) benzoxazolyl, (28) imidazopyrazinyl, (29) triazolopyrazinyl, 5 (30) naphthyridinyl, (31) furopyridinyl, (32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof, (33) pyridazinyl, (34) quinazolinyl, 10 (35) pteridinyl, (36) triazolopyrimidyl, (37) triazolopyrazinyl, (38) thiapurinyl, (39) oxapurinyl, and 15 (40) deazapurinyl, wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted, where the substituents are independently selected from: (a) C1-3 alkyl, unsubstituted or substituted with a substituent selected from: 20 (1') oxo, (2') hydroxy, (3') -OR 7 , (4') phenyl, (5') trifluoromethyl, and 25 (6') phenyl or mono, di or tri-substituted phenyl, where the substituents are independently selected from: hydroxy, cyano, halogen, and trifluoromethyl, (b) halogen, 30 (c) -OC1-6 alkyl, (d) trifluoromethyl, (e) hydroxy, (f) -NO2, (g) -(CH2)pS(O)k-(C1-6 alkyl), wherein p is 0, 1 or 2, 35 (h) -(CH2)pS(O)j-NH2, -9- WU Y/U4/94 PCT/US98/1499U (i) -(CH2)pS(O)j-NH(C1-6 alkyl), (j) -(CH2)pS(O)j-NHR 6 , (k) -(CH2)pS(O)j-NR 6 -(C1-6 alkyl), (1) -(CH2)pCONH2, 5 (m) -(CH2)pCONH-(C1-6 alkyl), (n) -(CH2)pCONHR 6 , (o) -(CH2)pCONR 6
R
7 , (p) -(CH2)pCO2H, (q) -(CH2)pCO2-(C1-6 alkyl), 10 (r) -(CH2)pNR 6
R
7 , (s) -(CH2)pNH-C(O)-C1-6alkyl, (t) -(CH2)pNH-C(O)-NH2, (u) -(CH2)pNH-C(O)-NHC1-6alkyl, (v) -(CH2)pNH-C(O)-N(C1-6 alkyl)2, 15 (w) -(CH2)pNH-S(O)k-C 1-6alkyl, (x) -(CH2)pN(C1-3alkyl)-C(O)-N(diC1-6 alkyl), (y) -(CH2)p-heteroaryl, -C(O)-heteroaryl or -(CH2)p-O-heteroaryl , wherein the heteroaryl is selected from the group consisting of: 20 (1') benzimidazolyl, (2') benzofuranyl, (3') benzoxazolyl, (4') furanyl, (5') imidazolyl, 25 (6') indolyl, (7') isooxazolyl, (8') isothiazolyl, (9') oxadiazolyl, (10') oxazolyl, 30 (11') pyrazinyl, (12') pyrazolyl, (13') pyridyl or oxopyridyl, (14') pyrimidyl, (15') pyrrolyl, - 10- WU 9U4 /94 PC'1Uh95/1499U (16') quinolyl, (17') tetrazolyl, (18') thiadiazolyl, (19') thiazolyl, 5 (20') thienyl, and (21') triazolyl, wherein the heteroaryl group of items (1') to (21') is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from: 10 (a') hydrogen, (b') C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, where the substituents are selected from: hydrogen and hydroxy, 15 (c') hydroxy, (d') oxo, (e') -OR 6 , (f) halogen, (g') trifluoromethyl, 20 (h') nitro, (i') cyano, (j') -NHR 6 , (k') -NR 6
R
7 , (1') -NHCOR 6 , 25 (m') -NR 6
COR
7 , (n') -NHCO2R 6 , (o') -NR 6 CO2R 7 , (p') -NHS(O)jR 6 , (q') -NR6S(O)jR 7 , 30 (r') -CONR 6
R
7 , (s') -COR 6 , (t') -CO2R 6 , and (u') -S(O)jR 6 ; 35 R 6 is selected from the group consisting of: -11- WU 991U4/94 PCUT/US9/1499U (1) hydrogen, (2) C1-6 alkyl, (3) substituted C1-6 alkyl, where the substituents are independently selected from: 5 (a) phenyl, (b) hydroxy, (c) oxo, (d) cyano, (e) halogen, 10 (f) trifluoromethyl, and (g) C5-8 cycloalkyl, (4) phenyl, (5) mono, di or tri-substituted phenyl, where the substituents are independently selected from: 15 (a) hydroxy, (b) C1-3alkyl, (c) cyano, (d) halogen, and (e) trifluoromethyl; 20
R
7 is selected from the group consisting of: (1) hydrogen, (2) C1-6 alkyl or C5-8 cycloalkyl, (3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the 25 substituents are independently selected from: (a) phenyl, (b) mono, di or tri-substituted phenyl, where the substituent is independently selected from: (1') hydroxy, 30 (2') C1-3alkyl, (3') cyano, (4') halogen, (5') trifluoromethyl, and (6') C1-3alkyloxy, 35 (b) hydroxy, - 12- WU Y1/U4 /94 PCI/US98/1499U (c) oxo, (d) cyano, (e) halogen, and (f) trifluoromethyl, 5 (4) phenyl, (5) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (a) hydroxy, (b) C1-3alkyl, 10 (c) cyano, (d) halogen, and (e) trifluoromethyl; or R 6 and R 7 may be joined together to form a 5-, 6-, or 7 15 membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from: 20 (1) hydroxy, (2) oxo, (3) cyano, (4) halogen, (5) trifluoromethyl, 25 m is an integer selected from 0, 1 and 2, n is an integer selected from 0, 1 and 2, and pharmaceutically acceptable salts thereof. Preferred compounds of the present invention include those 30 of formula Ia: N- R' R 13 - 13 - WU YYWU4 14 rUl/UZ95/14YYU Ia wherein:
R
1 is selected from a group consisting of: C3, C4, C5, C6, C7, or C8 linear or branched alkyl, which is 5 unsubstituted or mono, di or tri-substituted, where the substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) phenyl, 10 (d) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (1') phenyl, (2') hydroxy, (3') C1-3alkyl, 15 (4') cyano, (5') halogen, and (6') trifluoromethyl, (e) C1-6 alkyl, unsubstituted or substituted with hydroxy, (f) -NR 6
CO-R
7 , wherein R 6 is hydrogen or C1-3 alkyl, 20 unsubstituted or substituted with C5-8 cycloalkyl, and
R
7 is C1-6 alkyl, benzyl or phenyl which is unsubsituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy, (g) -COR 6 , 25 (h) -OR 6 , (i) -NR 6 S(O)j-R 7 , where j is 1 or 2, (j) -NR 6 S(O)j-heteroaryl, wherein heteroaryl is selected from the group consisting of: (1') benzimidazolyl, 30 (2') benzofuranyl, (3') benzoxazolyl, (4') furanyl, (5') imidazolyl, (6') indolyl, 35 (7') isooxazolyl, - 14- WO 99/U14794 PCT/US98/14990 (8') isothiazolyl, (9') oxadiazolyl, (10') oxazolyl, (11') pyrazinyl, 5 (12') pyrazolyl, (13') pyridyl, (14') pyrimidyl, (15') pyrrolyl, (16') quinolyl, 10 (17') tetrazolyl, (18') thiadiazolyl, (19') thiazolyl, (20') thienyl, and (21') triazolyl, 15 wherein the heteroaryl is unsubstituted or mono di or tri substituted, where the substituents are independently selected from: (a') phenyl, (b') hydroxy, 20 (c') oxo, (d') cyano, (e') halogen, and (f) trifluoromethyl; 25 R 2 is selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) C1-6 alkyl, (4) -O-C1-6 alkyl, 30 (5) phenyl, (6) -N(CH3)-CO-N(H)(CH3), (7) -N(H)-CO-O-CH3, and (8) -CO-CH3; 35 R 3 is selected from the group consisting of: - 15- WU YYiu174 04C/U595/149U (1) Ar, (2) -(C1-6 alkyl)-Ar, (3) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar, and (4) -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, wherein R 4 is selected from 5 hydrogen, C1-10 linear or branched alkyl, and CO-6 alkyl substituted with C3-8 cycloalkyl, (5) -N(R 4
)-CO-O-R
7 ; Ar is selected from the group consisting of: 10 (1) phenyl, (2) pyrazinyl, (3) pyrazolyl, (4) pyridyl, (5) pyrimidyl, and 15 (6) thienyl, wherein the Ar is unsubstituted or mono or di-substituted, and the substituents are independently selected from: (a) C1-3 alkyl, unsubstituted or substituted with (1') oxo, 20 (2') hydroxy, (3') -OR 7 , (4') phenyl, and (5') trifluoromethyl, (b) halogen, 25 (c) -OC1-6 alkyl, (d) trifluoromethyl, (e) -NO2, (f) CONR 6 -(C1-2 alkyl), (g) CO2H, 30 (h) CO2-(C1-2 alkyl), (i) CH2NR 6 -(C1-2 alkyl), (j) CH2NH-C(O)-C1-3alkyl, (k) CH2NH-C(O)NH2, (1) CH2NH-C(O)NHC1-3alkyl, 35 (m) CH2NH-C(O)N-diC1-3 alkyl), - 16- VV YYIulfi Y YL 1/U N95/ 14YYU (n) CH2NH-S(O)j-C1-3alkyl, (o) CH2-heteroaryl, with the heteroaryl is selected from the group consisting of: (1') imidazolyl, 5 (2') oxazolyl, (3') pyridyl, (4') tetrazolyl, (5') triazolyl, and the heteroaryl is unsubstituted, mono, di or tri 10 substituted, where the substituents selected from: (a') hydrogen, (b') C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, the substituents being selected from 15 hydrogen and hydroxy; m is an integer selected from 0, 1 and 2, n is an integer selected from 0, 1 and 2, with the proviso that the sum of m + n is2; 20 and pharmaceutically acceptable salts thereof. More preferred compounds of the present invention include those of formula Ib: R 3 >N- R 1 25 Ib wherein:
R
1 , R 2 and R 3 are as defined herein; and pharmaceutically acceptable salts thereof. 30 In the present invention it is preferred that - 17-
R
1 is selected from the group consisting of: C3, C4, C5, C6, C7, or C8 linear or branched alkyl, which is unsubstituted or mono, di or tri-substituted, where the substituents are independently selected from: 5 (a) hydroxy, (b) Cl or F, (c) phenyl, (d) mono, di or tri-substituted phenyl, where the substituents are independently selected from: 10 (1') phenyl, (2') hydroxy, (3') C1-3alkyl, (4') cyano, (5') halogen, and 15 (6') trifluoromethyl, (e) C1-6 alkyl, unsubstituted or substituted with hydroxy, (f) -NR 6
CO-R
7 , wherein R 6 is hydrogen or C1-3 alkyl, unsubstituted or substituted with C5-8 cycloalkyl, and
R
7 is C1-6 alkyl, benzyl or phenyl which is 20 unsubsituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy, (g) -COR 6 , (h) -OR 6 , (i) -NR 6 S(O)j-R 7 , where j is 1 or 2, 25 (j) -NR 6 S(O)j-heteroaryl, wherein heteroaryl is selected from the group consisting of: (1') benzimidazolyl, (2') benzofuranyl, (3') benzoxazolyl, 30 (4') furanyl, (5') imidazolyl, (6') indolyl, (7') isooxazolyl, (8') isothiazolyl, - 18- WV U VY/U4I / Y4.l .. I;Y/ Yt (9') oxadiazolyl, (10') oxazolyl, (11') pyrazinyl, (12') pyrazolyl, 5 (13') pyridyl, (14') pyrimidyl, (15') pyrrolyl, (16') quinolyl, (17') tetrazolyl, 10 (18') thiadiazolyl, (19') thiazolyl, (20') thienyl, and (21') triazolyl, wherein the heteroaryl is unsubstituted or mono di or tri 15 substituted, where the substituents are independently selected from: (a') phenyl, (b') hydroxy, (c') oxo, 20 (d') cyano, (e') halogen, and (f) trifluoromethyl. In the present invention it is preferred that if R 3 is Ar, m is 25 1, n is 1, and R 1 is C5 alkyl which bears a group selected from: -NR 6
R
7 ,
-NR
6
COR
7 , -NR 6 CO2R 7 , or -NR 6
CONHR
7 , then R 1 does not bear a substituent which is 2,3-dichlorophenyl. In the present invention it is preferred that 30 R 1 bears at least one substituent which is selected from: (a) -NR 6
CO-R
7 , wherein R 6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl, and R 7 is C1-6 alkyl, benzyl or phenyl which is unsubsituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy, and 35 (b) -NR 6 S(O)j-R 7 , where j is 1 or 2. - 19- WU YY/U419Y4 PCT/UN9Z5/14YYU In the present invention it is more preferred that
R
1 is selected from the group consisting of: C4, C5, C6, C7 or C8 linear or branched alkyl, which is mono, di 5 or tri-substituted, where the substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) phenyl, 10 (d) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (1') hydroxy, (2') methyl or ethyl, (3') Cl or F, and 15 (4') trifluoromethyl, (e) C1-6 alkyl, unsubstituted or substituted with hydroxy, (f) -NR 6
CO-R
7 , wherein R 6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl, and R 7 is C1-6 alkyl, benzyl or phenyl which is unsubsituted or substituted 20 with halo, CF3, C1-3alkyl, or C1-3alkoxy, (g) -NR 6 S(O)j-R 7 , where j is 1 or 2. In the present invention it is still more preferred that
R
1 is selected from the group consisting of: 25 C4, C5, or C6 linear alkyl, which is substituted, where the substituents are independently selected from: (a) phenyl, (b) mono, di or tri-substituted phenyl, where the substituents are independently selected from: 30 (1') hydroxy, (2') methyl or ethyl, (3') Cl or F, and (4') trifluoromethyl, (c) C1-6 alkyl, unsubstituted or substituted with hydroxy, -20wU vY/U4 /94 PC'CT/US9/1499U (d) -NR 6
CO-R
7 , wherein R 6 is methyl, unsubstituted or substituted with cyclohexyl, and R 7 is phenyl which is unsubstituted or substituted with Cl, F, CF3, Cl 3alkyl or C1-3alkoxy, and 5 (e) -NR 6 S(O)j-R 7 , where j is 1 or 2. In the present invention it is still more preferred that
R
1 is C4 linear alkyl, which is substituted, where the substituents are independently selected from: 10 (a) phenyl, (b) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (1') hydroxy, (2') methyl or ethyl, 15 (3') Cl or F, and (4') trifluoromethyl, (c) C1-6 alkyl, unsubstituted or substituted with hydroxy, and (d) -NR 6 S(O)j-R 7 , where R 6 is methyl, unsubstituted or 20 substituted with cyclohexyl, and R 7 is phenyl which is unsubstituted or substituted with Cl, F, CF3, Cl 3alkyl or C1-3alkoxy, and j is 1 or 2. In the present invention it is even more preferred that 25 R 1 is: R10 N" S0 2 -B I
R
11
-
R6
R
1 2 wherein: B is selected from the group consisting of: (a) phenyl, and -21- WU 99/U4/94 PCT/US9 /1499U (b) di or tri-substituted phenyl, wherein the substituents on phenyl are independently selected from: chloro, methyl, phenyl, C1-3alkoxy, and CF3; 5 R 6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl;
R
1 0 is selected from the group consisting of: (1) hydrogen, and (2) C1-6 alkyl, unsubstituted or substituted with hydroxy; 10
R
1 1 and R 1 2 are independently selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) methyl or ethyl, 15 (4) Cl or F, and (5) trifluoromethyl. In the present invention it is highly preferred that
R
1 is selected from the group consisting of: N, O 20
C
H
3 20
OH
3
-
CH
2 0H I I N, SO2 \/ NSO2 \ / OH 3 C OH 3 ,and In the present invention it is most preferred that
R
1 is selected from the group consisting of: - 22 - WU 99/U4 194 PCT/US98/1499U
CH
3 CH 3 0NS2 WSO2 O CH 3 CH 3
CH
2 0H
CH
2 0H IN SO2 N SO2
CH
3 CH 3 ,and In the present invention it is preferred that
R
2 is selected from the group consisting of: 5 (1) hydrogen, (2) hydroxy, (3) C1-6 alkyl, (4) -O-C1-6 alkyl, (5) phenyl, 10 (6) -N(CH3)-CO-N(H)(CH3), (7) -N(H)-CO-O-CH3, and (8) -CO-CH3. In the present invention it is more preferred that 15 R 2 is selected from the group consisting of: (1) hydrogen, (2) hydroxy, and (3) phenyl. 20 In the present invention it is most preferred that
R
2 is hydrogen. In the present invention it is preferred that
R
3 is selected from the group consisting of: -23 - WO 99/04794 PCTI/US98/1499U (1) Ar, (2) -(C1-6 alkyl)-Ar, (3) -(C1-6 alkyl)-O-(Cl-6 alkyl)-Ar, and (4) -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, wherein R 4 is selected from 5 hydrogen, C1-10 linear or branched alkyl, and C0-6 alkyl substituted with C3-8 cycloalkyl, (5) -N(R 4
)-CO-O-R
7 . In the present invention it is more preferred that 10 R 3 is selected from the group consisting of: (1) Ar, (2) -(C1-6 alkyl)-Ar, (3) -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, wherein R 4 is selected from hydrogen, C1-10 linear or branched alkyl, and CO-6 alkyl 15 substituted with C3-8 cycloalkyl, and (4) -N(R 4
)-CO-O-R
7 . In the present invention it is preferred that Ar is selected from the group consisting of: 20 (1) phenyl, (2) pyrazinyl, (3) pyrazolyl, (4) pyridyl, (5) pyrimidyl, and 25 (6) thienyl, wherein the Ar is unsubstituted or mono or di-substituted, and substituents are independently selected from: (a) C1-3 alkyl, unsubstituted or substituted with (1') oxo, 30 (2') hydroxy, (3') -OR 7 , (4') phenyl, and (5') trifluoromethyl, (b) CONR 6 -(C1-2 alkyl), 35 (c) CO2H, -24- VV j U 77/Y 1L, 1I /U 5/14YYU (d) CO2-(C1-2 alkyl), (e) CH2NR 6 -(C1-2 alkyl), (f) CH2NH-C(O)-C1-3alkyl, (h) CH2NH-C(O)NH2, 5 (i) CH2NH-C(O)NHC1-3alkyl, (j) CH2NH-C(O)N-diC 1-3 alkyl), (k) CH2NH-S(O)j-C 1-3alkyl, (1) CH2-heteroaryl, with the heteroaryl is selected from the group consisting of: 10 (1') imidazolyl, (2') oxazolyl, (3') pyridyl, (4') tetrazolyl, (5') triazolyl, 15 and the heteroaryl is unsubstituted, mono, di or tri substituted, where the substituents selected from: (a') hydrogen, (b') C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, 20 the substituents being selected from hydrogen and hydroxy. In the present invention it is more preferred that Ar is selected from: 25 phenyl, mono substituted phenyl or di-substituted phenyl, wherein the substituents are selected from the group consisting of: (a) C1-3 alkyl, unsubstituted or substituted with (1') oxo, 30 (2') hydroxy, or (3') -OR 6 , wherein R 6 is hydrogen or C1-3 alkyl, (b) -CH2NR 6 -(C1-2 alkyl), (c) -CH2NH-C(O)-C1-3alkyl, (d) -CH2NH-C(O)NH2, -25 - WU ) C IUCO4 FLN/UC9_5/14akyU (i) -CH2NH-C(O)NHC1- 3 alkyl, (j) -CH2NH-C(O)N-diC1- 3 alkyl), (k) -CH2NH-S(O)j-C1-3alkyl, (1) -CH2-heteroaryl, where heteroaryl is selected from the 5 group consisting of: (1') imidazolyl, (2') oxazolyl, (3') pyridyl, (4') tetrazolyl, 10 (5') triazolyl, and where heteroaryl is unsubstituted, mono, di or tri substituted, where the substituents are independently selected from: (a') hydrogen, 15 (b') C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted, where the substituents are selected from: hydrogen and hydroxy. 20 In the present invention it is more preferred that
R
3 is selected from: (1) phenyl, and (2) -N(R 4
)-CO-O-(C
1
-
6 alkyl)-phenyl, wherein R 4 is selected from hydrogen, Cl-10 linear or branched alkyl, and CO-6 25 alkyl substituted with C3-8 cycloalkyl. In the present invention it is even more preferred that
R
3 is:
-N(R
4 )-CO-O-(CH2)-phenyl, wherein R 4 is selected from hydrogen, 30 C1-6 linear or branched alkyl, and CH2 substituted with C3-8 cycloalkyl. In the present invention it is still more preferred that
R
3 is: -26- WV Y/U4 /Y P4/US98/149T)U
-N(R
4 )-CO-O-(CH2)-phenyl, wherein R 4 is selected from hydrogen and C1-6 alkyl. In the present invention it is most preferred that 5 R 3 is: -N(CH2CH3)-CO-O-(CH2)-phenyl. In the present invention it is preferred that m is an integer selected from 0, 1 and 2, 10 n is an integer selected from 0, 1 and 2, with the proviso that the sum of m + n is2. In the present invention it is more preferred that m is 1, and n is 1. 15 As appreciated by those of skill in the art, halo as used herein are intended to include chloro, fluoro, bromo and iodo. Similarly, C1-6, as in C1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5, or 6 carbons, such that C1-6alkyl specifically includes methyl, ethyl, 20 propyl, butyl, pentyl, hexyl, and cyclohexyl. Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. -27 - WU YYWU4 /Y4 LTuI/U05/14YYU Preferred compounds of the present invention include the compounds of the formula: Ra N N SO2 Me Rb wherein: Ra Rb hydrogen chloro 0 hydrogen 0 N 0 chloro 0 N hydrogen chloro /Ohydrogen /Ochloro 5 and pharmaceutically acceptable salts thereof. -28 wu VyJ/~1 PC/U/9 / 499U Specific compounds within the present invention include a compound which selected from the group consisting of: N S Me I 5 CI N S Me 0 0--/ -29- N,, 0 Me F, 0 -S NN Me 0" Me "N cI -30u Mus PCTL)/U9/149VU N 0 N 0 H N, o N N/S I N N 'S H N H H N S -N.. 3
H
2 N N 0 I0 H -31- Yy/uJ /Y4 FC'1/ U ~S/ 14991 NS Me
Z~CH
2
CH
3 H 0 N NS Z I - Me cI H N y0 N S 7 Me CI, N S\ Me 'N C O 2 Et -32- N / -'S N N -~ Me
N
Me N" N, -33 wU Yylue14 P/T/UN95/1499U Sa c01 II NO O " N s N3OS - 34 - W" /S
H
2 N,- 0" 0 N,S -35 - NO CH CIH 0 -36 - WU Y/UI4 /4T/U W5/l479U 0N, NS 0 J 10 00 H N, , 0 O N0, - 37 - 0 0 N N 'NMe
~CF
3 Me F N N-S Me ZO00H 3 H N N" /S 01 -38 - VVU YY/U14 Yf1 /OU Iu YO11*.YU ©I O N, ,O N 0 0" H N 0 N - 39- 0 N, N N\O S IH 0 0 N 'N-S N 11 0 -40- WY1177/"lyt 71 qu 5YL13 / 197yU - 01 NCl N N-S 0 OH 0 N NS HH o0 /o I O N ,O N Me Me F -41 - WV YJYIU4 IY4/UD~/49 OH '9 N N-S 0 NN 0 NN 00 NN N'* N-S M e N S 0 F -42- VVL YYIUR4 IVY4 1' /0370/1 7yU S NO OS S Ns , O 0 N bN s S/S N, -43- N,O S 01 I0 N NS Me
CH
3 0 O N NS I Me N NS Me I - 44 vv U I /7 tr~ 1U,)YO1'.YU N 00
N
Me N SI -45 wu "1 wwwi PCT/L)595/1499U 0 HN-( N N S I (aMe Cl 0 ,0 N Me Me Cl N N- S Me
CH
3 N N M \l N NMe NN -46wu vvivl P/'I'IUS95l499U 0o \S N, S 1 0 Me F OHO NN Me Cl -47 - -0 OjoJ ~~-S Me cI
CF
3 CI IOH N \ Me CI NN 0 A Me
OH
3
OH
3 -48 - N N-S Me
H
3 0
OH
3 0
OCH
3 N S Me cI
CF
3 610 H N., N S 7 Me -49 vv v77tow- 179 YL 1/u,5L J i70197U F F I OH NN, S0
M
e CI NRN, N OS 0 ]N" N,8,, N O O0 I NN N O N S 0 -50- WOJ 99/U4794 PC'Ii/US9S/1499U 0 y0 N N N M e N % s NNN a Me 0 N oI N J Me~~ Nc
OCH
3 0 -Me Cl N S\ Me C0 2 H
N
01 NS.. -52w V YIu s I/4 PC'I'/U98/1499U
H
2 N N N 0, H H N N " H0 - 53 - 0"N , o NNS "N 0
N
N, N0! -54 vv yyiuq4 IU/Jh/14YSU 0I H 0 0 ,,S 0 N o S N 'S N Me
OCH
3 -55 - O N SN N,
-
I Me CI 0 N N H N N Me" N' S 02 -0 I 0 - 56- OH
N
0 Me cI F NON Me CI dN- 0 " 0 N /S N -57 wu~ Myve7 PLIL)U595/ 149F9U 0NO N O 0 N Is 0 ) N N 0., NN' 0 N OS - 58 - .oA.. .,O VV1 YYU17 Y4 YL,1/ U3YO/1977U o N oA N 0, dN 0N S N , S -59- 0 N0 N' ~0 N 0" ' - 60vv'. 72'/UtIy ' r,1 7 U370/OI1'#77"' N ~ SO 2 Ph N, N N S Me CI ) N 0" 0 -61
-
wu YY/U4/4 PCTI/US98/1499U N 0 No N o NO'S N, 6I O N N '2 S - 62 - WUJ 99/'U4/94 PCTJUS98/14990) N ' o NNS N
-
o 020 -63 - WU 99/U4 /9~4 PC'I/US98/ 1499U oN' N N Me 'Nl CFCI .s 00 N 0 -6y 0 N0 YNr Ns 0N 00 0 NNt~~ 'S 0 -- 65 W V YIU4I/Y4 VUI/USi9Z5/149!U 0-s 0 Me cI 10 N N, Ph ~~ N0 10 PhO N0 N N 0 / N ' Me CI -66- WU) 9WU4 P0J4 PU'1'/US9S/1499I
,N
N, N N S, Me OH j N l a Me OH N Q N, N \ Me 00H 3 Me -67- WU ~ PCT/US98/1499J 020 0252 0 2 S cN -68 - W U VY/'U4 /YJ4 Ft I/U9S/14I9YU 0'. 0 0 NNo o Q~~ N , 0 N~NN 0 -69- WU YYU /Y PC'I/U S98/1499U 0 0 0Ci N' 0 - 70 vvu Yynu4 /Y t / 41IY 00 0 0% 00. 00 0 Ny W"J vy/U4 /Y4 cIu9/4 u 0 y0 CN < N~N' 0 0 N 0 0 0 0,~ N - 72 wu u v/14 PCT/US98/1499U o N,,O O N 0 S N N'S,,O 0 ~N 0 5O N NS , O N 0,, 0 0-N 0 O N 73 O - 73 - 00 00 0 N''' NJ:: - 74 - WU 99WU41/94 PCT/U595/14YMVU /0 O NS 0 N" 0 /0 O NS 0 ' N' 0" < 0 O~N 0 /0 0 NO,, - 75 - W~ 0JV/4/4FlUY/4V 00 0N 0 N~P "NN 00~ -76- WO) 99/U4/94 1'IUS9i/14991 1 N 0Q s 0 NN 0 0y I o NN 0N N 0 - 77 - WO 99/U4194 PCT/US98/14990 ON N NS Oo,, 1N N ,S N o 0 9 0 o N N N, o / N- 78 10 N'-N N0 0 -78- WU 99/U4-/94 PCI/7U S9/1499U N N 00' 0, 0 0 0~ -79- WU 9!)/4' /94i FTUN MDW14Y!)U 0 0 Os, NN'ISN 0 0 y0 C0. N 0 -80- WU YU/4/y4 UIT/US9?5/14YYU 0 0 03 0 0 o o o~N,,17I 0 N, s Ph I0 JO Ph 0 N H3C S
NH
3 5 -81 - WO 99/04794 PCT/US98/1499J 00 0 N~ NN 5 0 0 051 N , N N"' 0 -82wIj Yy/Ju' /Y4I'IU iZII9J 0 0 0.l 0" 0
F
3 0 C 0 Ph Me Nl
SO
2 Ph EtN OH PhCH 2 O 0 -83 - N'\
OF
3 0
CF
3 0 0 N ~ N 0 NS 0 5 N -84- NN I' 0 'N' X N 0 N1~4"0 No 0 02 Et N::DOH 0 -85 - Me N ,S Et , N" 'IOH 02 Sj 0 N S 0 N,, N 0 -86- O\ -87- W U VY/IIJ4 /Y41' iU 9 143U PhJ 0
SO
2 Ph Ph KN Me Ph I
SO
2 Ph Et, No OMe PhCH 2 Q 0 0' N~ S, 0 N>J cr 0 Ph 0 N, SO 2 Ph R,~OK Ph Me SOqPh Et ,Nc OMe 5PhCH 2 O 0 -88 vv~. YYIU14 Y4 YL, I I u l!Va/1qyyu Ph Me Et NNNHMeSOP PhCH 2 O' 0 o 1 . C o N S" y 0 a Ci 8-I NN o N" \ 0' o 7E Ph Me N OH PhCH 2 O 0 0 -90- OY N N :N, Sb 0 O OO O~ N ~N N, So -g O C N0 OOL 0 0 00 o 6 0 OH 0 N N 0 N O OH -92 - O N N N, SN N 0 s, O \ 0 0 OH o S 0 0 0 NH 2 - 93 - N ~ S O NH 2 yo o I 0 O\. 0s 0 NN. O sj O N N N o O O.N-1-0I " Oc, 0 O-94 - 94 - 00 O 1 0 0 HO K6 0 0 N NN KK.-~ S 00 HO Kr 0 - 95 v 77/Uy 17O N r% I L1 1YO/1"7U O O0 NN NS 0 S O HOO 0 O 00 O N Ni NS 0' I
H
2 N 0 09, 0 00 0 a ci
H
2 N 0 - 96 vv L:-," 77lv eix I.1 U3yO/ 197yU S 0yN,Aim N
H
2 N I O OO 0 O N o O 0 00 N 0 O N NN, NN ' 0 C C N 0 -97 - VV L 1 7/U 17 Dtr If ()3Y0/147YU S--S, oO 0 N SO O/ 00 SI Ph Me N N "S02P h CN N PhCH 2 0 0 O0 N ' N S H-8 N OH S N, I N-N Ph NN S02Ph OH 5 and pharmaceutically acceptable salts thereof. The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such -98 modulation comprising the administration of an effective amount of the compound. The present invention is directed to the use of the foregoing spiro-substituted azacycles as modulators of chemokine receptor activity. 5 In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR 3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4. The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be 10 demonstrated by methodology known in the art, such as the assay for CCR-1 and/or CCR-5 binding as disclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993), and the assay for CCR-2 and/or CCR-3 binding as disclosed by Daugherty, et al., J. Exp. Med., 183, 2349-2354 (1996). Cell lines for expressing the receptor of interest include those naturally 15 expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293. For example, a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Maryland as ATCC No. CRL-12079, on April 5, 1996. The utility of the 20 compounds in accordance with the present invention as inhibitors of the spread of HIV infection in cells may be demonstrated by methodology known in the art, such as the HIV quantitation assay disclosed by Nunberg, et al., J. Virology, 65 (9), 4887-4892 (1991). In particular, the compounds of the following examples had 25 activity in binding to either the CCR-5 receptor or the CCR-3 receptor in the aforementioned assays, generally with an IC50 of less than about 10 gM. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity. Mammalian chemokine receptors provide a target for 30 interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are 35 useful in the prevention and/or treatment of a wide variety of - 99- VV t J USlT 17- J Y.. jI tJ &2Oi A77V inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, an instant compound which inhibits one or 5 more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. 10 For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma) can be inhibited according to the present method. Similarly, an instant compound which promotes one or more functions of a mammalian chemokine receptor (e.g., a human chemokine) is administered to stimulate (induce or enhance) an 15 inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections. 20 In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. 25 However, the method can also be practiced in other species, such as avian species (e.g., chickens). Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the 30 actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response. Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, 35 including respiratory allergic diseases such as asthma, allergic - 100rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated 5 with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, 10 multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; 15 spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte 20 infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis. 25 Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune 30 disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, 35 Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, - 101filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), 5 cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum). The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases. 10 In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution 15 of screening assays for compounds which modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of 20 other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4. As appreciated in the art, thorough evaluation of 25 specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are commercial products to be sold for these purposes. 30 The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The present invention is further directed to the use of these 35 compounds in the prevention or treatment of infection by a retrovirus, in - 102 particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a 5 wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, 10 bites, accidental needle stick, or exposure to patient blood during surgery. In a preferred aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a human immunodeficiency virus to a chemokine receptor, such as CCR-5 and/or 15 CXCR-4, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the virus to the chemokine receptor. The subject treated in the methods above is a mammal, preferably a human being, male or female, in whom modulation of 20 chemokine receptor activity is desired. "Modulation" as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being 25 sought by the researcher, veterinarian, medical doctor or other clinician. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or 30 indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of' and or "administering a" 35 compound should be understood to mean providing a compound of the - 103 invention or a prodrug of a compound of the invention to the individual in need of treatment. Combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory 5 disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities. 10 For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an 15 interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, 20 indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as 25 phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. 30 The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS - 104 antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art. ANTIVIRALS 5 Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) 141 W94 Glaxo Wellcome HIV infection, AIDS, ARC (protease inhibitor) 1592U89 Glaxo Wellcome HIV infection, AIDS, ARC Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir - 105 - Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases (-) 6-Chloro-4(S)- Merck HIV infection, cyclopropylethynyl- AIDS, ARC 4(S)-trifluoro- (non-nucleoside methyl-1,4-dihydro- reverse 2H-3,1-benzoxazin- transcriptase 2-one inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globin Cytovene Syntex sight threatening Ganciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (protease inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomatic Japan) - 106vT VS j ;,, -fl . , 1f ti U/J - OI JL1t7S". ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Efavirenz, DMP- DuPont-Merck HIV infection, 266 Pharmaceuticals AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Famciclovir Smith Kline herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GW 141 Glaxo Welcome HIV infection, AIDS, ARC (protease inhibitor) GW 1592 Glaxo Welcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor) - 107 - HBYO97 Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (protease inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) - 108 - Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech (Houston TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV infections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZT - 109- Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies IMMUNO-MODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT Stimulating Factor HIV Core Particle Rorer seropositive HIV Immunostimulant - 110- IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts (aldeslukin) Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT Factor Remune Immune Response immunotherapeutic Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 -111- Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation Spiramycin Rhone-Poulenc cryptosporidial diarrhea -112- Intraconazole- Janssen Pharm. histoplasmosis; R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP OTHER Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT therapy Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS 5 It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS. 10 Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, 15 ddC or ddl. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S) -113hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarbo-xamido) piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred inhibitors of HIV protease 5 include nelfinavir and ritonavir. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include (-) 6-chloro-4(S)-cyclopropylethynyl 4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, which may be prepared by methods disclosed in EP 0,582,455. The preparation of ddC, ddl and AZT are also described in EPO 0,484,071. These combinations 10 may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations with the compounds of the present invention include the following (1) indinavir, with efavirenz or (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H 3,1-benzoxazin-2-one, and, optionally, AZT and/or 3TC and/or ddl and/or 15 ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other 20 agent(s). The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, 25 sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, 30 cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known 35 in the art of pharmacy. All methods include the step of bringing the -114active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided 5 solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising 10 the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, 15 troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents 20 selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. 25 These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, 30 stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be 35 coated by the techniques described in the U.S. Patents 4,256,108; -115- 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert 5 solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in 10 admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy propylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a 15 naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide 20 with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example 25 ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, 30 sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an 35 anti-oxidant such as ascorbic acid. -116- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting 5 agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a 10 vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and 15 hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening 20 agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension 25 may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among 30 the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such 35 as oleic acid find use in the preparation of injectables. -117- The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures 5 but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention 10 are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above 15 mentioned pathological conditions. In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the 20 dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the 25 compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. 30 The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific 35 compound employed, the metabolic stability and length of action of that -118compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Several methods for preparing the compounds of this 5 invention are illustrated in the following Schemes and Examples. Starting materials are made from known procedures or as illustrated. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. 10 SCHEME 1 RCHO, [H] R3
)
m R'X R3 )m 2 R1 RCO RCO
R
3 )m / Strong [H] (nN O~R The compounds of the present invention are prepared by alkylating heterocycle I under appropriate conditions to provide compound II (Scheme 1). The required starting materials for preparing 15 heterocycle I are available commercially or can be prepared using the methods given below. Thus, heterocycle I is combined with the appropriate aldehyde and the intermediate imine or iminium species is reduced to the tertiary amine chemically (e.g. using sodium cyanoborohydride, 20 sodium borohydride, or sodium triacetoxyborohydride) or catalytically (e.g. using hydrogen and palladium on carbon or Raney nickel catalyst) (Scheme 1). The aldehyde needed for this reaction can be prepared by -119methods generally known in the chemical literature; for the purposes of the present invention one preparation of a representative aldehyde is described in Hale, J.J.; Finke, P.E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993,3, 319-322. 5 In an alternative embodiment of the present invention, heterocycle I can be alkylated with an alkyl halide or alkyl sulfonate ester (with or without an added base to neutralize the mineral acid or sulfonic acid by-product) to give the desired compound (Scheme 1). The alkyl halide or alkyl sulfonate needed for this reaction can be 10 prepared by methods generally known in the chemical literature; for the purposes of the present invention an aldehyde, prepared as described above, can be reduced to an alcohol with sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, and the product alcohol converted to either the alkyl halide using methods 15 described in March J. "Advanced Organic Chemistry", 4th ed., John Wiley & Sons, New York, pp. 431-433 (1992), or alkyl sulfonate ester using methods described in March J. "Advanced Organic Chemistry", 4th ed., John Wiley & Sons, New York, p. 498-499 (1992). In an alternative embodiment of the present invention, I 20 can be acylated to give a tertiary amide; subsequent reduction with a strong reducing agent (e.g. diborane; borane in THF; borane dimethylsulfide, or lithium aluminum hydride) will give the desired compound (Scheme 1). The acylating agent needed for this reaction can be prepared by methods generally known in the chemical literature; for 25 the purposes of the present invention an aldehyde, prepared as described above, can be oxidized using such commonly used reagents as permanganate in acid or silver oxide, and the resulting acid activated as an acid chloride or mixed anhydride which can be used to acylate I. The product amide can in and of itself be a chemokine receptor modulator or 30 can be reduced as noted above to give the tertiary amine. Optionally, compound II may be further modified in subsequent reactions, as illustrated below. - 120 - SCHEME 2 HO OH Ph 3 P-Br 2 Br Br
CH
3 CN 1) ArSO 2
N(CH
3 )Na, DMF Me R2 m Me IR R2 m3 n\ -- "S, R 2) " )NH R 3 R 3 |1 R2 m- r (nBu) 3 SnH, THF R2 N R 3 n O O' PdCI 2 (Ph 3
P)
2 R \ ,S IV N TRs Rx (nBu) 3 Sn Me . RT RY Br R 2 , m R O--S z
R
3 nO PdCl 2 (Ph 3
)
2 , dioxane, A NS or Me Rs PdCl2(Ph3)2, Rx RT N-methylpyrrolidinone, A or V Pd(dba), P(furan) 3 , K 2 C00 3 , Rz N-methylpyrrolidinone, A R 2 m N -O"O 3O ,O
H
2 / 10% Pd/C, MeOH or S
H
2 / Pd(OH) 2 /C, MeOH, HOAc R e RS x
RT
VI S Rz In an alternative embodiment of the present invention, 5 compounds of interest can be prepared by activating the hydroxyl groups of 1,4-dihydroxy-2-butyne, for example by treatment with triphenyl phosphine dibromide in acetonitrile, to give 1,4-dibromo-2-butyne (Scheme 2). Displacement of one bromide with the sodium salt of an -121arylsulfonamide (wherein Rs and Rt are substituents on the phenyl or Ar as defined herein), followed by displacement of the other bromide with a suitable cyclic secondary amine, provides the acetylene derivative III. Palladium-catalysed hydrostannylation preferentially forms the 3 5 tributylstannyl olefin IV. The minor product from this reaction can also isolated and carried through the sequence described below. Compound IV can be converted to the corresponding 3-aryl derivative V by treatment with an aryl bromide (wherein Rx, Ry and Rz are substituents on the phenyl or heteroaryl as defined herein) in the presence of a 10 suitable palladium catalyst at or above room temperature. Suitable catalysts include palladium acetate and triphenylphosphine, bis(triphenylphosphine) palladium (II) chloride, or palladium (0) bis(dibenzylidineacetone) in the presence of triphenylphosphine or tri-2 furylphosphine. Suitable solvents include 1,4-dioxane, DMF, and N 15 methylpyrrolidinone. A base such as potassium carbonate or potassium phosphate may also be employed. Compound V may be employed as a chemokine receptor modulator itself or it can be reduced to saturated derivative VI by standard conditions, for example catalytic hydrogenation with palladium on carbon or with palladium hydroxide 20 in the presence of a mild acid such as acetic acid. - 122- SCHEME 3 O EDAC 0 S HOBT-H 2 0 N~OMe HN(Me)(OMe)*HCI RLi, -78C or Me Rx I Rx ~RMgBr, rt Rx7 R >R, SR z VII z VIll O R 6
NH
3 CI R R NaBH 3 CN - NH ArSO 2 CI
R
6 TEA Rx- Rx R Rz IX R Rz X 1) OsO 4 R Q NMO R o, o NR.S R acetone/ tBuOH/H 2 0 H S j~s2:1:1 E I 6 Rs RT 2) NalO 4 RT Rx R Rx.-\
THF:H
2 0 x R R R z XI 3:1 y z Xii R2 H R2 S)m ,,O R3R 6 - R NaBH 3 CN RT MeOH Rx Ry Rz XIII In an alternative embodiment of the present invention, the allyl acid VII (prepared, for example, as described in Hale et al; see 5 above) can be converted into the N-methyl-N-methoxy amide VIII, which is then treated with an alkyl or aryl metal reagent, for example methyllithium or butyllithium, to provide the ketone IX (Scheme 3). The ketone can be converted into an imine which can then be reduced to secondary amine X chemically, (e.g using sodium cyanoborohydride or 10 sodium borohydride), or catalytically (e.g. using hydrogen and - 123 palladium on carbon or Raney nickel catalyst). Acylation under standard conditions, for example with an acid chloride, provides the corresponding amide. Alternatively, amine X can be sulfonylated, for example with a alkyl or aryl sulfonyl chloride or an alkyl or aryl sulfonic 5 anhydride, to give (for aryl substituted sulfonylating reagents) sulfonamide XI. The allyl group in XI can be oxidatively cleaved to aldehyde XII with osmium tetroxide followed by sodium periodate or with ozone at low temperature. Reductive amination of aldehyde XII with azacycle I can then be carried out under the conditions described 10 above to give the desired product XIII. - 124- SCHEME 4 Ry Rz R Rz R 1) (COC)2 R CH2CI 2 , r.t. • O OH 2) N-lithio-2S-benzyl XIV oxazolidinone / N XV Ry Rz Ry Rz Ry ,zPh KHMDS, THF, \ 1) LiBH 4 , MeOH, trisyl azide THF, 00C HOAc /N 2) PPh 3 , THF/H20 OH XVI N 3 1 65C XV NH 2 R RPh 1) OsO 4 , NalO 4 Ry-,.Rz _ _ tB uO H , H 2 O R z Rx , Rx>\/ 1) triphosgene 2), NaCNBH 3 , THF, r.t. MeOH/THF R2 )m N 2) NaH, Mel O R2n O DMF, 70 C Me N% >O3 NH R3 X X Me N xviII 0 R3 Ry / Rz 0 Rx ,":". 1) 1M KOH, EtOH, 850C M e Rs R2 N" IR 2) ArSO 2 CI, Et 3 N, N z S //\ R CH2Cl 2 , 00C R3 HO O XX Preparation of hydroxymethyl derivatives of the target 5 compounds is outlined in Scheme 4. The oxazolidinone imide XV is prepared from acid XIV, by formation of the corresponding acid chloride (by treatment with oxalyl chloride or thionyl chloride) and addition of N lithio 2(S)-benzyl oxazolidinone. The enolate azidation can be accomplished by a variety of methods, such as the procedure of Evans, D. 10 A.; et. al. J. Am. Chem. Soc. 1990, 112, 4011-4030. Reduction of the oxazolidinone moiety of XVI can be carried out by a variety of metal - 125 alCTITIIT W"T flal 1F 9R1 hydride reagents (e.g. LiBH4/MeOH, LiAlH4, etc.). The azide is then reduced by treatment with PPh3/H20 to provide alcohol XVII. Formation of cyclic carbamate XVIII is accomplished by literature methods; i.e. phosgene, triphosgene or carbonyl diimidazole, followed by 5 N-alkylation with sodium hydride and methyl iodide. The target compounds are prepared by oxidative cleavage of the olefin to the aldehyde followed by reductive amination with an amine salt as described for Scheme 1, to provide XIX. Hydrolysis of the cyclic carbamate under basic conditions (for example, potassium hydroxide in 10 ethanol at elevated temperature) followed by selective amide formation at 0OC by combining with an acylating agent or a sulfonating agent such as an arylsulfonyl chloride gives the corresponding hydroxyamides or hydroxysulfonamides (i.e. XX). 15 SCHEME 5 R YN@,Rz RyV Rz RI R( x ) AgNO 3 1) (CO CI) 2 H 20
H
2 0 "OH 2) CH 2
N
2 , Et 2 0 N2 N2 O O VII 0 Ry~R R z 1) (COC1)2 Rx M /) 2) 0 OH s ./O M ~- s N N XXI Me XIV H R z 1) OsO 4 , H20, tBuOH Rx N-Me-morpholine-N-oxide R 2) NalO 4, H20, THF N XXII Me Compounds with alternate arrangements of an amide bond are prepared as shown in Scheme 5. Acid VII can be homologated - 126 under Arndt-Eistert conditions to give the chain-extended acid XIV, which can be derivatized under standard acylating conditions with, for example, an aniline derivative, to give the amide XXI. Oxidative cleavage of the olefin with osmium tetroxide or ozone then provides 5 aldehyde XXII as an intermediate suitable for coupling as described earlier. SCHEME 6 RYb--> z RY Rz R 1) (COCI)2 Rx Rx Il OH ~OH 2) CH 2
N
2 XIV 0 3) AgNO 3 , H 2 0 . XXIII I- OH XXIII O Ry Rz 0 1) (COCI) 2 Rx Rs 0MBrMg Me 2) HN(Me)OMe M NOMe THF Ry. Rz XXIV 0 Rx r"' 1) OsO 4 , H 2 0, tBuOH _ R N-Me-morpholine-N-oxide | Rs 2) NalO 4 , H 2 0, THF O XXV Ry Rz Rx Rs O XXVI 10 In addition, ketone derivatives are prepared by an extension of the chemistry given above, as shown in Scheme 6. An Arndt-Eistert chain extension of acid XIV provides heptenoic acid XXIII, which after conversion into N-methoxy-N-methyl amide XXIV, can be reacted with - 127 an aryl organometallic reagent, such as an aryl magnesium bromide, to provide ketone XXV. Routine oxidative cleavage then gives the desired aldehyde XXVI, which can be coupled with an appropriate amine as described above. 5 SCHEME 7 0 OH NMe 1) (COCI) 2 OMe Rz-I VII 2) HN(Me)OMe Rz Ry Rx Ry Rx 1) OsO 4
,H
2 0, tBuOH N R2 O-.. Me R2 /\JH N-Me-morpholine-N-oxide OMe + NH __ _ __ _OMe + ):r3 R - R3 2) NalO 4 , H 2 0, THF z I4\ XXVII Ry Rx R m O ArMgCI MeOH, NaBH 3 CN R 2 1,N Me mol. sieves R n \ - OMe
R
XXVIII z Ry Rx R2 0 R2 OH n \ NaBH 4 R3 - R3 n Rz-i Rs Rz-- Rs XXIX XXX Ry Rx Ry Rx Alcohol containing compounds are prepared according to procedures given in Scheme 7. Formation of the N-methyl-N-methoxy 10 amide of acid VII followed by oxidative cleavage of the olefin provides intermediate aldehyde XXVII. Coupling with an appropriate amine provides amide XXVIII. Addition of an organometallic reagent to - 128 compound XXVIII provides illustrated ketone XXIX. Treatment with a hydride reducing agent, such as sodium borohydride, then yields the desired alcohol XXX. SCHEME 8 0 LiAIH 4 OH (CF 3
SO
2 )O OH STHF 2,6-lutidine Rz II zR XXXI Rz VII Ry Rx Ry Rx x-Rs HNN N 'N R X XXXII Rs Ry R 1) OsO 4 , H 2 0, tBuOH O' N "'N N-Me-morpholine-N-oxide 2) NalO 4 , H 2 0, THF RzX l XXXIII 5 Ry Rx Formation of heterocycle compounds is carried out according to the procedure given in Scheme 8 for substituted imidazoles. Reduction of allyl acid VII with a strong reducing agent such as lithium aluminum hydride provides alcohol XXXI. In situ formation of the 10 trifluoromethanesulfonate ester of the formed alcohol allows for displacement of the triflate with a nucleophile such as 2-phenyl imidazole, to give imidazole XXXII. Oxidative cleavage under standard conditions provides the aldehyde XXXIII which can then be coupled under the conditions described above to the appropriate amine. 15 - 129 - SCHEME 9 0 LiAIH 4 ' OH NaH
OH:-
THF DMF R Rz VII XXXI Ry Rx Ry Rx RS R7 1) OsO4, H 2 0, tBuOH N-Me-morpholine-N-oxide
XO
/ 2) NalO 4 , H 2 0, THF I R Rs z0, XXXIV Ry Rx Rs R2 m R +NH O OR3 R2 O SRR2 NaBH 3 CN, R3 R mol. sieves R z XXXV z XXXVI Ry Rx Ry Rx Compounds with ether substituents are prepared by the route shown in Scheme 9. Thus, allyl acid VII can be reduced to alcohol 5 XXXI with, for example, lithium aluminum hydride. This alcohol can be alkylated by a Williamson ether synthesis, by deprotonation with a strong base such as sodium hydride or sodium hexamethyldisilazide followed by reaction with a benzyl halide such as benzyl bromide. The resulting ether XXXIV can be processed through the oxidative cleavage 10 steps described earlier to provide aldehyde XXXV. This aldehyde can then be coupled with an appropriate amine under reductive amination conditions to give XXXVI. Alternatively, reduction of XXXV to the corresponding alcohol followed by conversion to the bromide allows for alkylation with an amine to provide XXXVI. - 130 - SCHEME 10 O 1) HOBT, EDAC 0 H OtBu 2) ROH R'O O'Bu XXXVII XXXVIII O 1) HOBT, EDAC 0N H OBu 2) RR'NH R-N OtBu I XXXVII R' XXXIX O 1) HOBT, EDAC 0 HO OtBu 2) MeO(Me)NH MeO-N OtBu I XXXVII Me XL O N RMgX or RLi 0 MeO-N
N-K'
9 R/OB Me XL XLI O TFA, CH 2
CI
2 0R'ONH*TFA R-Bu R-- H-TFA O'Bu XLII XXXVIII XLII O N B TFA, CH 2 C1 2 ONHTFA -- RHT I OtBu R' XLIII R' XXXIX O TFA, CH2C1 2 0NCH*TFA R OtBu XLIV XLI The substituted amines employed in the preceding Schemes 5 can be obtained commercially in many cases or are prepared by a number of procedures. For example, as shown in Scheme 10, compound XXXVII, the N-t-butoxycarbonyl protected form of isonipecotic acid (4 piperidinecarboxylic acid) can be activated under standard conditions, for example with a carbodiimide, and converted into ester XXXVIII or -131amide XXXIX. Alternatively, acid XXXVII can be converted into the N methyl-N-methoxy amide, XL, which upon reaction with organomagnesium and organolithium reagents forms the ketone XLI. The Boc group of XXXVIII, XXXIX and XLI can be removed under 5 acidic conditions to provide secondary amines XLII, XLIII and XLIV, respectively. SCHEME 11 0 O 1) Oxalyl Chloride O N ',NN HON 2) NaN 3 ; toluene, C N O HO / OBn acetone 0 Bn XLV 3) heat XLVI ,C N ROH R'O N N O O Bn "H __/ OBn 0 XLVI XLVII cNNRR'NH N C OBn R R' H N OBn 0 XLVI RXLVIII R
H
2 ; Pd/C R, I H MeOH O N NH On H XLIX XLVII
RH
2 ; Pd/C I' H OBn MeOH N NNH R' OBnH XLVIII L 10 Alternatively, CBZ-protected piperidine XLV can be allowed to react with oxalyl chloride and then sodium azide, to provide the corresponding acyl azide, which can then be thermally rearranged to isocyanate XLVI (Scheme 11). Compound XLVI can be treated with an alcohol ROH or an amine RR'NH to form carbamate XLVII or urea - 132 - XLVIII, respectively, each of which can be deprotected with hydrogen in the presence of palladium on carbon to secondary amines XLIX or L. SCHEME 12 0~ NaH O0
(CH
2 )x OBn DMF (CH 2 ) OBn -CI XLVII' (x = 1-3) LI O O R, N N"-"Bn NaH, DMF RO. N N B H OBn R'X RBn XLVII LII 0 0 O N OH H 2 ; Pd/C O NNH
(CH
2 )x LOBn MeOH (CH 2 ) LI LIII O O R'0 NHN O H 2 ; Pd/C R'O I NH R OBn MeOH R 5 LII LIV If the carbamate XLVII has R = -(CH 2 )xCH 2 C1, where x = 1 3, then treatment with a suitable base, such as sodium hydride, lithium hexamethyldisilazide or potassium t-butoxide, can induce cyclization to compound LI (Scheme 12). For other R groups, carbamate XLVII can be 10 treated with an alkylating agent R'X,where R' = primary or secondary alkyl or alkyl-cycloalkyl, while X = bromide, iodide, tosylate, mesylate or trifluoromethanesulfonate, in the presence of a suitable base, such as sodium hydride, lithium hexamethyldisilazide or potassium t-butoxide, to give derivative LII. In each case, removal of the CBZ protecting group 15 under standard conditions provides the secondary amines LIII and LIV. - 133 - SCHEME 13 Me 0 N O t-BuOH; CuCI Me O N N "N_C N o Me 0 NoN<
-,
C H OBn XLVI OBn DMF LV LV , TFA*NH 2
CH
2
CI
2 OBn LVI O O RCOCI, CHCl2 OI
TFA*NH
2 N- 2 R N N OBn Pyridine H OBn LVI O LVII LVI ROCOCI, CH 2
CI
2 R 0
..
O N N O LV I ' Pyridine H OBn XLVII RR'NCOCI, CH 2
CI
2 O LVI Pyridine R'N N i N O or H X RNCO (R'= H) R' OBn XLVIII
RSO
2 CI , CH2Cl2 O ,O LVI R - S' N- N O pyridine H OBn LVIII 5 Additional derivatives of a piperidine with nitrogen functionality at C4 can be carried out as shown in Scheme 13. For example, if the ring nitrogen is protected with a CBZ group, as with isocyanate XLVI, treatment with tert-butyl alcohol in the presence of copper(I) chloride, provides Boc derivative LV. This compound can be 10 selectively deprotected to the free amine LVI. This amine can be acylated with an acid chloride, a chloroformate, an isocyanate, or a carbamyl chloride, to provide compounds LVII, XLVII or XLVIII. Alternatively, amine LVI can be sulfonated with an alkyl or arylsulfonyl chloride, to give sulfonamide LVIII. - 134- SCHEME 14 O O 0 0 R ) N-- N-- 0 H 2 ; Pd/C RO N NH H OBn MeOH H LVII LIX 0 H 2 ; Pd/C 0 RO N N O< MeOH R' 0 N - NH H OBn H XLVII XLIX O0 R " - H 2 ; Pd/C 0 'N N N-' R.s 3 NN R' H OBn MeOH R N- NH R, H XLVill L R 0' H; Pd/C O LVIII L LX 5 In each case, removal of the CBZ group under reductive conditions gives the desired secondary amines LIX, XLIX, L, and LX (Scheme 14). - 135 - SCHEME 15 Me O Me 0 Me
H
2 , Pd/C Me 0 N NH Me O N N- MeOH H OBn LV 0, LXI Me 0 HS Y N Me NNH + 06 -j Rs H0RT Rx LXI x R z Me 0 NaBH 3 CN, MeOH Me O K ,O Me 0 N N ,S mol. sieves H N - R 6 .- JRs RRT LXII x R z MeCOCI HCINH 2
R
6 | Rs MeOH RT LXIII R -" j z ~Ry Functionalization of the piperidine can also be carried out 5 after it has been coupled with an N1 substituent. For example, as shown in Scheme 15, reductive deprotection of CBZ derivative LV yields secondary amine LXI. Reductive amination with an appropriate aldehyde fragment (as described above) provides piperidine LXII. Removal of the Boc group under acidic conditions then gives primary 10 amine LXIII. This primary amine can then be functionalized by analogy to the chemistry given in Scheme 13. Compound LXI can also be alkylated as described above in Scheme 12, and then carried through the remaining sequence given in Scheme 15. - 136- SCHEME 16 RY Ry R y Rz / R x IRzbI- x 1) NaH, THF zN\R 2) B CN CN LXV LXlV Ry R , 1) RNH 2 , NaBH 3 CN RDIBAL-H z - Rx mol. sieves DIBAL-H 2) ArSO 2 CI, pyr CHO R Rz Y/ LXVI R z Rx 1) 9-BBN, THF R R R N 2) NaOH, H 2 0 2 HO N .. Ar N, -ArS SS OLIO LXVIII LXVII R L R yRx R2 H Ph 3 P-Br 2 R nH ,R R3
CH
3 CN Br N ,sAr DIEA, CH 3 CN, A 1OO R0 RZ /, Rx R2 R R2 m Ar LXIX R3 O O A method of preparing a backbone with an alternate spacing from the one described above is given in Scheme 16. 5 Deprotonation of a suitable phenylacetonitrile derivative LXIV with sodium hydride followed by addition of allyl bromide provides the allyl nitrile LXV. Reduction to the corresponding aldehyde LXVI is carried out with diisobutylaluminum hydride in THF. Reductive amination with a primary amine followed by sulfonylation then provides - 137 sulfonamide LXVII. Selective hydroboration of the terminal position of the olefin, for example with 9-BBN, followed by oxidation with basic hydrogen peroxide, then gives primary alcohol LXVIII. Conversion of this alcohol to the corresponding bromide with triphenylphosphine 5 dibromide complex followed by alkylation with a cyclic secondary amine then gives the desired product LXIX. SCHEME 17 RY RY Rzl</'- , y Rzl,/, Rx mCPBA z x RNH 2 ' LXX LXXI 0 Ry Ry Rz</ R x zArSO 2 C Rz</ Rx H DIEA, THF R HO N5 N- Ar HO ' R HONS A r I, \\ LXXII LXXIII 0 0 Ry 1) MeSO 2 CI, Et 3 N Rz- Rx EtOAc R3 R 2) R2 /gjm R N Ar R3 10 LXXIV Another backbone variation is prepared according to Scheme 17. Epoxidation of a suitably substituted styrene derivative LXX with an oxidizing agent such as mCPBA provides the epoxide LXXI 15 which is converted to the aminoalcohol LXXII by treatment with a primary amine RNH 2 . Treatment of LXXII with an acylating agent or a sulfonylating agent under mild conditions (as shown for the conversion to compound LXXIII) produces the corresponding neutral alcohol. - 138- Activation of the hydroxy group with, for example, methanesulfonyl chloride, followed by treatment with a secondary cyclic amine yields the aminosulfonamide LXXIV. 5 SCHEME 18 Ry Ry Rz Rx R Rx ,- Ac2O -,x IO O< toluene LXXVI HO OH LXXV R Rz</> Rx
RNH
2 0 LiAIH 4 , O O THFO 1-, N' R THF HO NR Ry LXXVII H R Rz \Rx R \R ArSO 2 CI /, DIEAS
HO"N
R D HO N 'Ar H R LXXVIII LXXIX R 1) MsCI, Et3N Rz/ R x 2) R2 m R O/0 R2 .N> vN Ar R3 nHn R Na 2
CO
3 , Me 2 CHCN R3 LXXX Another backbone variation is prepared according to Scheme 18. Treatment of 3-arylpentane-1,5-dioic acid LXXV with acetic 10 anhydride in toluene provides anhydride LXXVI. Addition of an amine
RNH
2 yields amidoacid LXXVII, which can be reduced with a strong reducing agent like lithium aluminum hydride to give aminoalcohol LXXVIII. Selective sulfonylation on nitrogen can be accomplished by - 139treatment with a suitable arylsulfonyl chloride, to produce sulfonamide LXXIX. Activation of the hydroxy group with methanesulfonyl chloride in the presence of triethylamine followed by addition of a cyclic secondary amine in isobutyronitrile in the presence of sodium carbonate 5 at elevated temperatures then provides the desired sulfonamidoamine LXXX. SCHEME 19 Ry Ry R z</ Rx R z /1Rx LiAIH 4 HO OH HO OH O O LXXXI R LXXXII Rz</) Rx NaH, t-BuSi(Me) 2 Cl ArSO 2 NHR THF TBDMSO OH DEAD, Ph3P, THF Ry LXXXIII Ry Rz-7/.. Rx R z-/z Rx R 1)Bu 4 NF, THF R R /R TBDMSO N.. SAr 2) MeSO2CI, EtOAc MsOAr liv' 2 N, Ar 0i 0 LXXXIV LXXXV 0O R R2 N'm Rz$/ Rx R3 nR2 m R LXXXVI NI N A r Na2CO3, Me2CHC N ' S R3 "00 O O 10 Another backbone variation is prepared according to Scheme 19. Reduction of 2-arylmalonic acid derivative LXXXI with lithium aluminum hydride provides diol LXXXII, which upon treatment with sodium hydride and t-butyldimethylsilyl chloride in THF produces selectively the monosilyl ether LXXXIII. Exposure of this 15 compound to an N-substituted arylsulfonamide in the presence of DEAD - 140 and triphenylphosphine in THF provides the sulfonamide LXXXIV. Removal of the silyl group, for example with tetrabutylammonium fluoride in THF, followed by treatment with methanesulfonyl chloride in ethyl acetate, yields the mesylate LXXXV. Treatment of this mesylate 5 with a cyclic secondary amine then provides the desired product LXXXVI. SCHEME 20
RNH
2 , MeOH ArSO 2 CI, Et 2 NEt 0 -r H NaBH 3 CN THF
OH
3 H LXXXVII 1) Os0 4 , NMMO, tBuOH R N'S, Ar N, ,Ar
CH
3 6' 2) NalO 4 , THF/H 2 0 O S A H3H 3 0 LXXXVII LXXXIX R2f7r R R3 R2 m N Ar R 3 N'S NaBH 3 CN, THF R3 CH3 OO XC 10 Another backbone variation is prepared according to Scheme 20. Reductive alkylation of the commercially available aldehyde LXXXVII with a suitable primary amine followed by sulfonylation provides sulfonamide LXXXVIII. Treatment of this olefin with osmium tetroxide followed by sodium periodate provides aldehyde LXXXIX. 15 Reductive amination with a cyclic secondary amine then provides the target compound XC. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. -141- The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. EXAMPLE 1 5 (R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methylbenzene sulfonamide Step A: (R,S)-N-(2-Phenylpent-4-en-1-yl)-N-methylbenzene 10 sulfonamide A solution of 2.0 g (11.4 mmol) of (R,S)-4-phenyl-5 methylamino-1-pentene (prepared as described by J. Hale et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and 6.0 mL (34 mmol) of diisopropylethylamine (DIPEA) in 25 mL of methylene 15 chloride was cooled in an ice/ethanol bath. To this was added 2.2 mL (17 mmol) of benzenesulfonyl chloride and after 5 min the ice bath was removed. After stirring for 16 h, the reaction mixture was diluted with methylene chloride and washed with water containing 20 mL of 2 N HC1. The aqueous layer was reextracted with methylene chloride and the 20 organic layers were washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (FCC) eluting with 5% ethyl acetate/hexanes to afford 3.2 g of the title compound. 1H NMR (400 MHz, CDCl3): 8 2.38 (p, J = 8, 1H), 2.55 (m, 1H), 2.57 (s, 25 3H), 2.94 (m, 2H), 3.41 (m, 1H), 4.95 (m, 2H), 5.62 (m, 1H), 7.1-7.3 (m, 5H), 7.45 (m, 2H), 7.52 (m, 1H), 7.69 (dd, J = 1.5 and 6, 2H). Step B: (R,S)-N-(2-Phenyl-4-oxobut-1-yl)-N-methylbenzene sulfonamide 30 To a solution of 1.0 g (3.2 mmol) of (R,S)-N-(2-phenylpent-4 en-1-yl)-N-methylbenzenesulfonamide from Step A in 7 mL of acetone, 3.5 mL of t-butanol and 3.5 mL of water was added 413 mg (3.5 mmol) of N-methylmorpholine-N-oxide followed by 0.14 mL of 4% osmium tetroxide in water. The reaction was stirred at rt for 16 h and was then 35 quenched with aqueous sodium bisulfite and concentrated in vacuo. The - 142 - WU 99/U4~/9I4 VU I/ U )7/149U residue was diluted with water and extracted twice with ether. The ether layers were each washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC eluting with 5% methanol in methylene chloride to afford the diol 5 intermediate. The above product was taken up in 10 mL of THF and 755 mg (3.5 mmole) of sodium periodate in 3 mL of water was added. The mixture was stirred at rt for 3 h, poured into water and extracted twice with ether. The ether layers were each washed with brine, combined, dried over sodium sulfate and concentrated in vacuo to afford 940 mg of 10 the title compound. 1H NMR (400 MHz, CDCl3): 6 2.62 (s, 3H), 2.75-2.9 (m, 2H), 3.14 (dd, J = 6 and 17, 1H), 3.39 (m, 1H), 3.55 (m, 1H), 7.15-7.35 (2 m, 5H), 7.46 (m, 2H), 7.53 (m, 1H), 7.70 (dd, J = 1.5 and 7, 2H), 9.78 (d, J = 1.2, 1H). 15 Step C: (R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt To a solution of 0.020 g (0.063 mmol) of (R,S)-N-(2-phenyl-4 oxobut-1-yl)-N-methylbenzenesulfonamide from Step B in 1.2 mL of THF were added 31 mg (0.19 mmol) of 4-phenylpiperidine, 3 A molecular 20 sieves and 0.011 mL of acetic acid. After stirring the mixture for 20 min, 27 mg (0.126 mmol) of sodium triacetoxy-borohydride was added. After 16 h the mixture was filtered through a pad of celite and the reaction flask and the pad were rinsed with water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice more with 25 ethyl acetate. The organic layers were each washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep TLC using 5% methanol in methylene chloride to isolate 25 mg of the free amine of the title compound as an oil. 1H NMR (400 MHz, CDC13): 8 1.80 (m, 5H), 1.9-2.3 (3 m, 5H), 2.4-2.5 (m, 30 1H), 2.59 (s, 3H), 2.9-3.1 (m, 4H), 3.35-3.45 (m, 1H), 7.1-7.3 (m, 10H), 7.4 7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.70 (dd, J = 1.5 and 7.0, 2H). Mass spectrum
(NH
3 /CI): m/z 463 (M+1, 100%). The hydrochloride salt of the title compound was prepared by dissolving the above oil in ether/methanol and addition of 2-3 equivalents of 1 M ethereal HC1. Evaporation of the - 143volatiles and drying in vacuo afforded 26 mg of the title salt as a white solid after trituration with ether. The following Examples were prepared following the 5 procedure described in Example 1, Step C but using the appropriate substituted amine in the reductive amination. EXAMPLE 2 10 (R,S)-N-[2-Phenyl-4-(4-benzylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 477 (M+1, 100%). 15 EXAMPLE 3 (R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonyl-4-phenylpiperidin- 1 yl)but-1-yll -N-methylbenzenesulfonamide 20 Mass spectrum (NH 3 /CI): m/z 534 (M+1, 100%).). EXAMPLE 4 (R,S)-N-[2-Phenyl-4-(4-aminocarbonyl-4-phenylpiperidin-1-yl)but-1-yl] 25 N-methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 506 (M+1), 249 (100%). EXAMPLE 5 30 (R,S)-N-[2-Phenyl-4-(4-hydroxymethyl-4-phenylpiperidin-1-yl)but-l-yl] N-methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 493 (M+1, 100%). 35 - 144- WU )/MU4I/V4 Vt I/UNflS14YYU~ EXAMPLE 6 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)but- 1 yll-N-methylbenzenesulfonamide 5 Mass spectrum (NH 3 /CI): m/z 521 (M+1, 100%). EXAMPLE 7 10 (R,S)-N- [2-Phenyl-4-(piperidin-1-yl)but-1-yl]-N-methylbenzene sulfonamide Mass spectrum (NH 3 /CI): m/z 387 (M+1, 100%). 15 EXAMPLE 8 (R,S)-N-[2-Phenyl-4-(4-pentylaminocarbonylpiperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide 20 Mass spectrum (NH 3 /CI): m/z 500 (M+1, 100%). EXAMPLE 9 (R,S)-N-[2-Phenyl-4-(4-isopropylaminocarbonylpiperidin-1-yl)but-1-yl] 25 N-methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 472 (M+1, 100%). EXAMPLE 10 30 (R,S)-N- [2-Phenyl-4-(4-methylaminocarbonylmethylene-4 phenylpiperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 534 (M+1, 100%). 35 - 145- EXAMPLE 11 (R,S)-N-[2-Phenyl-4-(4-methylaminocarbonyl(methylamino)methylene-4 phenvylpiperidin-1-yl)but-1-ylv -N-methylbenzenesulfonamide 5 Mass spectrum (ESI): m/z 563 (M+1, 100%). EXAMPLE 12 10 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminomethylene-4 phenylpiperidin-1-yl)but-1-yl] -N-methylbenzenesulfonamide Mass spectrum (ESI): m/z 550 (M+1, 100%). 15 EXAMPLE 13 (R,S)-N-[2-Phenyl-4-(4-methylaminocarbonylaminomethylene-4 phenylvpiperidin-1-vyl)but-1-vyl-N-methylbenzenesulfonamide 20 Mass spectrum (ESI): m/z 549 (M+1, 100%). EXAMPLE 14 (R,S)-N-[2-Phenyl-4-(4-(2-methyl)phenylpiperidin-1-yl)but-1l-yl]-N 25 methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 477 (M+1, 100%). EXAMPLE 15 30 (R,S)-N-[2-Phenyl-4-(4-morpholinocarbonylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 500 (M+1, 100%). 35 - 146- The following Examples were prepared following the procedure described in Example 1, Step A-C but starting with (R,S)-4-(2 chlorophenyl), (3,5-dichlorophenyl), (2-thienyl), (3-thienyl), or (cyclohexyl)-5-methylamino-1-pentene (prepared as described by J. Hale 5 et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and using the appropriate substituted piperidine in the reductive amination. EXAMPLE 16 10 (R,S)-N-[2-(2-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 497 (M+1, 100%). EXAMPLE 17 15 (R,S)-N-[2-(2-Thienyl)-4-(4-phenylpiperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide Mass spectrum (ESI): m/z 469 (M+1, 100%). 20 EXAMPLE 18 (R,S)-N-[2-(3-Thienyl)-4-(4-phenylpiperidin-1l-yl)but-1l-yl]-N methylbenzenesulfonamide Mass spectrum (ESI): m/z 469 (M+1, 100%). 25 EXAMPLE 19 (R,S)-N-[2-(3-Thienyl)-4-(4-benzylpiperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide 30 Mass spectrum (ESI): m/z 483 (M+1, 100%). EXAMPLE 20 (R,S)-N-[2-Cyclohexyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 35 methylbenzenesulfonamide Mass spectrum (NH 3 /CI): m/z 469 (M+I, 100%). - 147 - EXAMPLE 21 (R,S)-N-[2-(3,5-Dichlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 5 methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 531 (M+1, 100%). EXAMPLE 22 10 (R,S)-N-[2-(3-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide Step A: N- [4-(4-Phenylpiperidin-1-yl)but-2-yn-1-yl]-N methylbenzenesulfonamide 15 To a suspension of triphenylphosphine dibromide at 0 oC (prepared by addition of bromine to 53.5 g (210 mmol) of triphenylphosphine in 200 mL of acetonitrile at 0 oC) was added 8.0 g (93 mmol) of 2-butyne-1,4-diol. The reaction was stirred for 10 min, the ice bath was removed, the mixture was stirred for 2 hr, and then 20 concentrated in vacuo. The residue was triturated with ether and filtered to remove the precipitated triphenylphosphine oxide. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. The residue of crude dibromide was taken up in 50 mL of DMF under nitrogen and cooled in an ice bath. 25 A solution of the sodium salt of N-methylbenzene sulfonamide in 50 mL of DMF was prepared at 0 oC under nitrogen by portionwise addition of 3.2 g (80 mmol) of 60% sodium hydride over 0.5 h and then stirred with cooling for 0.5 h. This salt solution was added via canula over 15 min with cooling to the above dibromide solution. After 30 0.5 h, 18.0 g (110 mmol) of 4-phenylpiperidine was added and the reaction was stirred a further 2 h at rt. The reaction was diluted with water and extracted three times with ether. The ether layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FCC eluting with 30 35 to 50% ethyl acetate/hexanes to afford 11.3 g of title compound. - 148- 1H NMR (400 MHz, CDC13): 8 1.65-1.85 (m, 4H), 2.07 (dt, J = 3 and 8, 2H), 2.4 (m, 1H), 2.78 (br d, J = 11, 2H), 2.84 (s, 3H), 3.09 (t, J = 2, 2H), 4.07 (t, J = 2, 2H), 7.1-7.3 (2 m, 5H), 7.45-7.6 (m, 3H), 7.82 (dd, J = 1.5 and 7, 2H). Mass spectrum (NH 3 -CI): m/z 383 (M+1, 100%). 5 Step B: N-[4-(4-Phenylpiperidin-1-yl)-2-tributylstannylbut-2-en-1-yl] N-methylbenzenesulfonamide and N-[4-(4-Phenylpiperidin 1-yl)-3-tributylstannylbut-2-en-1l-yl]-N-methylbenzene sulfonamide 10 To a solution of 11.0 g (29 mmol) of N-[4-(4-phenyl-piperidin 1-yl)but-2-yn-1-yl]-N-methylbenzenesulfonamide from Step A in 75 mL of THF under nitrogen was added 400 mg (0.58 mmol) of dichlorobis(triphenylphosphine)palladium (II) and then 13.7 mL (51 mmol) of tributylstannane was added dropwise via syringe over 0.5 h. 15 After a further 0.5 h, the dark reaction (from precipitated palladium) was concentrated in vacuo. The residue was purified by FCC eluting with 20% ethyl acetate/hexanes to give 2.5 g of the higher Rf 3-stannyl title product. Elution with 30-40% ethyl acetate/hexanes afforded 10.8 g of the lower Rf 2-stannyl title compound. Further elution with 50-70% 20 ethyl acetate/hexanes afforded 3.5 g of recovered starting material. higher Rf product: 1H NMR (400 MHz, CDCl3): 5 0.8-0.9 (m, 6H), 0.87 (t, J = 7, 9H), 1.25-1.35 (m, 6H), 1.35-1.5 (m, 6H), 1.6-1.85 (2 m, 4H), 1.94 (dt, J = 3 and 8, 2H), 2.43 (m, 1H), 2.69 (s, 3H), 3.01 (br t, JH-Sn = 25, 2H), 3.78 (d, J = 6, 2H), 5.44 (br 25 ttt, J = 1.5 and 6, JH-Sn = 34, 1H), 7.1-7.3 (2 m, 5H), 7.5-7.65 (m, 3H), 7.77 (dd, J = 1.5 and 7.0, 2H). Lower Rf product: 1H NMR (400 MHz, CDCl3): 6 0.87 (t, J = 7, 9H), 0.95-1.05 (m, 6H), 1.25 1.4 (m, 6H), 1.45-1.6 (m, 6H), 1.7-1.85 (m, 4H), 1.92 (dt, J = 3 and 8, 2H), 30 2.42 (m, 1H), 2.48 (s, 3H), 2.96 (m, 2H), 3.74 (br t, JH-Sn = 23, 2H), 5.88 (br tt, J = 6, JH-Sn = 32, 1H), 7.1-7.3 (2 m, 5H), 7.5-7.65 (m, 3H), 7.77 (dd, J = 1.5 and 7.0, 2H). - 149- Step C: N-[2-(3-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-2-en- 1 vy -N-methylbenzenesulfonamide To 250 mg (0.37 mmol) of N-[4-(4-phenylpiperidin-1-yl)-2 tributylstannylbut-2-en-1-yl]-N-methylbenzenesulfonamide from Step B 5 in 0.4 mL of N-methylpyrrolidinone under argon was added 77 mg (0.55 mmol) of potassium carbonate, 8 mg (catalytic) of dichlorobis(triphenyl phosphine)palladium (II) and 0.067 mL (0.55 mmol) of 3-methylbromo benzene. The mixture was heated at 70 OC for 24 h, cooled, treated with aqueous sodium fluoride for 10 min, and partitioned between water and 10 ether. The water layer was reextracted with ether and each organic layer was washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FCC eluting with 25 50% ethyl acetate/hexanes to give 57 mg of product contaminated with stannane biproduct. The product was further purified by prep TLC (50% 15 ethyl acetate/hexanes) to afford 53 mg of title compound. 1H NMR (400 MHz, CDCl3): 8 1.7-1.9 (min, 4H), 2.0-2.2 (m, 2H), 2.32 (s, 3H), 2.6-2.6 (m, 1H), 2.50 (s, 3H), 3.05 (m, 2H), 3.20 (m, 2H), 4.12 (s, 2H), 6.11 (br t, J = 7, 1H), 7.07 (m, 1H), 7.15-7.35 (m, 8H), 7.52 (min, 2H), 7.60 (m, 1H), 7.74 (dd, J = 1.5 and 7, 2H). 20 Step D: (R,S)-N- [4-(4-Phenylpiperidin-1-yl)-2-(3-methylphenyl)-but- 1 yl]-N-methylbenzenesulfonamide A mixture of 46 mg (0.097 mmol) of N-[4-(4-phenylpiperidin 1-yl)-2-(3-methylphenyl)but-2-en-1-yl]-N-methylbenzenesulfonamide 25 from Step C, 12 mg of 20% palladium hydroxide/C (50% water), and 2 drops of acetic acid in 3 mL of methanol was hydrogenated at 40 psi for 24 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by prep TLC (50% ethyl acetate/hexanes) to afford 20 mg of title compound. A major biproduct 30 was cleavage of the 4-phenylpiperidine to give N-[2-(3-methylphenyl)but 1-yl]-N-methylbenzenesulfonamide. 1H NMR (400 MHz, CDC13): 5 1.8-2.0 (min, 5H), 2.1-2.3 (m, 3H), 2.32 (s, 3H), 2.38 (min, 1H), 2.51 (m, 2H), 2.61 (s, 3H), 2.88 (min, 2H), 3.21 (min, 2H), 3.32 (dt, J = 3 and 9, 1H), 6.96 (br s, 2H), 7.05 (d, J = 8, 1H), 7.15-7.3 (m, - 150- 6H), 7.46 (m, 2H), 7.54 (m, 1H), 7.70 (dd, J = 1.5 and 7, 2H). Mass spectrum (NH 3 -CI): m/z 477 (M+1, 100%). The following Examples were prepared following the 5 procedure described in Example 22, Steps C-D but using the appropriate substituted bromobenzene in Step C. EXAMPLE 23 10 (R,S)-N-[2-(3-Ethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 491 (M+I, 100%). EXAMPLE 24 15 (R,S)-N-[2-(3-Carboethoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 535 (M+l, 100%). 20 EXAMPLE 25 (R,S)-N- [2-(3-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 481 (M+l, 100%). 25 EXAMPLE 26 (R,S)-N-[2-(3-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt 30 Mass spectrum (NH 3 -CI): m/z 493 (M+1, 100%). EXAMPLE 27 -151- (R,S)-N-[2-(3,4-Difluorophenyl)-4-(4-phenylpiperidin-1-yl)but-l-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 499 (M+1, 100%). 5 EXAMPLE 28 (R,S)-N-[2-(3-Biphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 539 (M+1, 100%). 10 EXAMPLE 29 (R,S)-N-[2-(3-Pyridyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt 15 Mass spectrum (NH 3 -CI): m/z 464 (M+1, 100%). EXAMPLE 30 (R,S)-N- [2-(Naphthalen-2-yl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 20 methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 513 (M+1, 100%). EXAMPLE 31 25 (R,S)-N-[2-(4-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 553 (M+1, 100%). EXAMPLE 32 30 (R,S)-N-[2-(2-Pyridyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 464 (M+1, 100%). 35 EXAMPLE 33 - 152 - (R,S)-N-[2-(3-Fluoro-4-methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1 vyl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 495 (M+1, 100%). 5 EXAMPLE 34 (R,S)-N-[2-(3,4-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl] N-methylbenzenesulfonamide hydrochloride salt 10 Mass spectrum (NH 3 -CI): m/z 491 (M+1, 100%). EXAMPLE 35 (R,S)-N-[2-(3,5-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl] 15 N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 491 (M+1, 100%). EXAMPLE 36 20 (R,S)-N-[2-(4-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 493 (M+1, 100%). EXAMPLE 37 25 (R,S)-N-[2-(3-Trifluoromethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1 yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 531 (M+1, 100%). 30 EXAMPLE 38
(R,S)-N-[
2 -(3-Methyl-4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)but- 1 vyl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 495 (M+1, 100%). 35 - 153- EXAMPLE 39 (S)-N- 1[2-(3-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt 5 Step A: (S)-N- [2-(3-Chlorophenyl)pent-4-en-1-yl]-N methylbenzenesulfonamide A solution of 2.0 g (9.53 mmol) of (S)-4-(3-chorophenyl)-5 methylamino-1-pentene (prepared as described by J. Hale et al., 10 Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and 5.0 mL (28.6 mmol) of diisopropylethylamine (DIPEA) in 20 mL of methylene chloride was cooled in an ice/ethanol bath. To this was added 1.46 mL (11.4 mmol) of benzenesulfonyl chloride and after 5 min the ice bath was removed. After stirring for 16 h, the reaction mixture was diluted with 15 methylene chloride and washed with water containing 20 mL of 2 N HC1. The aqueous layer was reextracted with methylene chloride and the organic layers were washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (FCC) eluting with 15% ethyl acetate/hexanes 20 to afford 3.44 g of the title compound. 1H NMR (400 MHz, CDC13): 5 2.38 (p, J = 8, 1H), 2.55 (m, 1H), 2.59 (s, 3H), 2.94 (m, 2H), 3.37 (m, 1H), 4.95 (m, 2H), 5.60 (m, 1H), 7.05-7.3 (m, 4H), 7.46 (m, 2H), 7.55 (m, 1H), 7.69 (dd, J = 1.5 and 6, 2H). 25 Step B: (S)-N- [2-(3-Chlorophenyl)-4-oxo-but-1-yl]-N-methylbenzene sulfonamide To a solution of 3.33 g (9.53 mmol) of (S)-N-[2-(3 chlorophenyl)pent-4-en-1-yl]-N-methylbenzenesulfonamide from Step A in 16 mL of acetone, 8 mL of t-butanol and 8 mL of water was added 1.22 30 g (10.4 mmol) of N-methylmorpholine-N-oxide followed by 0.50 mL of 4% osmium tetroxide in water. The reaction was stirred at rt for 16 h and was then quenched with aqueous sodium sulfite and concentrated in vacuo after 20 min. The residue was diluted with water and extracted twice with ethyl acetate. The organic layers were each washed with - 154brine, combined, dried over sodium sulfate and concentrated in vacuo to afford the crude diol intermediate. The above product was taken up in 30 mL of THF and 2.45 g (11.4 mmole) of sodium periodate in 10 mL of water was added. The 5 mixture was stirred at rt for 2 h, poured into water and extracted twice with ether. The ether layers were each washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by FCC (20% ethyl acetate/hexanes) to afford 2.57 g of the title compound. 1H NMR (400 MHz, CDCl3): 8 2.63 (s, 3H), 2.75-2.9 (m, 2H), 10 3.14 (dd, J = 6 and 16, 1H), 3.35 (dd, J = 10 and 14, 1H), 3.55 (m, 1H), 7.15 7.35 (2 m, 4H), 7.46 (m, 2H), 7.53 (m, 1H), 7.70 (dd, J = 1.5 and 7, 2H), 9.78 (s, 1H). Step C: (S)-N- [2-(3-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl] 15 N-methylbenzenesulfonamide hydrochloride salt To a solution of 20 mg (0.057 mmol) of (S)-N-[2-(3 chlorophenyl)-4-oxo-but-1-yl]-N-methylbenzenesulfonamide from Step B in 1.0 mL of THF were added 27 mg (0.17 mmol) of 4-phenylpiperidine, 3 A molecular sieves and 0.010 mL of acetic acid. After stirring the 20 mixture for 20 min, 24 mg (0.113 mmol) of sodium triacetoxyborohydride was added. After 16 h the reaction was quenched with aqueous sodium bicarbonate, the mixture was filtered through a pad of celite and the reaction flask and the pad were rinsed with water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice more 25 with ethyl acetate. The organic layers were each washed with brine, combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep TLC using 2% triethylamine in 5% methanol/ethyl acetate to isolate 20 mg of the free amine of the title compound as an oil. 30 1H NMR (400 MHz, CDC13): 8 1.80 (m, 5H), 1.9-2.3 (3 m, 5H), 2.4-2.5 (m, 1H), 2.61 (s, 3H), 2.9-3.1 (m, 4H), 3.35-3.45 (m, 1H), 7.1-7.3 (m, 9H), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.70 (dd, J = 1.5 and 7.0, 2H). Mass spectrum (ESI): m/z 497 (M+1, 100%). The hydrochloride salt of the title compound was prepared 35 by dissolving the above oil in ether/methanol and addition of 2-3 - 155 equivalents of 1 M ethereal HC1. Evaporation of the volatiles and drying in vacuo afforded 21 mg of the title salt as a white solid after trituration with ether. 5 The following Examples were prepared following the procedure described in Example 39, Step C but using the appropriate substituted piperidine in the reductive amination. EXAMPLE 40 10 (S)-N-[4-(4-Benzylpiperidin-1-yl)-2-(3-chlorophenyl)but-1l-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 511 (M+1, 100%). 15 EXAMPLE 41 (S)-N-[4-(4-(3-Phenylprop-1-yl)piperidin-1-yl)-2-(3-chlorophenyl)but 1-yll]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 539 (M+1, 100%). 20 EXAMPLE 42 (S)-N-[2-(3-Chlorophenyl)-4-(4-t-butylpiperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide hydrochloride salt 25 Mass spectrum (NH 3 -CI): m/z 477 (M+1, 100%). EXAMPLE 43 (S)-N-[2-(3-Chlorophenyl)-4-(4-(cis-octahydro-2H-benzimidazol-2-on- 1 30 yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 559 (M+1, 100%). EXAMPLE 44 35 -156- W") nI4/yq MU I /U NY5/14YYU (S)-N-[2-(3-Chlorophenyl)-4-(4-(1,2,3,4-tetrahydro-2H-quinazolin-2-on-1 yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 567 (M+1, 100%). 5 EXAMPLE 45 (S)-N-[2-(3-Chlorophenyl)-4-(3-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt 10 Mass spectrum (ESI): m/z 497 (M+1, 100%). EXAMPLE 46 (S)-N-[2-(3-Chlorophenyl)-4-(4-hydroxy-4-phenylpiperidin-1-yl)but- 1-yl] 15 N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 513 (M+1, 100%). EXAMPLE 47 20 (S)-N-[2-(3-Chlorophenyl)-4-(4-(2,3-dihydro-2H-benzimidazol-2-on-1 yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 553 (M+1, 100%). 25 EXAMPLE 48 (S)-N-[2-(3-Chlorophenyl)-4-[4,4-diphenylpiperidin-1l-yl]-butyl)-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 573 (M+1, 100%). 30 EXAMPLE 49 (S)-N-[4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1l-yl]-2-(3-chlorophenyl) but- 1-yll -N-methylbenzenesulfonamide hydrochloride salt 35 Mass spectrum (NH 3 -CI): m/z 547 (M+1, 100%). - 157 - WU 99/U4 /94~ VL 1/U fl5/14Y9U EXAMPLE 50 (S)-N-[4-(4-Acetyl-4-phenylpiperidin-1-yl)-2-(3-chlorophenyl)but- 1-yl]-N 5 methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 539 (M+1, 100%). EXAMPLE 51 10 (S)-N-[4-[4-(4-Chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1l-yl]-2 (3-chlorophenyl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 614 (M+1, 100%). 15 EXAMPLE 52 (S)-N-[2-(3-Chlorophenyl)-4-[4-(2-methoxycarbonylphenyl)piperidin-l-yl] but-1 -yll -N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 555 (M+1, 100%). 20 EXAMPLE 53 (S)-N-[2-(3-Chlorophenyl)-4-[4-hydroxy-4-(3-trifluoromethyl)phenyl-piper idin- 1-yll -but- 1-yl -N-methylbenzenesulfonamide hydrochloride salt 25 Mass spectrum (NH 3 -CI): m/z 581 (M+1, 100%). EXAMPLE 54 (S)-N-[2-(3-Chlorophenyl)-4-[4-(4-fluorophenyl)-4-hydroxypiperidin- 1 30 vyll but- 1-yll -N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 531 (M+1, 100%). EXAMPLE 55 35 (S)-N-[2-(3-Chlorophenyl)-4-[4-(2-oxo-4H-benzo [d] [1,3]oxazin-1-yl)piper idin- 1-yl] but- 1-yll -N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 568 (M+1, 100%). - 158- WU 9I/U41/94 PCT/Uh98/1499U EXAMPLE 56 (S)-N- [2-(3-Chlorophenyl)-4- [4-(2-oxo-3H-benzo [d] [1,4]oxazin-1-yl)piper idin- 1-yl but- 1-ylv] -N-methylbenzenesulfonamide hydrochloride salt 5 Mass spectrum (NH 3 -CI): m/z 568 (M+1, 100%). EXAMPLE 57 (S)-N-[4-(4-Benzoylpiperidin-1-yl)-2-(3-chlorophenyl)but-1l-yl]-N 10 methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 525 (M+1, 100%). EXAMPLE 58 15 (S)-N- [2-(3-Chlorophenyl)-4- [4-(2-methoxy)phenylpiperidin- 1-yl]but- 1 yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 527 (M+1, 100%). EXAMPLE 59 20 (S)-N-[2-(3-Chlorophenyl)-4-(4-piperidin-1-ylpiperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 504 (M+1, 100%). 25 The following Examples were prepared using the procedure described in Example 39 but utilizing the appropriate substituted 4 phenyl pentene derivative (prepared as described by J. Hale et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) as the starting material. 30 EXAMPLE 60 (S)-N- [2-(3,4-Methylenedioxyphenyl)-4-(4-phenylpiperidin-1-yl)but- 1 vll-N-methylbenzenesulfonamide hydrochloride salt 35 Mass spectrum (ESI): m/z 507 (M+1, 100%). -159- W)U YWU41I4 C /UN95/I 149Y9U EXAMPLE 61 (S)-N-[2-(4-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 5 methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 -CI): m/z 481 (M+1, 100%). EXAMPLE 62 10 (S)-N-[2-(3,4-Dichlorophenyl)-4-(4-phenylpiperidin-1-yl)-but-1-yl]-N ethylbenzenesulfonamide hydrochloride salt Following essentially the same procedure as described in Example 39 but utilizing (S)-4-(3,4-dichorophenyl)-5-ethylamino-1 15 pentene (prepared as described by J. Hale et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) as the starting material, the title compound was prepared. 1H NMR (400 MHz, CDC13): 8 0.955 (t, J = 8, 3H), 1.5-1.9 (3 m, 5H), 1.9-2.3 (2 m, 5H), 2.4-2.6 (m, 1H), 2.8-3.05 (m, 3H), 3.05-3.2 (m, 3H) 3.44 (dd, J = 8 20 and 13, 1H), 7.03 (br d, J = 7, 1H), 7.15-7.4 (m, 7H), 7.45 (t, J = 7, 2H), 7.52 (br t, J = 7, 1H), 7.70 (dd, J = 1.5 and 7, 2H). Mass spectrum (NH 3 -CI): m/z 545 (M+l, 100%). EXAMPLE 63 25 (R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methylphenyl acetamide The title compound was prepared following the procedure 30 described in Example 1, Steps A-C but substituting phenylacetyl chloride in Step A. Mass spectrum (NH 3 -CI): m/z 441 (M+1, 100%). EXAMPLE 64 - 160wU 99/U4/4 PCT/US95/1499U (R,S)-N-[2-Phenyl-4- [4-acetyl(ethylamino)piperidin- l-yl]but- l-yl] -N methylbenzenesulfonamide Step A: (1-Benzvyloxycarbonylpiperidin-4-yl)isocyanate 5 To a solution of 9.72 g (34.8 mmol) of 1-benzyloxycarbonyl-4 carboxypiperidine in 100 mL of methylene chloride was added 2 drops of DMF and then slowly 3.34 mL (38.3 mmol) of oxalyl chloride. The reaction was stirred at rt for 1 h (gas evolution had stopped) and the volatiles were removed in vacuo followed by evaporation of a portion of 10 toluene. The above residue was taken up in 100 mL of acetone and slowly added to a solution of 5.66 g (87 mmol) of sodium azide in 25 mL of water and 25 mL of acetone while stirred in an ice bath. The reaction was stirred at 0 oC for 1.5 h and then diluted with ice water and 15 extracted twice with 2x150 mL of toluene. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to about 100 mL in vacuo with a minimum of heating. The remaining solution was slowly heated to 85 oC for 1.5 h and then concentrated to dryness in vacuo to afford about 9.5 g of crude title 20 product which can be used directly in subsequent reactions. Step B: 1-Benzyloxycarbonyl-4-t-butoxvcarbonylaminopiperidine A solution of 3.2 g (12.3 mmol) of (1-benzyloxycarbonyl piperidin-4-yl)isocyanate from Step A in 25 mL of DMF was slowly added 25 to a suspension of CuC1 3 in 25 mL of DMF and 12 mL of t-butanol. The reaction was stirred for 24 h and then diluted with water and extracted twice with 1:1 ether:ethyl acetate. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 20% 30 ethyl acetate/hexanes to afford 685 mg of title compound. 1H NMR (400 MHz, CDC13): 8 1.26 (m, 2H), 1.42 (s, 9H), 1.90 (br d, J = 12, 2H), 2.90 (br t, 2H), 3.58 (m, 1H), 4.08 (m, 2H), 4.42 (br s, 1H), 5.09 (s, 2H), 7.33 (m, 5H). Step C: 1-Benzyloxycarbonyl-4-t-butoxycarbonyl(ethylamino) 35 piperidine -161- To a solution of 476 mg (1.42 mmol) of 1-benzyloxycarbonyl-4 t-butoxycarbonylaminopiperidine and 0.24 mL (2.8 mmol) of ethyl iodide in 10 mL of DMF was added 85 mg (2.1 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred for 16 h and was then poured into 5 water and extracted three times with ether. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 15% ethyl acetate/hexanes to afford 409 mg of title compound. 1H NMR (400 MHz, CDC13): 8 1.06 (t, J = 7, 3H), 1.44 (s, 9H), 10 1.5-1.7 (2 m, 4H), 2.78 (m, 2H), 3.1 (m, 2H), 4.10 (m, 1H), 4.25 (m, 2H), 5.10 (s, 2H), 7.33 (m, 5H). Step D: 4-t-Butoxycarbonvyl(ethylamino)piperidine A solution of 400 mg (1.1 mmol) of 1-benzyloxycarbonyl-4-t 15 butoxycarbonyl(ethylamino)piperidine from Step C in 4 mL of methanol was hydrogenated with 40 mg of 10% Pd/C under a hydrogen balloon for 16 h. The reaction was filtered and concentrated in vacuo to give the title compound which was used directly in the next step. 20 Step E: (R,S)-N-[2-Phenyl-4-[4-t-butoxycarbonyl(ethylamino) piperidin- 1-yllbut- 1-yl] -N-methylbenzenesulfonamide Using essentially the same procedure as Example 1, Step C, 235 mg (1.0 mmol) of 4-t-butoxycarbonyl(ethylamino)piperidine from Step D and 212 mg of (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N 25 methylbenzenesulfonamide from Example 1, Step B afforded 360 mg of title compound. 1H NMR (400 MHz, CDC13): 5 1.06 (t, J = 7, 3H), 1.43 (s, 9H), 1.5-2.2 (5 m, 10H), 2.56 (s, 3H), 2.90 (m, 4H), 3.10 (m, 2H), 3.38 (m, 1H), 3.83 (m, 1H), 7.1-7.3 (m, 5H), 7.45 (m, 2H), 7.54 (m, 1H). Mass spectrum (ESI): m/z 530 (M+1, 100%). 30 Step F: (R,S)-N- [2-Phenyl-4- [4-(ethylamino)piperidin-1-yl]but- 1-yl ] N-methylbenzenesulfonamide hydrochloride salt A solution of 10 mmol of HCI in 10 mL of methanol was prepared by slowly adding 0.70 mL (10 mmol) of acetyl chloride with ice 35 bath cooling. To this was added 251 mg (0.489 mmol) of (R,S)-N-[2 - 162phenyl-4- [4-t-butoxycarbonyl(ethylamino)piperidin- 1-yl] but- 1-yl] -N methylbenzenesulfonamide. After stirring at rt for 16 h, the volatiles were removed in vacuo to give the title compound. Mass spectrum (ESI): m/z 430 (M+1, 100%). 5 Step G: (R,S)-N-[2-Phenyl-4- [4-acetyl(ethylamino)piperidin- 1-yl]but 1-yl]-N-methylbenzenesulfonamide hydrochloride salt To a solution of 45 mg (0.089 mmol) of (R,S)-N-[2-phenyl-4-[4 (ethylamino)piperidin- l-yl]but- 1-yl]-N-methylbenzenesulfonamide 10 hydrochloride salt in 2 mL of methylene chloride at 0 oC was added 0.067 mL (0.38 mmol) of DIPEA and 0.014 mL (0.19 mmol) of acetyl chloride. The reaction was stirred at rt for 16 h and then was quenched with aqueous sodium carbonate and extracted three times with methylene chloride. The organic layers were each washed with a portion of brine, 15 dried over sodium sulfate, combined and concentrated. The residue was purified by prep TLC eluting with 10% methanol in methylene chloride and converted to the hydrochloride salt to afford 40 mg of title compound. Mass spectrum (ESI): m/z 472 (M+1, 100%). 20 EXAMPLE 65 (R,S)-N-[2-Phenyl-4-[4-(oxazolidin-2-on-3-yl)piperidin- 1-yl]but- 1-yl]-N methylbenzenesulfonamide hydrochloride salt 25 Step A: 1-Benzyloxycarbonyl-4-(oxazolidin-2-on-3-yl)piperidine To a solution of 0.53 g (2.0 mmol) of(1 benzyloxycarbonylpiperidin-4-yl)isocyanate from Example 64, Step A in 10 mL of methylene chloride was added 690 mg (2.0 mmol) of 2 chloroethanol and 5 mg (cat) of DMAP. The reaction was stirred under 30 nitrogen at rt for 24 h and then evaporated to dryness to give the crude 2 chloroethylcarbamate intermediate. The above residue was taken up in 10 mL of DMF under nitrogen and 197 mg (4.93 mmol) of 60% sodium hydride in mineral oil was added. The reaction was stirred at rt for 1 h and then poured into 35 water containing 3 mL of 2 N hydrochloric acid and extracted twice with - 163ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 70% ethyl acetate/hexanes to afford 533 mg of title compound. 1H NMR (400 MHz, CDCl3): 8 1.55 (m, 2H), 1.76 (br d, 5 J = 10, 2H), 2.83 (min, 2H), 3.46 (t, J = 8, 2H), 3.87 (m, 1H), 4.27 (min, 2H), 4.31 (t, J = 8, 2H), 5.10 (s, 2H), 7.35 (min, 5H). Step B: 4-(Oxazolidin-2-on-3-yl)piperidine Using essentially the same procedure as in Example 64, 10 Step D, 525 mg (1.72 mmol) of 1-benzyloxycarbonyl-4-(oxazolidin-2-on-3 yl)piperidine from Step A was hydrogenated to afford 250 mg of the title compound. Step C: (R,S)-N-[2-Phenyl-4-[4-(oxazolidin-2-on-3-yl)piperidin- 1 15 yl] but- 1-yl -N-methylbenzenesulfonamide hydrochloride salt Using essentially the same procedure as in Example 1, Step C, the piperidine derivative from Step B was utilized to reductively alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to provide the title compound. 20 Mass spectrum (ESI): m/z 472 (M+1, 100%). EXAMPLE 66 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(ethylamino)piperidin-1-yl)but- 1 25 yll-N-methylbenzenesulfonamide hydrochloride salt Step A: 1-Benzvloxycarbonvl-4-(methoxycarbonylamino)piperidine To a solution of 1.0 g (3.9 mmol) of (1-benzyloxycarbonyl piperidin-4-yl)isocyanate from Example 64, Step A in 10 mL of methanol 30 was added 5 mg (cat) of DMAP. The reaction was stirred under nitrogen at rt for 24 h and then poured into water containing 2 mL of 2 N hydrochloric acid and was extracted twice with ethyl acetate. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to give 1.4 g of the crude title 35 compound which can be used directly in subsequent reactions. 1H NMR - 164 - (400 MHz, CDCl3): 5 1.32 (m, 2H), 1.92 (br d, J = 10, 4H), 2.91 (v br t, 2H), 3.66 (br s, 3H + 1H), 4.10 (m, 2H), 4.58 (br s, 1H), 5.09 (s, 2H), .7.33 (m, 5H). 5 Step B: 1-Benzyloxycarbonyl-4-imethoxycarbonyl(ethylamino)] piperidine To 82 mg (0.28 mmol) of 1-benzyloxycarbonyl-4 (methoxycarbonylamino)piperidine from Step A and 0.045 mL (0.56 mmol) of ethyl iodide in 4 mL of DMF under nitrogen was added 22 mg 10 (0.56 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 1 h and was then poured into water containing 1 mL of 2 N hydrochloric acid and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting 15 with 50% ethyl acetate/hexanes to afford 87 mg of title compound. 1H NMR (400 MHz, CDC13): 5 1.07 (t, J = 7, 3H), 1.5-1.8 (min, 4H), 2.79 (min, 2H), 3.15 (m, 2H), 3.68 (s, 3H), 4.10 (min, 1H), 4.26 (min, 2H), 5.10 (s, 2H), 7.34 (m, 5H). 20 Step C: 4- [Methoxycarbonvl(ethylamino) piperidine Using essentially the same procedure as in Example 64, Step D, 85 mg (0.27 mmol) of 1-benzyloxycarbonyl-4-[methoxycarbonyl (ethylamino)]piperidine from Step B was hydrogenated to afford 37 mg of the title compound. 25 Step D: (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(ethylamino) piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Using essentially the same procedure as in Example 1, Step 30 C, the piperidine derivative from Step C was utilized to reductively alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to provide the title compound. Mass spectrum (ESI): m/z 488 (M+1, 100%). EXAMPLE 67 - 165 - (R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonylaminopiperidin-l1-yl)but-1 yll -N-methylbenzenesulfonamide 5 Step A: 1-Benzyloxycarbonyl-4-(dimethylaminocarbonylamino) piperidine To 0.83 g (3.2 mmol) of (1-benzyloxycarbonylpiperidin-4 yl)isocyanate from Example 64, Step A in 10 mL was added 16 mL (32 mmol) of 2 M dimethylamine in THF. The reaction was stirred under 10 nitrogen at rt for 24 h and then poured into water containing 20 mL of 2 N hydrochloric acid and was extracted twice with ethyl acetate. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to give 0.95 g of the crude title compound which can be used directly in subsequent reactions. 15 1H NMR (400 MHz, CDC13): 8 1.25 (m, 2H), 1.95 (br d, J = 10, 2H), 2.86 (br s, 6H + 2H), 3.79 (m, 1H), 4.0-4.25 (m, 3H), 5.09 (s, 2H), 7.35 (m, 5H). Step B: 4-(Dimethylaminocarbonylamino)piperidine Using essentially the same procedure as in Example 64, 20 Step D, 1.4 g (4.6 mmol) of 1-benzyloxycarbonyl-4 (dimethylaminocarbonylamino)piperidine from Step A was hydrogenated to afford 690 mg of the title compound. Step C: (R,S)-N- [2-Phenyl-4-(4-dimethylaminocarbonylamino 25 piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide Using essentially the same procedure as in Example 1, Step C, the piperidine derivative from Step C was utilized to reductively alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to provide the title compound. 30 Mass spectrum (ESI): m/z 473 (M+1, 100%). EXAMPLE 68 (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(prop-1-ylamino)piperidin- 1 35 yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt - 166- Step A: 4-Azido- 1-t-butoxvcarbonvlpiperidine To a solution of 45.3 g (172 mmol) of 4-bromo-1-t butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol) 5 of sodium azide and 2.5 g (17 mmol) of sodiun iodide. The reaction was stirred at rt for 24 h and then at 60 oC for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether:hexanes. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and 10 concentrated. The residue was purified by FCC eluting with 5 - 10% ethyl acetate/hexanes to afford 39 g of title compound having a trace of elimination biproduct. 1H NMR (400 MHz, CDCl3): 8 1.43 (s,9H), 1.52 (m, 2H), 1.85 (m, 2H), 3.07 (m, 2H), 3.55 (m, 1H), 3.78 (m, 2H). 15 Step B: 4-Amino- 1-t-butoxycarbonylpiperidine A solution of 4.05 g (17.9 mmol) of 4-azido-1-t butoxycarbonylpiperidine from Step A in 50 mL of methanol was hydrogenated with 350 mg of 10% Pd/C under a hydrogen balloon for 16 h 20 when the reaction was complete by TLC (10% ethyl acetate/hexanes). The catalyst was filtered off and the volatiles removed in vacuo to give 3.5 g of title compound which was used directly in subsequent reactions. Step C: 4-Benzvyloxycarbonylamino- 1-t-butoxvcarbonylpiperidine 25 To a solution of 1.2 g (6.0 mmol) 4-amino-1-t butoxycarbonylpiperidine from Step B in 40 mL of methylene chloride was added 3.15 mL (18 mmol) of DIPEA and 1.03 mL (7.2 mmol) of benzyl chloroformate while cooled in an ice bath. After 0.5 h the reaction was quenched with aqueous sodium carbonate and extracted three times 30 with methylene chloride. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 25% ethyl acetate/hexanes to afford 1.94 g of title compound. - 167 - 1H NMR (400 MHz, CDC13): 5 1.26 (min, 2H), 1.42 (s, 9H), 1.90 (br d, J = 12, 2H), 2.90 (br t, 2H), 3.58 (m, 1H), 4.08 (min, 2H), 4.42 (br s, 1H), 5.09 (s, 2H), 7.33 (m, 5H). 5 Step D: 4-Benzyloxycarbonyl(prop-1-ylamino)- 1-t butoxycarbonvlpiperidine To 110 mg (0.32 mmol) 4-benzyloxycarbonylamino-1-t butoxycarbonylpiperidine from Step C and 0.16 mL (1.6 mmol) of n propyl iodide in 2 mL of DMF under nitrogen was added 26 mg (0.65 10 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 16 h and was then poured into water and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FCC eluting with 20% ethyl acetate/hexanes to afford 90 mg of 15 title compound. Step E: 4-Benzyloxycarbonyl(prop-1-ylamino)piperidine hydrochloride salt To a solution of 2.4 mmol of HCI in 2 mL of methanol 20 (prepared by the addition of 0.17 mL of acetyl chloride at 0 oC and stirring for 10 min) was added 90 mg of 4-benzyloxycarbonyl(prop-1-ylamino)-1-t butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at which time the reaction was complete by TLC (20% ethyl acetate/hexanes) and was evaporated to dryness in vacuo to afford 75 mg 25 of the title compound as the hydrochloride salt. Step F: (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(prop-1 ylamino)piperidin-1-yl)but- 1-yl] -N-methylbenzene sulfonamide hydrochloride salt 30 Using essentially the same procedure as in Example 1, Step C, the piperidine derivative from Step E was utilized to reductively alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to provide the title compound. Mass spectrum (NH 3 /CI): m/z 578 (M+1, 100%). - 168 - V X~ %-, ~ ft I UOJOI -K7 The following Examples were prepared following the procedure described in Example 1, Step C but using the appropriate substituted piperidine in the reductive amination step (prepared by analogy to the piperidine derivatives in Examples 64-68). 5 EXAMPLE 69 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminopiperidin- 1 -yl)but-1-yl] N-methylbenzenesulfonamide 10 Mass spectrum (ESI): m/z 460 (M+1, 100%). EXAMPLE 70 (R,S)-N-[2-Phenyl-4-(4-aminocarbonylaminopiperidin-1-yl)but-l1-yl]-N 15 methylbenzenesulfonamide Mass spectrum (ESI): m/z 445 (M+1, 100%). EXAMPLE 71 20 (R,S)-N-[2-Phenyl-4-(4-aminopiperidin-1-yl)but-1-yl]-N-methylbenzene sulfonamide hydrochloride salt Mass spectrum (ESI): m/z 402 (M+1, 100%). EXAMPLE 72 25 (R,S)-N-[2-Phenyl-4-(4-acetylaminopiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 444 (M+1, 100%). 30 EXAMPLE 73 (R,S)-N-[2-Phenyl-4-(4-isopropylcarbonylaminopiperidin-1-yl)but- 1 yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 472 (M+1, 100%). 35 EXAMPLE 74 - 169- (R,S)-N- [2-Phenyl-4-(4-methylsulfonylaminopiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 480 (M+1, 100%). 5 EXAMPLE 75 (R,S)-N-[2-Phenyl-4-(4-isopropylcarbonyl(ethylamino)piperidin- 1 yl)but-1-yll]-N-methylbenzenesulfonamide hydrochloride salt 10 Mass spectrum (ESI): m/z 500 (M+I, 100%). EXAMPLE 76 (R,S)-N- [2-Phenyl-4-(4-methylsulfonyl(ethylamino)piperidin-1-yl)but 15 1-yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 508 (M+1, 100%). EXAMPLE 77 20 (R,S)-N- [2-Phenyl-4-(4-t-butoxycarbonylaminopiperidin-1-yl)but-1-yl] N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 502 (M+1, 100%). EXAMPLE 78 25 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(methylamino)piperidin-1-yl)but 1-yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (PB-EI): m/z 474 (M+1), 211 (100%). 30 EXAMPLE 79 (R,S)-N-[2-Phenyl-4-(4-(pyrrolidin-2-on-1-yl)piperidin-1-yl)but-1l-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (PB-EI): m/z 470 (M+1), 160 (100%). 35 EXAMPLE 80 - 170- Vv1 " - L -,1 U3/70114 77,U (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclobutylmethylamino) piperidin-1-yl)but-1-yl]l-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (PB-EI): m/z 528 (M+1), 160 (100%). 5 EXAMPLE 81 (R,S)-N-[2-Phenyl-4-(4-ethoxycarbonyl(ethylamino)piperidin-1-yl)but- 1 yll]-N-methylbenzenesulfonamide hydrochloride salt 10 Mass spectrum (PB-EI): m/z 502 (M+1), 160 (100%). EXAMPLE 82 (R,S)-N-[2-Phenyl-4-(4-isobutyloxycarbonyl(ethylamino)piperidin- 1 15 yl)but-1-vyl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (PB-EI): m/z 530 (M+1), 160 (100%). EXAMPLE 83 20 (R,S)-N-[2-Phenyl-4-(4-piperidin-2-on-1-ylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 484 (M+1), 347 (100%). EXAMPLE 84 25 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(benzylamino)piperidin-1-yl)but 1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (ESI): m/z 550 (M+1, 100%). 30 EXAMPLE 85 (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(prop-1-ylamino)piperidin- 1 yl)but-1-yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 502 (M+1), 118 (100%). 35 EXAMPLE 86 -171- (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(but-1-ylamino)piperidin-1 yl)but-1-vyl-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 516 (M+1), 132 (100%). 5 EXAMPLE 87 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclohexylmethylamino)-piper idin-1-vyl)but-1-yll-N-methylbenzenesulfonamide hydrochloride salt 10 Mass spectrum (NH 3 /CI): m/z 556 (M+1, 100%). EXAMPLE 88 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclopropylmethylamino)-piper 15 idin-1-vl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 514 (M+1, 100%). EXAMPLE 89 20 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(pent-1-ylamino)piperidin- 1 yl)but-1-vyll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 530 (M+1, 100%). EXAMPLE 90 25 (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(pent-1-ylamino)piperidin- 1 yl)but-1-yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 530 (M+1, 100%). 30 EXAMPLE 91 (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(methylamino)piperidin- 1 yl)but-1-yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 550 (M+1, 100%). 35 - 172- EXAMPLE 92 (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(ethylamino)piperidin-1-yl)but 1-vyl]-N-methylbenzenesulfonamide hydrochloride salt 5 Mass spectrum (PB-EI): m/z 564 (M+1), 160 (100%). EXAMPLE 93 (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(but-1-ylamino)piperidin- 1 10 yl)but-1-vyl-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 592 (M+1, 100%). EXAMPLE 94 15 (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(pent-1-ylamino)piperidin- 1 vl)but-1-yll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 606 (M+1, 100%). EXAMPLE 95 20 (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(cyclobutylmethylamino)-piper idin-1-yl)but-1-vll-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 604 (M+1, 100%). 25 EXAMPLE 96 (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(cyclohexylmethylamino)-piper idin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt Mass spectrum (NH 3 /CI): m/z 632 (M+I, 100%). 30 EXAMPLE 97
(S)-N-[
2 -(3-Chlorophenyl-4-(4-benzyloxycarbonyl(ethylamino)-piperidin- 1 yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride salt - 173 - VV Ij. 1,U /7.. -L_ 1 /U1Y5/14YYU The title compound was prepared using essentially the same procedure as in Example 39, Step C. The piperidine subunit was prepared by analogy to the procedure given in Example 68. Mass spectrum (NH 3 /CI): m/z 598 (M+1, 100%). 5 EXAMPLE 98 (R,S)-N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide hydrochloride salt 10 Step A: N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-2-en-1-yl]-N methylbenzenesulfonamide To 250 mg (0.37 mmol) of N-[4-(4-phenylpiperidin-1-yl)-3 tributylstannylbut-2-en-1-yl]-N-methylbenzenesulfonamide from 15 Example 21, Step B (isomeric higher Rf product) in 0.5 mL of N methylpyrrolidinone under argon was added 75 mg (0.55 mmol) of potassium carbonate, 8 mg (2% cat) of dichlorobis(triphenylphosphine) palladium (II) and 90 mg (0.55 mmol) of bromobenzene. The mixture was heated at 70 oC for 24 h, cooled, treated with aqueous sodium 20 fluoride for 10 min, and partitioned between water and ether. The water layer was reextracted with ether and each organic layer was washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FCC eluting with 20-25% ethyl acetate/hexanes to give 120 mg of title product as an oil. 25 1H NMR (400 MHz, CDCl3): 8 1.55-1.6 (m, 2H), 2.75 (br d, J = 11, 2H), 2.00 (br dt, J= 2 and 14, 2H), 2.42 (m, 1H), 2.78 (s, 3H), 2.93 (br d, J = 11, 2H), 3.33 (s, 2H), 4.05 (d, J = 6.5, 2H), 5.78 (t, J = 6.5, 1H), 7.1-7.4 (3 min, 5H), 7.5 7.65 (min, 3H), 7.84 (dd, J = 1.5 and 7, 2H). Mass spectrum (ESI): m/z 461 (M+I, 100%). 30 Step B: (R,S)-N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide A mixture of 90 mg (0.20 mmol) of N-[3-phenyl-4-(4 phenylpiperidin-1-yl)but-2-en-1-yl]-N-methylbenzenesulfonamide from 35 Step A, 12 mg of 20% palladium hydroxide/C (50% water), and 2 drops of - 174- VV IkJ 7J1v? 1 t r%1,uII /U 7/1't,,u1 acetic acid in 3 mL of methanol was hydrogenated at 40 psi for 24 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by prep TLC (50% ethyl acetate/ hexanes) to afford 20 mg of title compound. A major biproduct was cleavage of the 4 5 phenylpiperidine to give N-(3-phenylbut-1-yl)-N methylbenzenesulfonamide. 1H NMR (400 MHz, CDC13): 8 1.5-1.8 (inm, 5H), 1.95 (br t, J = 11, 1H), 2.1-2.25 (2 m, 2H), 2.45 (min, 2H), 2.57 (min, 1H), 2.6-2.7 (min, 2H), 2.68 (s, 3H), 2.9 (min, 2H), 3.0-3.2 (2 m, 2H), 7.1-7.3 (min, 5H), 7.45 (min, 2H), 7.54 (min, 1H), 7.69 (dd, J = 1.5 and 7, 2H). Mass spectrum 10 (ESI): m/z 463 (M+1, 100%). EXAMPLE 99 (R,S)-N-Methyl-N-[2-methyl-2-phenyl-4-(4-phenylpiperidin-1-yl)but- 1 15 yllbenzenesulfonamide hydrochloride Step A: (R,S)-N-Methyl(2,5-dimethyl-2-phenylhex-4-envl)amine Methylamine hydrochloride (500 mg, 7.41 mmol), triethylamine (1.00 mL, 725 mg, 7.17 mmol), and 3 A molecular sieve 20 pellets (1.05 g) were added to a stirred solution of 2,5-dimethyl-2 phenylhex-4-enal (500 mg, 2.47 mmol) in 5.0 mL of methanol at room temperature. After 1 h, the mixture was cooled in an ice bath and acetic acid (0.29 mL, 0.30 g, 5.1 mmol) was added followed by sodium cyanoborohydride (310 mg, 4.93 mmol). The mixture was allowed to 25 slowly come to room temperature and stirred 16 h before being diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated aqueous sodium chloride (30 mL). The aqueous layers were extracted with ethyl acetate (30 mL) and the combined organic layers were dried over sodium sulfate, decanted, and 30 evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol in ethyl acetate to give 415 mg the title compound. 1H NMR (400 MHz, CD3OD): 8 1.34 (s, 3H), 1.54 (s, 3H), 1.59 (s, 3H), 2.27 (s, 3H), 2.30 (dd, J = 14 and 8, 1H), 2.39 (dd, J = 14 and 7.5, 1H), 2.66 (d, J = 12, 1H), 2.87 (d, J = 12, 1H), 4.88 (t, J = 7.5, 1H), 7.18 (t, 35 J = 7, 1H), 7.28-7.36 (min, 4H). - 175 - Mass spectrum (NH 3 /CI): m/z 218 (M+1, 100%). Step B: (R,S)-N-Methyl-N-(2,5-dimethyl-2-phenylhex-4-en- 1 yl)benzenesulfonamide 5 Using essentially the same procedure as in Example 1 (Step A), (R,S)-N-methyl(2,5-dimethyl-2-phenylhex-4-enyl)amine from Step A above was allowed to react with benzenesulfonyl chloride in THF to give the title compound as a colorless oil. 1H NMR (400 MHz, CDC13): 8 1.42 (s, 3H), 1.59 (s, 6H), 2.09 (s, 3H), 2.33 (dd, J = 15 and 8, 1H), 2.50 (dd, J = 15 10 and 6, 1H), 2.94 (d, J = 13, 1H), 3.40 (d, J = 13, 1H), 4.83 (bt, J = 7, 1H), 7.17, t, J = 7, 1H), 7.23-7.33 (m, 4H), 7.48 (t, J = 7.5, 2H), 7.55 (t, J = 7.5, 1H), 7.72 (d, J = 7.5, 2H). Mass spectrum (NH 3 /CI): m/z 358 (M+1, 100%). Step C: (R,S)-N-Methyl-N-(2-methyl-2-phenyl-4-oxobut- 1 15 yl)benzenesulfonamide To a solution of (R,S)-N-methyl-N-(2,5-dimethyl-2 phenylhex-4-en-1-yl)benzenesulfonamide (300 mg, 0.839 mmol) from Step B in 6.0 mL of acetone, 3.0 mL of t-butanol and 1.5 mL of water was added 0.145 mL (118 mg, 0.012 mmol) of 2.5% osmium tetroxide in t 20 butanol followed by 433 mg (3.70 mmol) of N-methylmorpholine-N-oxide. The reaction was stirred at room temperature for 18 h and was then quenched with 3 g of aqueous sodium bisulfite and concentrated in vacuo. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The aqueous layer was extracted with 25 dichloromethane (2 x 20 mL) and the combined organic layers were dried over sodium sulfate, decanted, and evaportated to give the diol intermediate. The above product was dissolved in 9.0 mL of THF and 3.0 mL of water, and treated with 323 mg (1.51 mmol) of sodium periodate. After 2 h, additional sodium periodate (150 mg, 0.70 mmol) was added 30 and the mixture was stirred 1 h longer. Most of the THF was removed in vacuo and the residue was patitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were dried (sodium sulfate), decanted, and evaporated. The residue was re-dissolved in 9.0 mL of - 176- VV"JYIt7tr.L Y%-I OO kt7.7k THF and 3.0 mL of water, and sodium periodate (450 mg, 2.1 mmol) was added in three equal portions at 1.5 h intervals. The mixture was stirred for 1.5 h after the addition of the last portion, and then worked up as before. Flash column chromatography on silica gel, eluting with 20% 5 ethyl acetate in hexane gave 210 mg of the title compound as a colorless syrup. 1H NMR (400 MHz, CDC13): 8 1.64 (s, 3H), 2.21 (s, 3H), 2.78 (dd, J = 16 and 2.5, 1H), 3.15 (d, J = 13, 1H), 3.19 (dd, J = 16 and 2.5, 1H), 3.23 (d, J = 13, 1H), 7.23-7.28 (m, 1H), 7.32-7.40 (m, 4H), 7.52 (t, J = 7.5, 2H), 7.59 (t, J = 7.5, 1H), 7.74 (d, J = 7.5, 2H), 9.62 (t, J = 2.5, 1H). Mass spectrum 10 (ESI): m/z 332 (M+1, 100%). Step D: (R,S)-N-Methyl-N- [2-methyl-2-phenyl-4-(4-phenyl-piperidin 1-yl)but-1-yllbenzenesulfonamide hydrochloride Using essentially the same procedure as in Example 1 (Step 15 C), (R,S)-N-methyl-N-(2-methyl-2-phenyl-4-oxobut-1-yl)benzene sulfonamide from Step C above was allowed to react with 4-phenyl piperidine to give the free amine of the title compound as a colorless film. 1H NMR (400 MHz, CD3OD): 5 1.50 (s, 3H), 1.70-1.93 (m, 5H), 2.06 2.23 (m, 3H), 2.11 (s, 3H), 2.29 (td, J = 12 and 4, 1H), 2.40-2.59 (m, 2H), 3.03 20 (d, J = 14, 1H), 3.03-3.15 (m, 2H), 3.41 (d, J = 14, 1H), 7.15 (t, J = 7, 1H), 7.19-7.29 (m, 5H), 7.34 (t, J = 7.5, 2H), 7.42 (d, J = 8, 2H), 7.57 (t, J = 7.5, 2H), 7.64 (t, J = 7.5, 1H), 7.76 (d, J = 8, 2H). Mass spectrum (ESI): m/z 477 (M+1, 100%). The hydrochloride salt of the title compound was prepared by dissolving the free base in ethanol 25 and adding 1.5 equivalents of aqueous 2 N HC1. Evaporation of the solvent gave the title salt as a white solid. EXAMPLE 100 30 (R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-methyl-2 phenylbut-1-yl]-N-methylbenzenesulfonamide hydrochloride Using essentially the same procedure as in Example 1 (Step C), (R,S)-N-methyl-N-(2-methyl-2-phenyl-4-oxobut-1-yl)benzene 35 sulfonamide (from Example 99, Step B) was allowed to react with 4 - 177 benzyloxycarbonyl(ethylamino)piperidine (prepared by analogy to Example 68) to give the free amine of the title compound as a colorless film. 1H NMR (400 MHz, CD3OD): 8 1.11 (t, J = 7, 3H), 1.47 (s, 3H), 1.60 1.70 (m, 2H), 1.72-1.86 (m, 3H), 1.91-2.06 (m, 3H), 2.10 (s, 3H), 2.20 (td, J = 5 12 and 3, 1H), 2.28-2.38 (m, 1H), 2.90-3.02 (m, 2H), 3.00 (d, J = 14, 1H), 3.24 (t, J = 7, 2H), 3.99 (d, J = 14, 1H), 3.78-3.90 (b, 1H), 5.11 (s, 2H), 7.21 (t, J = 7, 1H), 7.27-7.42 (m, 9H), 7.56 (t, J = 7, 2H), 7.63 (t, J = 7.5, 1H), 7.75 (d, J = 7.5, 2H). Mass spectrum (NH 3 /CI): m/z 578 (M+I, 100%). The hydrochloride salt of the title compound was prepared by dissolving the 10 free base in ethanol and adding 1.5 equivalents of aqueous 2 N HC1. Evaporation of the solvent gave the title salt as a clear glass. EXAMPLE 101 15 (R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-ethyl-2 phenvlbut-1-vyl]-N-methylbenzenesulfonamide hydrochloride Step A: (R,S)-2-Ethyl-2-phenvlpent-4-enenitrile A solution of 2-phenylpent-4-enenitrile (500 mg, 3.18 mmol) 20 in THF (6.5 mL) was stirred in an ice bath and 1.5 M lithium diisopropylamide monotetrahydrofuran complex in cyclohexane (2.16 mL, 3.23 mmol) was added. After 10 min, the ice bath was removed and the solution was stirred at room temperature for 1 h. The solution was cooled in a dry ice/isopropanol bath and iodoethane (0.280 mL, 546 mg, 25 3.50 mmol) was added. The reaction was allowed to warm to -20 'C over 30 min, and was then stirred 2 h at room temperature. The mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride (30 mL). The organic layer was washed with saturated aqueous sodium chloride (30 mL), dried over sodium sulfate, 30 decanted, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 5% ether in hexane to give the title compound as 537 mg of yellow oil. 1H NMR (400 MHz, CDC13): 8 0.93 (t, J = 7.5, 3H), 1.94 (dq, J = 14 and 7, 1H), 2.08 (dq, J = 14 and 7, 1H), 2.68 (d, J = 7, 2H), 5.12 (d, J = 10, 1H), 5.13 - 178- (d, J = 16, 1H), 5.65 (ddt, J = 16, 10, and 7, 1H), 7.28-7.35 (m, 1H), 7.35-7.42 (m, 4H). Step B: (R,S)-2-Ethyl-2-phenylpent-4-enal 5 A solution of 500 mg (2.70 mmol) of (R,S)-2-ethyl-2 phenylpent-4-enenitrile from Step A in 2.0 mL of ether was cooled in an ice bath and 1.5 M diisobutylaluminum hydride in toluene (2.65 mL, 3.97 mmol) was added. The solution was stirred for 2 h at 0 oC, then quenched by the addition of 15 mL of 2 N aqueous HC1 and stirred for 1 h. 10 The mixture was extracted with ether (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, decanted, and evaporated to give 410 mg of the title compound. 1H NMR (400 MHz, CDC13): 5 0.80 (t, J = 7.5, 3H), 1.94-2.05 15 (m, 2H), 2.67 (dd, J = 14 and 7, 1H), 2.74 (dd, J = 14 and 7, 1H), 5.03 (d, J = 10, 1H), 5.07 (d, J = 16, 1H), 5.53 (ddt, J = 16, 10, and 7, 1H), 7.22 (d, J = 8, 2H), 7.29 (t, J = 8, 1H), 7.39 (t, J = 8, 2H). Step C: (R,S)-N-Methyl(2-ethyl-2-phenylpent-4-enyl)amine 20 Using essentially the same procedure as in Example 99 (Step A), the crude (R,S)-2-ethyl-2-phenylpent-4-enal from Step B above gave the title compound as an amber liquid. 1H NMR (400 MHz, CD3OD): 8 0.69 (t, J = 7.5, 3H), 1.74 (q, J = 7.5, 2H), 2.27 (s, 3H), 2.48 (dd, J = 14 and 7, 1H), 2.56 (dd, J = 14 and 7, 1H), 2.77 (s, 2H), 5.00 (dmin, J = 10, 25 1H), 5.07 din, J = 16, 1H), 5.61 (ddt, J = 16, 10, and 7, 1H), 7.16-7.22 (m, 1H), 7.30-7.37 (m, 4H). Mass spectrum (ESI): m/z 204 (M+1, 100%). Step D: (R,S)-N-(2-Ethyl-2-phenylpent-4-enyl)-N-methylbenzene sulfonamide 30 Using essentially the same procedure as in Example 1 (Step A), (R,S)-N-methyl(2-ethyl-2-phenylpent-4-enyl)amine from Step A above was allowed to react with benzenesulfonyl chloride in THF to give the title compound as an amber syrup. 1H NMR (400 MHz, CDCl3): 5 0.82 (t, J = 7.5, 3H), 1.85 (q, J = 7.5, 2H), 1.94 (s, 3H), 2.59 (dd, J = 14 and 7, 1H), 35 2.73 (dd, J = 14 and 7, 1H), 3.08 (d, J = 14, 1H), 3.25 (d, J = 14, 1H), 5.10 - 179- TV~~~ %- YJlr LI U0701I X (dm, J = 10, 1H), 5.16 (bd, J = 16, 1H), 5.89 (ddt, J = 16, 10, and 7, 1H), 7.20 (d, J = 7, 1H), 7.27-7.36 (m, 4H), 7.51 (t, J = 7, 2H), 7.58 (t, J = 7, 1H), 7.73 (d, J = 7, 2H). Mass spectrum (ESI): m/z 344 (M+1, 33%), 361 (M+NH 3 +1, 100%). 5 Step E: (R,S)-N-(2-Ethyl-2-phenyl-4-oxobut-1-yl)-N-methyl benzenesulfonamide Using essentially the same procedure as in Example 1 (Step B), (R,S)-N-(2-ethyl-2-phenylpent-4-enyl)-N-methylbenzenesulfonamide 10 from Step D above was oxidized to give the title compound as a syrup. 1H NMR (400 MHz, CDCl3): 8 0.79 (t, J = 7.5, 3H), 1.92-2.07 (m, 2H), 2.06 (s, 3H), 2.94 (d, J = 14, 1H), 2.96 (dd, J = 17 and 3, 1H), 3.22 (bd, J = 17, 1H), 3.65 (d, J = 14, 1H), 7.22-7.38 (m, 5H), 7.53 (t, J = 7, 2H), 7.60 (t, J = 7, 1H), 7.74 (d, J = 7, 2H), 9.92 (dd, J = 3 and 2, 1H). 15 Mass spectrum (ESI): m/z 346 (M+1, 85%), 363 (M+NH3+1, 100%). Step F: (R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl) 2-ethyl-2-phenylbut-1-yl]-N-methylbenzenesulfonamide hydrochloride 20 Using essentially the same procedure as in Example 1 (Step C), (R,S)-N-(2-ethyl-2-phenyl-4-oxobut-1-yl)-N-methylbenzene sulfonamide from Step E above was allowed to react with 4 benzyloxycarbonyl(ethylamino)piperidine (prepared by analogy to Example 68) to give the free amine of the title compound as a colorless 25 film. 1H NMR (400 MHz, CD3OD): 8 0.87 (t, J = 7, 3H), 1.12 (t, J = 7, 3H), 1.63-2.24 (m, 11H), 1.89 (s, 3H), 2.50-2.60 (m, 1H), 3.04 (bd, J = 10, 1H), 3.11 (bd, J = 10, 1H), 3.16 (d, J = 14, 1H), 3.22 (d, J = 14, 1H), 3.26 (q, J = 7, 2H), 3.82-3.96 (b, 1H), 5.12 (s, 2H), 7.20 (t, J = 7, 1H), 7.28-7.42 (m, 4H), 7.58 (t, J = 7, 2H), 7.65 (t, J = 7, 1H), 7.74 (d, J = 7, 2H). Mass spectrum (ESI): m/z 30 592 (M+1, 100%). The hydrochloride salt of the title compound was prepared by dissolving the free base in ethanol and adding 1.5 equivalents of aq. 2 N HC1. Evaporation of the solvent gave the title salt as a white glass. - 180 - While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be 5 made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the 10 specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance 15 with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. - 181 -

Claims (16)

1. A compound of the formula: R23 N- R 1 R 3 / 5 wherein: wherein: R 1 is selected from a group consisting of: C3, C4, C5, C6, C7, or C8 linear or branched alkyl, which is unsubstituted or mono, di or tri-substituted, where the 10 substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) phenyl, (d) mono, di or tri-substituted phenyl, where the 15 substituents are independently selected from: (1') phenyl, (2') hydroxy, (3') C1-3alkyl, (4') cyano, 20 (5') halogen, and (6') trifluoromethyl, (e) C1-6 alkyl, unsubstituted or substituted with hydroxy, (f) -NR 6 CO-R 7 , wherein R 6 is hydrogen or C1-3 alkyl, unsubstituted or substituted with C5-8 cycloalkyl, and 25 R 7 is C1-6 alkyl, benzyl or phenyl which is unsubsituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy, (g) -COR 6 , (h) -OR 6 , 30 (i) -NR 6 S(O)j-R 7 , where j is 1 or 2, (j) -NR 6 S(O)j-heteroaryl, wherein heteroaryl is selected from the group consisting of: - 182 - (1') benzimidazolyl, (2') benzofuranyl, (3') benzoxazolyl, (4') furanyl, 5 (5') imidazolyl, (6') indolyl, (7') isooxazolyl, (8') isothiazolyl, (9') oxadiazolyl, 10 (10') oxazolyl, (11') pyrazinyl, (12') pyrazolyl, (13') pyridyl, (14') pyrimidyl, 15 (15') pyrrolyl, (16') quinolyl, (17') tetrazolyl, (18') thiadiazolyl, (19') thiazolyl, 20 (20') thienyl, and (21') triazolyl, wherein the heteroaryl is unsubstituted or mono di or tri substituted, where the substituents are independently selected from: 25 (a') phenyl, (b') hydroxy, (c') oxo, (d') cyano, (e') halogen, and 30 (f) trifluoromethyl; R 2 is selected from the group consisting of: (1) hydrogen, (2) hydroxy, 35 (3) C1-6 alkyl, - 183- (4) -O-C1-6 alkyl, (5) phenyl, (6) -N(CH3)-CO-N(H)(CH3), (7) -N(H)-CO-O-CH3, and 5 (8) -CO-CH3; R 3 is selected from the group consisting of: (1) Ar, (2) -(C1-6 alkyl)-Ar, 10 (3) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar, and (4) -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, wherein R 4 is selected from hydrogen, C1-10 linear or branched alkyl, and CO-6 alkyl substituted with C3-8 cycloalkyl, (5) -N(R 4 )-CO-O-R 7 ; 15 Ar is selected from the group consisting of: (1) phenyl, (2) pyrazinyl, (3) pyrazolyl, 20 (4) pyridyl, (5) pyrimidyl, and (6) thienyl, wherein the Ar is unsubstituted or mono or di-substituted, and the substituents are independently selected from: 25 (a) C1-3 alkyl, unsubstituted or substituted with (1') oxo, (2') hydroxy, (3') -OR 7 , (4') phenyl, and 30 (5') trifluoromethyl, (b) halogen, (c) -OC1-6 alkyl, (d) trifluoromethyl, (e) -NO2, - 184- VV"J 77U I T% L I UOJ70IJL' (f) CONR 6 -(C1-2 alkyl), (g) CO2H, (h) C02-(C1-2 alkyl), (i) CH2NR 6 -(C1-2 alkyl), 5 (j) CH2NH-C(O)-C1-3alkyl, (k) CH2NH-C(O)NH2, (1) CH2NH-C(O)NHC1-3alkyl, (m) CH2NH-C(O)N-diCl1-3 alkyl), (n) CH2NH-S(O)j-Cl-3alkyl, 10 (o) CH2-heteroaryl, with the heteroaryl is selected from the group consisting of: (1') imidazolyl, (2') oxazolyl, (3') pyridyl, 15 (4') tetrazolyl, (5') triazolyl, and the heteroaryl is unsubstituted, mono, di or tri substituted, where the substituents selected from: (a') hydrogen, 20 (b') C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, the substituents being selected from hydrogen and hydroxy; and pharmaceutically acceptable salts thereof. 25
2. The compound of Claim 1 wherein: R 1 bears at least one substituent which is selected from: (a) -NR 6 CO-R 7 , wherein R 6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl, and R 7 is C1-6 alkyl, 30 benzyl or phenyl which is unsubsituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy, and (b) -NR 6 S(O)j-R 7 , where j is 1 or 2.
3. The compound of Claim 1 wherein: - 185 - R 1 bears at least one substituent which is: -NR 6 S(O)j-R 7 , wherein R 6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl, and R 7 is C1-6 alkyl, benzyl or phenyl which is unsubsituted or substituted 5 with halo, CF3, C1-3alkyl, or C1-3alkoxy, and where j is 1 or 2.
4. The compound of Claim 1 wherein: R 1 is selected from the group consisting of: 10 C4, C5, or C6 linear alkyl, which is substituted, where the substituents are independently selected from: (a) phenyl, (b) mono, di or tri-substituted phenyl, where the substituents are independently selected from: 15 (1') hydroxy, (2') methyl or ethyl, (3') Cl or F, and (4') trifluoromethyl, (c) C1-6 alkyl, unsubstituted or substituted with hydroxy, 20 (d) -NR 6 CO-R 7 , wherein R 6 is methyl, unsubstituted or substituted with cyclohexyl, and R 7 is phenyl which is unsubstituted or substituted with Cl, F, CF3, C1 3alkyl or C1-3alkoxy, and (e) -NR 6 S(O)j-R 7 , where j is 1 or 2. 25
5. The compound of Claim 1 wherein: R 1 is C4 linear alkyl, which is substituted, where the substituents are independently selected from: (a) phenyl, 30 (b) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (1') hydroxy, (2') methyl or ethyl, (3') Cl or F, and - 186- (4') trifluoromethyl, (c) C1-6 alkyl, unsubstituted or substituted with hydroxy, and (d) -NR 6 S(O)j-R 7 , where R 6 is methyl, unsubstituted or 5 substituted with cyclohexyl, and R 7 is phenyl which is unsubstituted or substituted with Cl, F, CF3, Cl 3alkyl or C1-3alkoxy, and j is 1 or 2.
6. The compound of Claim 1 wherein: 10 R 1 is selected from the group consisting of: N, SO2 - CH 3 CH 3 CH 2 0H NSO2 \ SNO2 \ /- CH 3 - OH 3 ,and
7. The compound of Claim 1 wherein: 15 R 1 is selected from the group consisting of: CH 3 CH 3 - I N , SO2 N, SO O OH 3 OH 3 - 187 - CH 2 OH CH 2 OH NSO2 /NSO2 S OH 3 C CH 3 , and
8. The compound of Claim 1 wherein: R 2 is selected from the group consisting of: 5 (1) hydrogen, (2) hydroxy, and (3) phenyl.
9. The compound of Claim 1 wherein: 10 R 2 is hydrogen.
10. The compound of Claim 1 wherein: R 3 is selected from: (1) Ar, 15 (2) -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, wherein R 4 is selected from hydrogen, C1-10 linear or branched alkyl, and C0-6 alkyl substituted with C3-8 cycloalkyl.
11. The compound of Claim 1 wherein: 20 R 3 is -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, wherein R 4 is selected from hydrogen, C1-10 linear or branched alkyl, and CO-6 alkyl substituted with C3-8 cycloalkyl.
12. The compound of Claim 1 wherein: 25 R 3 is selected from: (1) phenyl, and (2) -N(R 4 )-CO-O-(C1-6 alkyl)-phenyl, wherein R 4 is selected from hydrogen, C1-10o linear or branched alkyl, and C0-6 alkyl substituted with C3-8 cycloalkyl. 30 - 188-
13. The compound of Claim 1 wherein: R 3 is: -N(R 4 )-CO-O-(CH2)-phenyl, wherein R 4 is selected from hydrogen, C1-6 linear or branched alkyl, and CH2 substituted with 5 C3-8 cycloalkyl.
14. The compound of Claim 1 wherein: R 3 is: -N(R 4 )-CO-O-(CH2)-phenyl, wherein R 4 is selected from hydrogen 10 and C1-6 alkyl.
15. A compound which is selected from the group consisting of: N NS IMe CI C"f ---- N' N NN - I Me 15 Cl1 - 189 - ~o,, N N, NSb, 0 S I Me 0 o--- 0 N NS - I Me 0 O N NS Me F N Sb Me CI - 190 - N S, Me CI CI o N I' O N N' H o N NS d, H N 0 N 0 N ,S H H - 191 - 0 N" N-.. H 2 N N 01 c H Me 'N CH 2 CH 3 0 0N N -- N N I Me 'N H N y0 N S N' 0 M e - 192 - N s Me CO 2 Et NN N 1S Me CI -193 N, 0, s N" ~Ns ,O OS II O Ns , NkN N O,10" - 194 - c I 0 N0
195- vv YY) l 71 'II U S9Z/1499U NO0 0H 2 0H 3 CI HO' 0" -196 - wu w/U ,yq PCT/UN9S/1499U 0 0 o 01 01 O O,, H o, s HI S "N 0 0 - 197 - wu Myive m PC/L)59S/1499U 0 0 N ,eS NMe CF 3 0 O N ,S I Me F \ O N N-\S Me N OCH 3 H N, ,O -18 - 198 - WV YY!IU4 /Y PCI] U S981499U 0 N, P' ~N 0 0 H N - 199 - 0 N IH ~cI '-'IN-S- N 11 0 - 200 - WOJ 99/U4 /94 PCT/US98/1499J -100 N N-SI 0 OH 00 Me Me F -201- WU YJ5'U4 /Y 9FI PI! U S9N/I499U OH "-,IN-S- N 1 0 N 0 0 k\ // Me N 0 Me N S" Me F F - 202 - Wku!IV/U4i94 PC'I'11JS98/1499J Is N 'P W~l /S /7 N 01 -3 WV. 99/U.4 /94 PCI/U S98114990 N N -S 1 Me ZCOH 3 N S, Me IN N - 204 - WO U4/9 PCTIUS98/1499J N ~ 0 N - Me Me N N, s 1 01 - 205 - 0 HN-( o N.C ' K- N Me N. CIl~ N0N"S\ N1 0 -~Me CH N S Me C206 w Yiu i/V< PCT/US98/14990 0 \ - O-.. N S Me F CH 3 0 S"1 N N \\ I0 CI IOOH o,,~ N Sb Me Cl - 207 - WO 99/0U4794 PCT/US98/14990 -0 I N S Me CI CF 3 Cl ~IOH OHO o N, S Ns CI N ,S NO Me CH 3 CH 3 - 208 - WO 99/U4794 PCT/US98/14990 N N-S Me H 3 C OH 3 0 00H 3 N S :1 7 Me CF 3 0IOH N S Me CI - 209 - WV YYIU4f/Y4 1cF U S98S/1499 OIH N " Me cI 01 N, N,.. N0' 0 0 Nd -" N J: 01S 0 -210- 0 y0 0NN N' 0 a Me 'N. 0 N S - I Me N. NN Me -211- vu y/u4 iv4 PCT/US98/1499U O C H 3 N S I Me N N S Me CO2 OO~~ N 0 N S -212- W U ! FIU4 V4 PC TI'US98 /1499 0 N,' H H 0 Nd N~ H -213- wu vi/u4 /4 PCT/US98/14990 N, 0 01 " , N 0 H 0 N, N01 0 N, N " N~ 01 6' N NS - 214 - NI O NJ: S HI O N N'-S o NJ: 0" // 0 N ', S, S Me OCH 3 -215- W U 4 /YIJI4 I'I/ U NRi/14Il9U Me CI 0 N N 0 Me"'N~j 02 10 0 -216- WU NWU4 /94 CIT/)U9I/14YYU OH 0 N S Me Cl F O S N-S-o Me Cl CI N- 0 ON 0 O N ' 0 N 0S -217- WU) 99/U4 /9J4 U/S S14IU 0 AN: S-o 0~ N, NJN 0 Nd NS 0 NJ NJ:D -218- o N N-1 s N I s N ,s 0oAJN N...° 9,S 0 N 0 , S -219- VV L1 /U09 I ,+r% I',1 U nYO/19747U 0 o, N o' s 0 N, S O N N S - 220 - N ~ SO 2 Ph N- N N \s Me 0 Nk N0; 0 N -221- vV L.77IV 1,7" r %-110 0/1 JUo - o N OS "O N NI, " Nd ( o N0 0 NN, ( N O N N ' - 222 - vv u lyrum iI/ J 0L, 110) 4I'77UL N 00 o N N ,s/ O N N ',S 0 N' 0 2 S - 223 - 7Me CF 3 N S :1 M e C I S, 0 'N'"ef N -c 0 00 0 N0',\N 0 - 224 - Vy" U O-r'. I J7JO O N O NNS O, O N N N "\ O0 -25 \ ON -N N S - 225 - NO Me ci 0 N0 PhO'N 0 N0 Nh 0 N, NN Me 'N ci - 226 - vv .7 7YIJ tt I A 1/ IN-N N Q '51 7 Me OH >Me CI OH 0,~ N NO'1 7 Me CID OCH 3 N \O -Me CI - 227 - 0 2 S N-. 02S N N 802 02 -228 - 0 N,, N"o yz ~ N0'~ os 0 NN ' - 229 - vV I 77/Ut 171 L JE I U O I70/1 .7U 0 y0 0,. "'S,. No I OO O N 0. 20 0N N N s - 230 - O 0 o\s N N N, S I NN S NNN2S1 - 231 - 00 N ' s oo o0 N-N N - 232 - 00 o N, o NC 0S 0 0 N0 N - 233 - V YL7 7/IVP 17 FL110/070/1 It77U ON N O OON 0 O N ONJO 00 o N 8S O~N 0O 0 N 234 - ON N O,0 /0 O NS N s O O O 0 O~O 0 //0 0 N / 0 N 0Oo - 235 - 00 0 NJ: 0 N \ 0 - 236 - vv 'J 1 I''~ I % , LI ~JI U 01 7 ol o NS NN\O o j O N NS~ 0 - 237 - O NLJ N N S 0 10 0j N N SO oj O N N NS - 238 - 1 0 0 N N N SN, 0 0 0 OO) 0,N N NlSb -029N -239 - 0 y0 0, VVU 77e / 17t F0110 0/ 1 77UeIJ', ~ 00 N NsNS0 0 y0 0\ ' N NN Sb ,oJo IN - 240 - ,vv K- ,J A / U 13.701 A N 0N 0 N, H3S Ph 0 H 3 0 ' H 3 0 H3C Ph 0 N4 0 K 5 -241- O O N,N N"' 5 00 0 - 242 - 00 0~ N~N 00 0 F 3 0 0 N NS Ph Me N Et, N OH PhCH 2 O 0 - 243 - So 0 NN CF 3 0 CF 3 0 o j o\ 0 - 244 - VVL177/Ul 1.7 £ 10 7/ 7 O /) 0N N 0 o@= O 0 O 0 Me N SO Et OH 5245 - 245 - VV17 71Uq- 1t FL,11JO70/1A77" Me So Et N DOH 02 NN O 0 O N N S O o o- 0 N NS 0 O 24 -N N' S O - 246 - vvJ -17 Uf I U0701O Ilt.77V 0 00 5 - 247 - Phi Ph~0K SO 2 Ph Me Ph I Et ,N N OMeSOh PhCH 2 O> 0 0 N~C 0 Ph o N, SO 2 Ph PhO N Ph Me SO 2 Ph Et ,Nc OMe 5 PhCH 2 0 0 - 248 - Ph Me Et NNNHMeSOP PhCH 2 O 0 ,, 0 0~ ~NN N N 0oN N , 0 N 0 I 24-I VV" 77/U,41714~~o~ r- , /U3011"7 o sj Ph Me N OH PhCH 2 O 0 0 - 250 - 00 0 0 0 NN S\\ 0 a ci -251- 'N. WS O 0 0 ~ N N N 0 ~z O OH QY ~N 0 NS. 00 O OH - 252 - 0~ N. O OH OY Nk'.I-~, N% 0 O NH 2 O N O:S,\N Y ~N~N 00 O NH 2 -253 - S O. N N N SO O ° O o 0 N' O\3 0 0 N, S - 254 - O0 N N SO 0O \ 0 0 NO \ O oO 0O N ,, N IC 0O 0 HO K O -255 0 N ~N N, SOX~' YI HO K 0 - 255 - HO) 0 00"N H 2 NI 0 ON N 5 0 - 256 - O N I N NS O \K yS H 2 N 0 oSj 0 Oy N, N, Sb N\K ON, 0 - 257 - O 0 / S N O Ph Me N CN N PhCH 2 0 0O 00 N 7NS H N OH S N I N-N S0 2 Ph OH 5 and pharmaceutically acceptable salts thereof. - 258 - 16. A compound which is selected from the group consisting of: (R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methylbenzene 5 sulfonamide; (R,S)-N-[2-Phenyl-4-(4-benzylpiperidin-1-yl)but-1l-yl]-N-methylbenzene sulfonamide; 10 (R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonyl-4-phenylpiperidin-1 yl)but-1-yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-aminocarbonyl-4-phenylpiperidin-1-yl)but-1l-yl] N-methylbenzenesulfonamide; 15 (R,S)-N-[2-Phenyl-4-(4-hydroxymethyl-4-phenylpiperidin-1-yl)but-1l-yl] N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)but-1 20 yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(piperidin-1-yl)but-1-yl] -N-methylbenzene sulfonamide; 25 (R,S)-N-[2-Phenyl-4-(4-pentylaminocarbonylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-isopropylaminocarbonylpiperidin-1-yl)but-1l-yl] N-methylbenzenesulfonamide; 30 (R,S)-N- [2-Phenyl-4-(4-methylaminocarbonylmethylene-4-phenyl piperidin-1-yl)but-1l-yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-methylaminocarbonyl(methylamino)methylene-4 35 phenylpiperidin-1-yl)but-1l-yl]-N-methylbenzenesulfonamide; - 259 - (R,S)-N- [2-Phenyl-4-(4-methoxycarbonylaminomethylene-4 phenylpiperidin-1-yl)but- l-yl] -N-methylbenzenesulfonamide; 5 (R,S)-N- [2-Phenyl-4-(4-methylaminocarbonylaminomethylene-4 phenylpiperidin-1-yl)but- l-yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-(2-methyl)phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 10 (R,S)-N-[2-Phenyl-4-(4-morpholinocarbonylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; (R,S)-N-[2-(2-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but- l-yl]-N 15 methylbenzenesulfonamide; (R,S)-N-[2-(2-Thienyl)-4-(4-phenylpiperidin-1-yl)but- l-yl]-N methylbenzenesulfonamide; 20 (R,S)-N-[2-(3-Thienyl)-4-(4-phenylpiperidin-1-yl)but- l-yl]-N methylbenzenesulfonamide; (R,S)-N-[2-(3-Thienyl)-4-(4-benzylpiperidin-1-yl)but- l-yl]-N-methyl benzenesulfonamide; 25 (R,S)-N-[2-Cyclohexyl-4-(4-phenylpiperidin-1-yl)but-1-yl] -N-methyl benzenesulfonamide; (R,S)-N-[2-(3,5-Dichlorophenyl)-4-(4-phenylpiperidin-1-yl)but- l-yl]-N 30 methylbenzenesulfonamide; (R,S)-N-[2-(3-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methyl benzenesulfonamide; - 260 - (R,S)-N- [2-(3-Ethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methyl benzenesulfonamide; (R,S)-N-[2-(3-Carboethoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 5 methylbenzenesulfonamide; (R,S)-N- [2-(3-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 10 (R,S)-N-[2-(3-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yll-N methylbenzenesulfonamide; (R,S)-N-[2-(3,4-Difluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 15 (R,S)-N-[2-(3-Biphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; (R,S)-N-[2-(3-Pyridyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 20 methylbenzenesulfonamide; (R,S)-N-[2-(Naphthalen-2-yl)-4-(4-phenylpiperidin-1-yl)b ut-1-yl]-N methylbenzenesulfonamide; 25 (R,S)-N-[2-(4-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; (R,S)-N-[2-(2-Pyridyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 30 (R,S)-N-[2-(3-Fluoro-4-methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1 yl] -N-methylbenzenesulfonamide; (R,S)-N-[2-(3,4-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl] 35 N-methylbenzenesulfonamide; - 261 - (R,S)-N-[2-(3,5-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl] N-methylbenzenesulfonamide; 5 (R,S)-N-[2-(4-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; (R,S)-N-[2-(3-Trifluoromethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1 yl]-N-methylbenzenesulfonamide; 10 (R,S)-N-[2-(3-Methyl-4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1 yl]-N-methylbenzenesulfonamide; (S)-N-[2-(3-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N 15 methylbenzenesulfonamide; (S)-N-[4-(4-Benzylpiperidin-1-yl)-2-(3-chlorophenyl)but-1-yl]-N methylbenzenesulfonamide; 20 (S)-N-[4-(4-(3-Phenylprop-1-yl)piperidin-1-yl)- 2 -(3-chlorophenyl)but 1-yl]-N-methylbenzenesulfonamide; (S)-N-[2-(3-Chlorophenyl)-4-(4-t-butylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 25 (S)-N-[2-(3-Chlorophenyl)-4-(4-(cis-octahydro-2H-benzimidazol-2-on-1 yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide; (S)-N-[2-(3-Chlorophenyl)-4-(4-(1,2,3,4-tetrahydro-2H-quinazolin-2-on-1 30 yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide; (S)-N-[2-(3-Chlorophenyl)-4-(3-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 35 (S)-N-[2-(3-Chlorophenyl)-4-(4-hydroxy-4-phenylpiperidin-1-yl)but-1-yl] - 262 - V- - II1 - I tJ OI i/ t70 . N-methylbenzenesulfonamide; (S)-N-[2-(3-Chlorophenyl)-4-(4-(2,3-dihydro-2H-benzimidazol-2-on- 1 yl)piperidin-1l-yl)but-1l-yl]-N-methylbenzenesulfonamide; 5 (S)-N-[2-(3-Chlorophenyl)-4-[4,4-diphenylpiperidin-1l-yl]-butyl}-N methylbenzenesulfonamide; (S)-N-[4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl] -2-(3-chlorophenyl) 10 but- 1-yl]-N-methylbenzenesulfonamide; (S)-N-[4-(4-Acetyl-4-phenylpiperidin-1-yl)- 2 -(3-chlorophenyl)but-1l-yl]-N methylbenzenesulfonamide; 15 (S)-N- [4- [4-(4-Chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl]-2 (3-chlorophenyl)but-1-yl] -N-methylbenzenesulfonamide; (S)-N- [2-(3-Chlorophenyl)-4- [4-(2-methoxycarbonylphenyl)piperidin-1-yl] but- 1-yl] -N-methylbenzenesulfonamide; 20 (S)-N- [2-(3-Chlorophenyl)-4- [4-hydroxy-4-(3-trifluoromethyl)phenyl-piper idin- l-yl]-but- 1-yl]-N-methylbenzenesulfonamide; (S)-N- [2-(3-Chlorophenyl)-4- [4-(4-fluorophenyl)-4-hydroxypiperidin- 1 25 yl]but- 1-yl] -N-methylbenzenesulfonamide; (S)-N- [2-(3-Chlorophenyl)-4- [4-(2-oxo-4H-benzo [d] [1,3] oxazin-1-yl)piper idin- 1-yl] but- 1-yl] -N-methylbenzenesulfonamide; 30 (S)-N- [2-(3-Chlorophenyl)-4- [4-(2-oxo-3H-benzo [d] [1,4] oxazin-1-yl)piper idin- 1-yl] but- 1-yl] -N-methylbenzenesulfonamide; (S)-N-[4-(4-Benzoylpiperidin-1-yl)-2-(3-chlorophenyl)but-1l-yl]-N methylbenzenesulfonamide; 35 - 263 - (S)-N- [2-(3-Chlorophenyl)-4- [4-(2-methoxy)phenylpiperidin- 1-yl] but- 1 yl]-N-methylbenzenesulfonamide; (S)-N-[2-(3-Chlorophenyl)-4-(4-piperidin-1-ylpiperidin-1-yl)but-1-yl]-N 5 methylbenzenesulfonamide; (S)-N-[2-(3,4-Methylenedioxyphenyl)-4-(4-phenylpiperidin-1-yl)but- 1 yl]-N-methylbenzenesulfonamide; 10 (S)-N-[2-(4-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; (S)-N-[2-(3,4-Dichlorophenyl)-4-(4-phenylpiperidin-l1-yl)-but-1-yl]-N ethylbenzenesulfonamide; 15 (R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1l-yl]-N-methylphenyl acetamide; (R,S)-N-[2-Phenyl-4-[4-acetyl(ethylamino)piperidin- l-yl]but- l-yl]-N 20 methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-[4-(oxazolidin-2-on-3-yl)piperidin- l-yl]but- l-yl]-N methylbenzenesulfonamide; 25 (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(ethylamino)piperidin-1-yl)but- 1 yl]-N-methylbenzenesulfonamide; (R,S)-N- 1[2-Phenyl-4-(4-dimethylaminocarbonylaminopiperidin-1-yl)but- 1 yl]-N-methylbenzenesulfonamide; 30 (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(prop-1-ylamino)piperidin-1 yl)but-l-yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminopiperidin-1-yl)but-1l-yl] 35 N-methylbenzenesulfonamide; - 264 - (R,S)-N-[2-Phenyl-4-(4-aminocarbonylaminopiperidin-1-yl)but-1-yl] -N methylbenzenesulfonamide; 5 (R,S)-N-[2-Phenyl-4-(4-aminopiperidin-1-yl)but-1-yl]-N-methylbenzene sulfonamide; (R,S)-N-[2-Phenyl-4-(4-acetylaminopiperidin-1-yl)but-1-yl]-N methylbenzenesulfonamide; 10 (R,S)-N-[2-Phenyl-4-(4-isopropylcarbonylaminopiperidin-1-yl)but- 1 yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-methylsulfonylaminopiperidin-1-yl)but-1-yl]-N 15 methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-isopropylcarbonyl(ethylamino)piperidin-1 yl)but-1-yl]-N-methylbenzenesulfonamide; 20 (R,S)-N-[2-Phenyl-4-(4-methylsulfonyl(ethylamino)piperidin-1-yl)but 1-yl]-N-methylbenzenesulfonamide; (R,S)-N- [2-Phenyl-4-(4-t-butoxycarbonylaminopiperidin-1-yl)but- 1-yl] N-methylbenzenesulfonamide; 25 (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(methylamino)piperidin-1-yl)but 1-yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-(pyrrolidin-2-on-1-yl)piperidin-1-yl)but-1l-yl]-N 30 methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclobutylmethylamino) piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide; - 265 - (R,S)-N- [2-Phenyl-4-(4-ethoxycarbonyl(ethylamino)piperidin- 1-yl)but- 1 yl] -N-methylbenzenesulfonamide; (R,S)-N- [2-Phenyl-4-(4-isobutyloxycarbonyl(ethylamino)piperidin- 1 5 yl)but-1-yl] -N-methylbenzenesulfonamide; (R,S)-N- [2-Phenyl-4-(4-piperidin-2-on- 1-ylpiperidin-1-yl)but- l-yl] -N methylbenzenesulfonamide; 10 (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(benzylamino)piperidin- 1-yl)but l-yl] -N-methylbenzenesulfonamide; (R, S)-N- [2-Phenyl-4-(4-methoxycarbonyl(prop- 1-ylamino)piperidin- 1 yl)but-1-yl] -N-methylbenzenesulfonamide; 15 (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(but- 1-ylamino)piperidin- 1 yl)but-1-yl] -N-methylbenzenesulfonamide; (R,S )-N- [2-Phenyl-4-(4-methoxycarbonyl( cyclohexylmethylamino)-piper 20 idin- 1-yl)but- l-yl] -N-methylbenzenesulfonamide; (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(cyclopropylmethylamino)-piper 1dn- 1-yl)but- l-yl] -N-methylbenzenesuli'onamide; 25 (R,S)-N- [2-Phenyl-4-(4-methoxycarbonyl(pent- 1-ylamino)piperidin- 1 yl)but-1-yl] -N-methylbenzenesulfonamide; (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(methylamino)piperidin- 1 yl)but-1-yl] -N-methylbenzenesulfonamide; 30 (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(ethylamino)piperidin- 1-yl)but l-yl] -N-methylbenzenesulfonamide; (R,S)-N- [2-Phenyl-4-(4-benzyloxycarbonyl(but- 1-ylamino)piperidin- 1 35 yl)but- l-yl] -N-methylbenzenesulfonamide; - 266 - (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(pent-1-ylamino)piperidin-1 yl)but-1l-yl]-N-methylbenzenesulfonamide; 5 (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(cyclobutylmethylamino)-piper idin-l1-yl)but-1l-yl]-N-methylbenzenesulfonamide; (R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(cyclohexylmethylamino)-piper idin-1-yl)but-1l-yl]-N-methylbenzenesulfonamide; 10 (S)-N-[2-(3-Chlorophenyl-4-(4-benzyloxycarbonyl(ethylamino)-piperidin-1 yl)but-1-yl]-N-methylbenzenesulfonamide; (R,S)-N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-1l-yl]-N 15 methylbenzenesulfonamide; (R,S)-N-Methyl-N-[2-methyl-2-phenyl-4-(4-phenylpiperidin-1-yl)but- 1 yl]benzenesulfonamide; 20 (R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-methyl-2 phenylbut-1-yl]-N-methylbenzenesulfonamide; and (R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-ethyl-2 phenylbut-1-yl]-N-methylbenzenesulfonamide; 25 and pharmaceutically acceptable salts thereof. 17. A pharmaceutical composition which comprises an 30 inert carrier and a compound of Claim 1. - 267 - vyj %- 17 IUOYOIL?7 18. A method for the modulation of chemokine receptor activity in a mammal comprising the administration of an effective amount of a compound of formula I: R 2 M N- R' R 3n 5 I wherein: R 1 is selected from a group consisting of: linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, 10 wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from: (a) hydroxy, (b) oxo, 15 (c) cyano, (d) halogen which is selected from F, Cl, Br, and I, (e) trifluoromethyl, (f) phenyl (g) mono, di or tri-substituted phenyl, where the 20 substituents are independently selected from: (1') phenyl, (2') hydroxy, (3') C1-3alkyl, (4') cyano, 25 (5') halogen, (6') trifluoromethyl, (7') -NR 6 COR 7 , (8') -NR 6 CO2R 7 , (9') -NR 6 CONHR 7 , 30 (10') -NR 6 S(O)jR 7 , wherein j is 1 or 2, (11') -CONR 6 R 7 , - 268 - VVLNJ 77/ U4 It rL 1/LUOY7/1 77qU (12') -COR 6 , (13') -CO2R 6 , (14') -OR 6 , (15') -S(O)kR 6 , wherein k is 0, 1 or 2, 5 (h) C1-6 alkyl, unsubstituted or substituted with hydroxy, (i) -NR 6 R 7 , (j) -NR 6 COR 7 , (k) -NR 6 CO2R 7 , (1) -NR 6 CONHR 7 , 10 (m) -NR 6 S(O)j-R 7 , (n) -CONR 6 R 7 , (o) -COR 6 , (p) -CO2R 6 , (q) -OCOR 6 , 15 (r) -CN, (s) -OR 6 , (t) -S(O)kR 6 , (u) -NR 6 CO-heteroaryl, (v) -NR 6 S(O)j-heteroaryl, and 20 (w) heteroaryl, wherein heteroaryl is selected from the group consisting of: (1') benzimidazolyl, (2') benzofuranyl, (3') benzoxazolyl, 25 (4') furanyl, (5') imidazolyl, (6') indolyl, (7') isooxazolyl, (8') isothiazolyl, 30 (9') oxadiazolyl, (10') oxazolyl, (11') pyrazinyl, (12') pyrazolyl, (13') pyridyl, -269 - vv IF % 1 1 U I O70 X?77 (14') pyrimidyl, (15') pyrrolyl, (16') quinolyl, (17') tetrazolyl, 5 (18') thiadiazolyl, (19') thiazolyl, (20') thienyl, and (21') triazolyl, wherein the heteroaryl is unsubstituted or mono di or tri 10 substituted, where the substituents are independently selected from: (a") phenyl, (b") hydroxy, (c") oxo, 15 (d") cyano, (e") halogen, and (f') trifluoromethyl; R 2 is selected from the group consisting of: (1) hydrogen, 20 (2) hydroxy, (3) C1-6 alkyl, (4) substituted C1-6 alkyl, where the substituents are independently selected from: (a) phenyl, 25 (b) hydroxy, (c) oxo, (d) halogen, (e) trifluoromethyl, (f) -N(R 4 )(R 5 ), wherein R 4 and R 5 are independently 30 selected from hydrogen, C 1-10 linear or branched alkyl, and CO-6 alkyl substituted with C3-8 cycloalkyl, (g) -N(R 4 )-CO-O-(R 5 ), and (h) -N(R 4 ')-CO-N(R 4 )(R 5 ), wherein R 4 ' is selected from the definitions of R 4 , 35 (5) -O-C1-6 alkyl, and -270 - VVL" 771Ut 174 I011/.0701 77V (6) phenyl; R 3 is selected from the group consisting of: (1) Ar, (2) -N(R 4 )-CO-O-(C1-6 alkyl)-Ar, 5 (3) -N(R 4 )-CO-O-R 7 , (4) -(C1-6 alkyl)-Ar, (5) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar, and (6) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar; Ar is selected from the group consisting of: 10 (1) phenyl, (2) pyridyl, (3) pyrimidyl, (4) naphthyl, (5) furyl, 15 (6) pyrryl, (7) thienyl, (8) isothiazolyl, (9) imidazolyl, (10) benzimidazolyl, 20 (11) tetrazolyl, (12) pyrazinyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, 25 (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyl, 30 (21) purinyl, (22) isoxazolyl, (23) thiazolyl, (24) oxazolyl, (25) triazinyl, and 35 (26) benzthiazolyl, -271- VT .J'f lVV-i i J'.i .I I LJ L 2 J~l'- I* .7lS (27) benzoxazolyl, (28) imidazopyrazinyl, (29) triazolopyrazinyl, (30) naphthyridinyl, 5 (31) furopyridinyl, (32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof, (33) pyridazinyl, (34) quinazolinyl, (35) pteridinyl, 10 (36) triazolopyrimidyl, (37) triazolopyrazinyl, (38) thiapurinyl, (39) oxapurinyl, and (40) deazapurinyl, 15 wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted, where the substituents are independently selected from: (a) C1-3 alkyl, unsubstituted or substituted with a substituent selected from: (1') oxo, 20 (2') hydroxy, (3') -OR 7 , (4') phenyl, (5') trifluoromethyl, and (6') phenyl or mono, di or tri-substituted phenyl, 25 where the substituents are independently selected from: hydroxy, cyano, halogen, and trifluoromethyl, (b) halogen, (c) -OC1-6 alkyl, 30 (d) trifluoromethyl, (e) hydroxy, (f) -NO2, (g) -(CH2)pS(O)k-(C1-6 alkyl), wherein p is 0, 1 or 2, (h) -(CH2)pS(O)j-NH2, 35 (i) -(CH2)pS(O)j-NH(C1-6 alkyl), -272 - (j) -(CH2)pS(O)j-NHR 6 , (k) -(CH2)pS(O)j-NR 6 -(C1-6 alkyl), (1) -(CH2)pCONH2, (m) -(CH2)pCONH-(C1-6 alkyl), 5 (n) -(CH2)pCONHR 6 , (o) -(CH2)pCONR 6 R 7 , (p) -(CH2)pCO2H, (q) -(CH2)pCO2-(C1-6 alkyl), (r) -(CH2)pNR 6 R 7 , 10 (s) -(CH2)pNH-C(O)-C1-6alkyl, (t) -(CH2)pNH-C(O)-NH2, (u) -(CH2)pNH-C(O)-NHC1-6alkyl, (v) -(CH2)pNH-C(O)-N(C1-6 alkyl)2, (w) -(CH2)pNH-S(O)k-C1-6alkyl, 15 (x) -(CH2)pN(C1-3alkyl)-C(O)-N(diCl1-6 alkyl), (y) -(CH2)p-heteroaryl, -C(O)-heteroaryl or -(CH2)p-O-heteroaryl , wherein the heteroaryl is selected from the group consisting of: (1') benzimidazolyl, 20 (2') benzofuranyl, (3') benzoxazolyl, (4') furanyl, (5') imidazolyl, (6') indolyl, 25 (7') isooxazolyl, (8') isothiazolyl, (9') oxadiazolyl, (10') oxazolyl, (11') pyrazinyl, 30 (12') pyrazolyl, (13') pyridyl or oxopyridyl, (14') pyrimidyl, (15') pyrrolyl, (16') quinolyl, - 273 - (17') tetrazolyl, (18') thiadiazolyl, (19') thiazolyl, (20') thienyl, and 5 (21') triazolyl, wherein the heteroaryl group of items (1') to (21') is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from: (a') hydrogen, 10 (b') C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, where the substituents are selected from: hydrogen and hydroxy, (c') hydroxy, 15 (d') oxo, (e') -OR 6 , (f) halogen, (g') trifluoromethyl, (h') nitro, 20 (i') cyano, (j') -NHR 6 , (k') -NR 6 R 7 , (1') -NHCOR 6 , (m') -NR 6 COR 7 , 25 (n') -NHCO2R 6 , (o') -NR 6 CO2R 7 , (p') -NHS(O)jR 6 , (q') -NR6S(O)jR 7 , (r') -CONR 6 R 7 , 30 (s') -COR 6 , (t') -CO2R 6 , and (u') -S(O)jR 6 ; R 6 is selected from the group consisting of: (1) hydrogen, 35 (2) C1-6 alkyl, -274 - VV LF I7 tv t Y % , 11 jO UI JA ZJJ- V (3) substituted C1-6 alkyl, where the substituents are independently selected from: (a) phenyl, (b) hydroxy, 5 (c) oxo, (d) cyano, (e) halogen, (f) trifluoromethyl, and (g) C5-8 cycloalkyl, 10 (4) phenyl, (5) mono, di or tri-substituted phenyl, where the substituents are independently selected from: (a) hydroxy, (b) C1-3alkyl, 15 (c) cyano, (d) halogen, and (e) trifluoromethyl; R 7 is selected from the group consisting of: (1) hydrogen, 20 (2) C1-6 alkyl or C5-8 cycloalkyl, (3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from: (a) phenyl, (b) mono, di or tri-substituted phenyl, where the 25 substituent is independently selected from: (1') hydroxy, (2') C1-3alkyl, (3') cyano, (4') halogen, 30 (5') trifluoromethyl, and (6') Cl-3alkyloxy, (b) hydroxy, (c) oxo, (d) cyano, - 275 - 7711" 7/17'911 KL.1/, A ury a (e) halogen, and (f) trifluoromethyl, (4) phenyl, (5) mono, di or tri-substituted phenyl, where the substituents 5 are independently selected from: (a) hydroxy, (b) C1-3alkyl, (c) cyano, (d) halogen, and 10 (e) trifluoromethyl; or R 6 and R 7 may be joined together to form a 5-, 6-, or 7 membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono 15 or di-substituted, the substituents independently selected from: (1) hydroxy, (2) oxo, (3) cyano, 20 (4) halogen, (5) trifluoromethyl, m is an integer selected from 0, 1 and 2, n is an integer selected from 0, 1 and 2, and pharmaceutically acceptable salts thereof. 25 19. A method for the modulation of chemokine receptor activity in a mammal comprising the administration of an effective amount of the compound of Claim 1. 30 20. A method for preventing infection by HIV, treating infection by HIV, delaying of the onset of AIDS, or treating AIDS comprising the administration to a patient of an effective amount of the compound of Claim 1. -276 -
AU85760/98A 1997-07-25 1998-07-21 Cyclic amine modulators of chemokine receptor activity Abandoned AU8576098A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US5375497P 1997-07-25 1997-07-25
US60053754 1997-07-25
GB9800958 1998-01-16
GBGB9800958.2A GB9800958D0 (en) 1998-01-16 1998-01-16 Cyclic amine modulators of chemokine activity
PCT/US1998/014990 WO1999004794A1 (en) 1997-07-25 1998-07-21 Cyclic amine modulators of chemokine receptor activity

Publications (1)

Publication Number Publication Date
AU8576098A true AU8576098A (en) 1999-02-16

Family

ID=26312958

Family Applications (1)

Application Number Title Priority Date Filing Date
AU85760/98A Abandoned AU8576098A (en) 1997-07-25 1998-07-21 Cyclic amine modulators of chemokine receptor activity

Country Status (5)

Country Link
EP (1) EP1003514A4 (en)
JP (1) JP2002510327A (en)
AU (1) AU8576098A (en)
CA (1) CA2296314A1 (en)
WO (1) WO1999004794A1 (en)

Families Citing this family (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6743594B1 (en) 1995-06-06 2004-06-01 Human Genome Sciences, Inc. Methods of screening using human G-protein chemokine receptor HDGNR10 (CCR5)
US6025154A (en) 1995-06-06 2000-02-15 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor HDGNR10
KR20010087395A (en) * 1998-11-17 2001-09-15 프리돌린 클라우스너, 롤란드 비. 보레르 4-aroyl-piperidin-ccr-3 receptor antagonists iii
WO2000035877A1 (en) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company Heterocyclic piperidines as modulators of chemokine receptor activity
DE69926919D1 (en) 1998-12-18 2005-09-29 Bristol Myers Squibb Pharma Co N-UREIDOALKYLPIPERIDINES AS MODULATORS OF THE ACTIVITY OF CHEMOKIN RECEPTORS
WO2000035454A1 (en) 1998-12-18 2000-06-22 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
PE20001420A1 (en) * 1998-12-23 2000-12-18 Pfizer CCR5 MODULATORS
US7217714B1 (en) 1998-12-23 2007-05-15 Agouron Pharmaceuticals, Inc. CCR5 modulators
EP1013276A1 (en) 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalkanes as CCR5 modulators
IL145401A0 (en) 1999-03-24 2002-06-30 Anormed Inc Chemokine receptor binding heterocyclic compounds
US6750348B1 (en) 1999-03-24 2004-06-15 Anormed, Inc. Chemokine receptor binding heterocyclic compounds
CA2371618A1 (en) * 1999-04-28 2000-11-09 Yuji Ishihara Cyclic amide compounds, their production and use
WO2000066558A1 (en) * 1999-05-04 2000-11-09 Schering Corporation Piperazine derivatives useful as ccr5 antagonists
US6387930B1 (en) 1999-05-04 2002-05-14 Schering Corporation Piperidine derivatives useful as CCR5 antagonists
US6391865B1 (en) 1999-05-04 2002-05-21 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
SK286968B6 (en) * 1999-05-04 2009-08-06 Schering Corporation Piperidine-piperidinyl derivatives useful as CCR5 antagonists, pharmaceutical composition comprising them and the use of them
US6689765B2 (en) 1999-05-04 2004-02-10 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
EP1050307A1 (en) * 1999-05-06 2000-11-08 Applied Research Systems ARS Holding N.V. CCR4 antagonists in sepsis
AU5473400A (en) 1999-06-11 2001-01-02 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
WO2000076511A1 (en) 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
AU5600100A (en) 1999-06-11 2001-01-02 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6472410B1 (en) 1999-06-11 2002-10-29 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6358979B1 (en) 1999-06-11 2002-03-19 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
WO2000076513A1 (en) 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
JP4688381B2 (en) * 1999-06-11 2011-05-25 メルク・シャープ・エンド・ドーム・コーポレイション N-cyclopentyl modulator of chemokine receptor activity
SE9902987D0 (en) 1999-08-24 1999-08-24 Astra Pharma Prod Novel compounds
PE20010628A1 (en) 1999-10-01 2001-06-18 Takeda Chemical Industries Ltd CYCLIC AMINE COMPOUNDS, THEIR PRODUCTION AND THEIR USE
SE9903544D0 (en) 1999-10-01 1999-10-01 Astra Pharma Prod Novel compounds
ATE325790T1 (en) 1999-10-05 2006-06-15 Takeda Pharmaceutical UREA COMPOUNDS, A PROCESS FOR THEIR PRODUCTION AND THEIR USE
GB2359081A (en) 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active thiazolopyrimidines
GB2359078A (en) 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
GB2359551A (en) 2000-02-23 2001-08-29 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
GB0005642D0 (en) 2000-03-10 2000-05-03 Astrazeneca Uk Ltd Chemical compounds
AR033517A1 (en) 2000-04-08 2003-12-26 Astrazeneca Ab PIPERIDINE DERIVATIVES, PROCESS FOR THE PREPARATION AND USE OF THESE DERIVATIVES IN THE MANUFACTURE OF MEDICINES
GB0011838D0 (en) * 2000-05-17 2000-07-05 Astrazeneca Ab Chemical compounds
US6667314B2 (en) 2000-05-26 2003-12-23 Pfizer, Inc. Tropane derivatives useful in therapy
CN100355753C (en) * 2000-05-26 2007-12-19 辉瑞大药厂 Intermediates for the preparation of therapeutically useful tropane derivatives
GB0013060D0 (en) * 2000-05-31 2000-07-19 Astrazeneca Ab Chemical compounds
BR0111878A (en) 2000-06-30 2005-05-24 Bristol Myers Squibb Co N-ureido- (heterocycloalkyl) piperidines as modulators of chemokine receptor activity
TWI227231B (en) * 2000-07-12 2005-02-01 Novartis Ag 4-benzoyl-piperidine derivatives for treating conditions mediated by CCR-3
GB0017174D0 (en) * 2000-07-12 2000-08-30 Novartis Ag Organic compounds
GB0021670D0 (en) 2000-09-04 2000-10-18 Astrazeneca Ab Chemical compounds
CA2425259A1 (en) 2000-10-11 2002-04-18 Tularik, Inc. Modulation of ccr4 function
SE0003828D0 (en) 2000-10-20 2000-10-20 Astrazeneca Ab Novel compounds
WO2002046156A2 (en) 2000-12-06 2002-06-13 Sepracor, Inc. 4,4-disubstituted piperidines for use as dopamine, serotonin and norepinephrine ligands
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
GB0104050D0 (en) 2001-02-19 2001-04-04 Astrazeneca Ab Chemical compounds
GB0107228D0 (en) 2001-03-22 2001-05-16 Astrazeneca Ab Chemical compounds
AR033452A1 (en) 2001-03-29 2003-12-17 Schering Corp CCR5 ANTAGONISTS USEFUL FOR THE TREATMENT OF AIDS
GB0108099D0 (en) * 2001-03-30 2001-05-23 Hoffmann La Roche Aminopiperidine derivatives
SE0101322D0 (en) 2001-04-12 2001-04-12 Astrazeneca Ab Novel compounds
US7144903B2 (en) 2001-05-23 2006-12-05 Amgen Inc. CCR4 antagonists
KR20040013090A (en) 2001-07-02 2004-02-11 아스트라제네카 아베 Piperidine Derivatives Useful as Modulators of Chemokine Receptor Activity
GB0117899D0 (en) 2001-07-23 2001-09-12 Astrazeneca Ab Chemical compounds
GB0120461D0 (en) 2001-08-22 2001-10-17 Astrazeneca Ab Novel compounds
AU2002326948A1 (en) 2001-09-18 2003-04-01 Bristol-Myers Squibb Company Piperizinones as modulators of chemokine receptor activity
GB0122503D0 (en) 2001-09-18 2001-11-07 Astrazeneca Ab Chemical compounds
SE0103818D0 (en) 2001-11-15 2001-11-15 Astrazeneca Ab Chemical compounds
US7354932B2 (en) 2001-12-21 2008-04-08 Anormed, Inc. Chemokine receptor binding heterocyclic compounds with enhanced efficacy
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
TW200303304A (en) 2002-02-18 2003-09-01 Astrazeneca Ab Chemical compounds
TW200305395A (en) * 2002-03-15 2003-11-01 Novartis Ag Organic compounds
SE0200843D0 (en) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
SE0200844D0 (en) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
EP1490346B1 (en) * 2002-03-29 2009-12-02 Schering Corporation Stereoselective alkylation of chiral 2-methyl-4-protected piperazines
TW200409630A (en) 2002-09-12 2004-06-16 Bristol Myers Squibb Co N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
GB0221828D0 (en) 2002-09-20 2002-10-30 Astrazeneca Ab Novel compound
WO2004028530A1 (en) 2002-09-26 2004-04-08 Bristol-Myers Squibb Company N-substituted heterocyclic amines as modulators of chemokine receptor activity
WO2004041279A1 (en) * 2002-10-30 2004-05-21 Merck & Co., Inc. Gamma-aminoamide modulators of chemokine receptor activity
CA2509711A1 (en) 2002-12-13 2004-07-01 Smithkline Beecham Corporation Piperidine derivatives as ccr5 antagonists
KR101078505B1 (en) * 2003-03-14 2011-10-31 오노 야꾸힝 고교 가부시키가이샤 Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
ES2315647T3 (en) 2003-03-24 2009-04-01 Actimis Pharmaceuticals, Inc. 2-PHENOXY AND 2-PHENYLSULFONAMIDE DERIVATIVES WITH ANTIGONIST ACTIVITY OF CCR3 FOR THE TREATMENT OF ASTHMA AND OTHER INFLAMMATORY OR IMMUNOLOGICAL DISORDERS.
SE0300957D0 (en) 2003-04-01 2003-04-01 Astrazeneca Ab Chemical compounds
WO2004092169A1 (en) 2003-04-18 2004-10-28 Ono Pharmaceutical Co., Ltd. Spiropiperidine compound and medicinal use thereof
SE0301369D0 (en) 2003-05-09 2003-05-09 Astrazeneca Ab Chemical compounds
JP3939744B2 (en) 2003-06-11 2007-07-04 メルク エンド カムパニー インコーポレーテッド Substituted 3-alkyl and 3-alkenyl azetidine derivatives
AU2004272275B2 (en) * 2003-09-15 2009-02-26 Novartis Ag 1, 3-disubstituted azetidine derivatives for use as CCR-3 receptor antagonists in the treatment of inflammatory and allergic diseases
GB0328243D0 (en) 2003-12-05 2004-01-07 Astrazeneca Ab Methods
SE0400208D0 (en) 2004-02-02 2004-02-02 Astrazeneca Ab Chemical compounds
WO2005105841A2 (en) 2004-03-12 2005-11-10 Human Genome Sciences, Inc. Human g-protein chemokine receptor (ccr5) hdgnr10
TW200610761A (en) 2004-04-23 2006-04-01 Astrazeneca Ab Chemical compounds
PE20090123A1 (en) 2004-09-13 2009-03-10 Ono Pharmaceutical Co A HETEROCYCLIC DERIVATIVE CONTAINING NITROGEN AND A DRUG CONTAINING THE SAME AS THE ACTIVE INGREDIENT
WO2006129679A1 (en) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Spiropiperidine compound and medicinal use thereof
US7790747B2 (en) * 2005-06-15 2010-09-07 Genzyme Corporation Chemokine receptor binding compounds
ES2397418T3 (en) 2005-07-21 2013-03-06 Astrazeneca Ab Piperidine derivatives
DK1942108T3 (en) 2005-10-28 2013-12-09 Ono Pharmaceutical Co Compound containing basic group and use thereof
ES2407115T3 (en) 2005-11-18 2013-06-11 Ono Pharmaceutical Co., Ltd. Compound containing a basic group and its use
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
MX2008011414A (en) 2006-03-10 2008-09-22 Ono Pharmaceutical Co Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient.
JP5257068B2 (en) 2006-05-16 2013-08-07 小野薬品工業株式会社 Compound containing acidic group which may be protected and use thereof
US20090325992A1 (en) 2006-07-31 2009-12-31 Ono Pharmaceutical Co., Ltd. Compound having cyclic group bound thereto through spiro binding and use thereof
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration
US8592395B2 (en) 2009-07-24 2013-11-26 Glaxosmithkline Llc Therapeutic compounds
EP2741777B1 (en) 2011-08-12 2017-01-18 INSERM - Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for treatment of pulmonary hypertension
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
EP3233077A4 (en) 2014-12-19 2018-08-08 The Broad Institute Inc. Dopamine d2 receptor ligands
US10953003B2 (en) 2015-12-14 2021-03-23 X4 Pharmaceuticals, Inc. Methods for treating cancer
WO2017106332A1 (en) 2015-12-14 2017-06-22 X4 Pharmaceuticals, Inc. Methods for treating cancer
WO2017112894A1 (en) 2015-12-22 2017-06-29 X4 Pharmaceuticals, Inc. Methods for treating immunodeficiency disease
US11337969B2 (en) 2016-04-08 2022-05-24 X4 Pharmaceuticals, Inc. Methods for treating cancer
CA3027498A1 (en) 2016-06-21 2017-12-28 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof
CA3027495A1 (en) 2016-06-21 2017-12-28 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof
WO2017223243A1 (en) 2016-06-21 2017-12-28 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof
US10548889B1 (en) 2018-08-31 2020-02-04 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
CN110483490B (en) * 2019-08-29 2023-02-03 苏州汉德创宏生化科技有限公司 Synthesis method of 3- (piperidine-4-yl) oxazolidine-2-ketone and salt thereof
JP2023517956A (en) 2020-03-10 2023-04-27 エックス４ ファーマシューティカルズ， インコーポレイテッド Methods of treating neutropenia
US11629196B2 (en) 2020-04-27 2023-04-18 Incelldx, Inc. Method of treating SARS-CoV-2-associated hypercytokinemia by administering a human monoclonal antibody (PRO-140) that inhibits CCR5/CCL5 binding interactions

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9100505D0 (en) * 1991-01-10 1991-02-20 Shell Int Research Piperidine derivatives
GB9321557D0 (en) * 1992-11-03 1993-12-08 Zeneca Ltd Carboxamide derivatives
GB9310713D0 (en) * 1993-05-24 1993-07-07 Zeneca Ltd Aryl substituted heterocycles
FR2719311B1 (en) * 1994-03-18 1998-06-26 Sanofi Sa Compounds that are selective antagonists of the human NK3 receptor and their use as drugs and diagnostic tools.
US5434158A (en) * 1994-04-26 1995-07-18 Merck & Co., Inc. Spiro-substituted azacycles as neurokinin-3 antagonists
GB9502644D0 (en) * 1995-02-10 1995-03-29 Zeneca Ltd Heterocyclic derivatives
JP2000504677A (en) * 1996-02-09 2000-04-18 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー Sulfonamide derivatives for 5HT7 receptor antagonists
US5789422A (en) * 1996-10-28 1998-08-04 Schering Corporation Substituted arylalkylamines as neurokinin antagonists
IL125658A0 (en) * 1997-08-18 1999-04-11 Hoffmann La Roche Ccr-3 receptor antagonists

Also Published As

Publication number Publication date
WO1999004794A1 (en) 1999-02-04
EP1003514A4 (en) 2000-10-11
EP1003514A1 (en) 2000-05-31
CA2296314A1 (en) 1999-02-04
JP2002510327A (en) 2002-04-02

Similar Documents

Publication Publication Date Title
AU8576098A (en) Cyclic amine modulators of chemokine receptor activity
US6136827A (en) Cyclic amine modulations of chemokine receptor activity
US6476054B1 (en) Cyclic amine modulators of chemokine receptor activity
US6166037A (en) Pyrrolidine and piperidine modulators of chemokine receptor activity
WO1999038514A1 (en) Cyclic amine modulators of chemokine receptor activity
US6303593B1 (en) 3-thienyl and 3-furanyl pyrrolidine modulators of chemokine receptor activity
US6362201B1 (en) 3-cyclopropyl and 3-cyclobutyl pyrrolidine modulators of chemokine receptor activity
US6013644A (en) Spiro-substituted azacycles as modulators of chemokine receptor activity
US6489354B1 (en) 3-alkyl substituted pyrrolidine modulators of chemokine receptor activity
US6124319A (en) 3,3-disubstituted piperidines as modulators of chemokine receptor activity
US5962462A (en) Spiro-substituted azacycles as modulators of chemokine receptor activity
CA2298813A1 (en) Pyrrolidine and piperidine modulators of chemokine receptor activity
CA2278309A1 (en) 3,3-disubstituted piperidines as modulators of chemokine receptor activity
WO1998025604A1 (en) Spiro-substituted azacycles as modulators of chemokine receptor activity
US6498161B1 (en) Pyrrolidine modulators of chemokine receptor activity
WO1998025617A1 (en) Substituted aryl piperazines as modulators of chemokine receptor activity
US6511994B2 (en) Modulators of CCR5 chemokine receptor activity
US6372764B1 (en) Pyrrolidine modulators of chemokine receptor activity
WO1998025605A1 (en) Spiro-substituted azacycles as modulators of chemokine receptor activity
US6500844B1 (en) Cyclopentyl modulators of chemokine receptor activity
WO2000076514A1 (en) Cyclopentyl modulators of chemokine receptor activity
US6506777B1 (en) Cyclopentyl modulators of chemokine receptor activity
US6472410B1 (en) N-cyclopentyl modulators of chemokine receptor activity
US6538002B1 (en) Cyclopentyl modulators of chemokine receptor activity
EP1192133B1 (en) N-cyclopentyl modulators of chemokine receptor activity

Legal Events

Date Code Title Description
MK5 Application lapsed section 142(2)(e) - patent request and compl. specification not accepted