WO2004010943A2 - Benzanilides substitues utilises comme modulateurs du recepteur ccr5 - Google Patents

Benzanilides substitues utilises comme modulateurs du recepteur ccr5 Download PDF

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WO2004010943A2
WO2004010943A2 PCT/US2003/023524 US0323524W WO2004010943A2 WO 2004010943 A2 WO2004010943 A2 WO 2004010943A2 US 0323524 W US0323524 W US 0323524W WO 2004010943 A2 WO2004010943 A2 WO 2004010943A2
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carboxamide
methoxyphenyl
piperidinyl
galkyl
biphenyl
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WO2004010943A3 (fr
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William E. Bondinell
Michael J. Neeb
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon 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
    • C07D211/08—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
    • C07D211/08—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
    • C07D211/26—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 nitrogen 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
    • C07D211/08—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
    • C07D211/34—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring 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
    • C07D401/12—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 chain containing hetero atoms as chain links

Definitions

  • This invention relates to substituted benzanilides which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8).
  • this invention relates to the treatment and prevention of disease states mediated by CCR5.
  • T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases.
  • Increased numbers or enhanced activation state of T cells, especially CD4+ T cells have been demonstrated in the synovium of individuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci.
  • T cells as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors.
  • chemokines a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues.
  • RANTES which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors.
  • the CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991).
  • RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells.
  • RANTES was originally identified as gene product induced late after antigen activation of T-cells (TJ. Schall, J. Jongstra, BJ. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include epithelial and endothelial cells (C. Stellato, L.A. Beck, G.A. Gorgone, D. Proud, et al., J. Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devergne, G. Gorgone, A. Portier, et al., J.
  • RANTES mRNA is rapidly upregulated in response to IL-1 or TNFv
  • RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1- 1995)
  • increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate.
  • RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P J. Nelson, and A.M. Krensky, Clin. Immunother.
  • CCR5 when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells that are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
  • T cells express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans.
  • atopic disorders for example, atopic dermatitis and allergies
  • sarcoidosis for example, atopic dermatitis and allergies
  • idiopathic pulmonary fibrosis and other fibrotic diseases for example, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans.
  • CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
  • Patent 3,931,195 issued Jan. 6, 1976; and U.S. Patent 4,000,143, issued Dec. 28, 1976.
  • WO 99/01127, published January 14, 1999 discloses substituted benzanilides useful for modulating CCR5-mediated diseases.
  • the present invention is to novel compounds of formula (I) and their use as CCR5 modulators for the treatment and or prophylaxis of certain disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans.
  • the preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.
  • the present invention is directed to a method of preventing or treating CCR5-mediated diseases in a mammal, preferably a human, by administering to the mammal an effective amount of a CCR5 receptor ligand, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention is directed to methods for making and using the compounds of formula (I), as well as pharmaceutical compositions of formula (I) or a pharmaceutically acceptable salts or solvates thereof.
  • the present invention is directed to the use of a CCR5 receptor ligand in the manufacture of a medicament for the prophylaxis or treatment of certain disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, for example in a mammal such as a human.
  • COPD COPD
  • asthma and atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic
  • the present invention is directed to a CCR5 receptor ligand, or a pharmaceutically acceptable salt, or solvate thereof, for use in the prophylaxis or treatment of certain disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, for example in a mammal such as a human.
  • COPD COPD
  • asthma and atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • sarcoidosis or idiopathic pulmonary fibrosis and other fibrotic diseases
  • atherosclerosis
  • the present invention is also directed to combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory disorders or diseases, including asthma and allergic diseases, as well as rheumatoid arthritis and atherosclerosis, and those pathologies noted above, and is illustrated by the combination of the compounds of this invention and other compounds which are know for such utilities.
  • the present invention is further directed to combinations of the present compounds of formula (I) with one or more agents useful in the prevention or treatment of AIDS.
  • the compounds of this invention may be effectively administered, whpther at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to the skilled artisan.
  • substituted benzanilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt or solvate thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, preferably humans.
  • atopic disorders for example, atopic dermatitis and allergies
  • sarcoidosis or idiopathic pulmonary fibrosis and other fibrotic diseases
  • atherosclerosis psoriasis
  • CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a co-receptor for entry into cells, selective receptor modulators may be useful in the treatment of HTV infection.
  • Compounds of formula (I) for use herein as CCR5 modulators include the 5- HT ligands as described in international application publication number WO 95/15954, published 15 June 1995, (U.S.S.N. 08/652,581, filed June 7, 1996); international application publication number WO 95/17398, published 29 June 1995, (U.S.S.N. 08/663,291, filed June 21, 1996); international application publication number WO 95/26328, published 5 October 1995, (USSN 08/718,481, filed Sept. 26, 1996); international application publication number WO 96/06079, published 29 February 1996, (USSN 08/793,428, filed Feb.
  • Preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.
  • a preferred group of compounds for use herein are those compounds of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof:
  • Ar represents a group selected from (i), (ii) or (iii); wherein: the basic nitrogen in moiety E may be optionally quaternized with Ci.galkyl or is optionally present as the N-oxide; R 1 ' and R 2 ' are independently one or more of hydrogen, C ⁇ _6alkyl, C2- galkenyl, C2_6al ynyl, C3_7cycloalkyl, C . ⁇ cycloalkenyl, aryl, (CH2) NR 7 'R 8 ', (CH 2 ) a 'NR 7 'COR 9 ', (CH 2 )a'NR 7 'CO 2 R 10 ', (CH 2 )a'NR 7 'SO 2 R 11 ', (CH2)a'CONR 12 'R 13 ', hydroxyCi .galkyl, Ci ⁇ alkoxyalkyl (optionally substituted by a C ⁇ _4alkoxy or hydroxy group),
  • R ' and R ' are independently one or more of hydrogen, Cx.galkyl, 03. 7cycloalkyl, C ⁇ .gcycloalkenyl, hydroxyC ⁇ _6alkyl, C ⁇ . ⁇ alkylOC ⁇ . ⁇ alkyl, CONR 29 'R30', CO2R 31 ', cyano, aryl, trifluoromethyl, NR 29 'R30', nitro, hydroxy, C ⁇ _6alkoxy, acyloxy, or halogen;
  • R ⁇ ' is one or more of hydrogen, Cj.gaikyl, C _6alkoxy or halogen;
  • R ⁇ ' and R ⁇ ' form a fused benzo ring optionally substituted with C ⁇ _6 alkyl, Ci.galkoxy or halogen;
  • R 7 ' and R 8 ' are independently hydrogen or C ⁇ _galkyl, or together with the nitrogen to which they are attached, R 7 ' and R 8 ' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • R 9 ' is hydrogen, C ⁇ _6alkyl or Cj ⁇ alkoxy alkyl; R 10 ' is C ⁇ _6alkyl;
  • R! 1' is Cx.galkyl or phenyl
  • R! 2 ' and R ⁇ 3 ' are independently hydrogen or C ⁇ alkyl, or together with the nitrogen to which they are attached, R 12 ' and R ⁇ 3 ' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • Rl4' is C ⁇ _4alkyl, optionally substituted by C ⁇ _6alkoxy;
  • Rl5' and R ⁇ ' are independently hydrogen or C ⁇ _6alkyl
  • R 17 ' is hydrogen or C ⁇ _6alkyl
  • R! 8 ' is hydrogen or C ⁇ .galkyl
  • R ⁇ 9 ' and R 2 ⁇ ' are independently hydrogen or C ⁇ _6alkyl
  • R 2 !' is hydrogen or C ⁇ _6alkyl
  • R 22 ' is hydrogen or Ci .galkyl optionally substituted with one or two substituents selected from C ⁇ _galkyl, C ⁇ _6alkoxy, hydroxy, or NR 7 'R 8 ;
  • R 2 ' and R 2 4' are independently hydrogen or C ⁇ ..galkyl;
  • R 2 ⁇ ' and R ⁇ ' are independently hydrogen or Cx.galkyl, or together with the nitrogen to which they are attached, R 2 ⁇ ' and R 2 ⁇ ' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • R 27 ' is hydrogen or C ⁇ _6alkyl;
  • R 28 ' is C ⁇ _6alkyl
  • R 29 ', R30' and R31' are independently hydrogen or C ⁇ _ ⁇ alkyl
  • R3 2 is Cx.galkyl, hydroxyC ⁇ _6alkyl, or C ⁇ _4alkanoyl
  • R33' is hydrogen or C j .galkyl; R ' is hydrogen or C ⁇ _6alkyl;
  • R35' is hydrogen or C ⁇ _galkyl
  • R36' and R3 7 ' are independently hydrogen or C ⁇ _galkyl or together with the nitrogen to which they are attached, R 6' and R3 7 form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 43 ', wherein R 4 3' is Cx.galkyl, COR 44 ' or CO2R 4 ⁇ ', wherein R 44 ' and R45' are independently hydrogen or C ⁇ _6alkyl;
  • R3 8 ' is hydrogen or Ci.galkyl
  • R 39 ' is C ⁇ _ 6 alkoxy, CO 2 H, CO 2 C ⁇ _6alkyl or CONR 3 6'R37' ;
  • R40' is C ⁇ _ 6 alkyl;
  • R41' and R 42 ' are independently hydrogen or Cj.galkyl;
  • P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
  • a' is 1, 2, 3 or 4;
  • b' is O, 1, 2 or 3;
  • c' is 1, 2 or 3;
  • d' is 0, 1, 2, 3, 4, 5, or 6;
  • e' is 1, 2, 3, 4, 5 or 6; and further wherein, when Ar is (i), (ii) or (iii), and
  • A is CONR 46 ', NHCO, - NHCH2, or CH2NH, wherein R 4 ⁇ ' is hydrogen or C ⁇ _6alkyl, E represents a group (a):
  • R! and R 2 are independently hydrogen or C ⁇ _galkyl; alternatively is OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 ;
  • R3 and R 4 are independently hydrogen, C ⁇ _6alkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ alkyl, aryl, CONR ⁇ R 11 , NR 10 R n , hydroxy, OCOR 12 , NHCOCF3, NHSO 2 R 13 , NHCO 2 R 14 or NHCOC()-6alkyl wherein the alkyl of NHCOCQ. galkyl is optionally substituted by OH;
  • R 5 is hydrogen, C ⁇ _ 6 alkyl, aryl, CN, CONR 15 R 16 , CO 2 R 17 , trifluoromethyl, NHCO2R 18 , hydroxy, C ⁇ _6alkoxy, benzyloxy, OCH2C ⁇ 2C ⁇ _ 6 alkyl, OCF3, S(O) d R 19 , SO 2 NR 20 R 21 or halogen;
  • R 7 , R 8 , RlO, Rll, Rl 2 , Rl5, R16, R17, R20 5 R21 5 R22 S and R 23 are independently hydrogen or Cx.galkyl;
  • R 9 is hydrogen, Cx.galkyl, or phenylC ⁇ _6alkyl
  • R 13 , R 14 , R 18 , and R 19 are independently C ⁇ alkyl
  • a is 1, 2, 3, or 4
  • b is 1 or 2
  • c and d are independently 0, 1 or 2
  • e is 2, 3 or 4
  • f is O, 1, 2 or 3
  • Ar is (i), (ii) or (iii)
  • A is CONR 46 ', NHCO, or CH2NH, wherein R 4 ⁇ ' is hydrogen or C _galkyl, alternatively, E represents a group (b):
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are independently hydrogen or C ⁇ _galkyl;
  • R 0 is hydrogen, Cx.galkyl, or C3_7cycloalkyl
  • J is oxygen, CR 36 R 37 , or NR38 ? or J is a group S(O)k;
  • R34 ; 35 5 36 5 R37 ; anc ⁇ R38 are independently hydrogen or Cx.galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is O, 1, 2, or 3; k is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, -
  • R3 and R40 are independently hydrogen or Cx.galkyl;
  • R41 is a group of formula (d):
  • R41 is a group of formula (e):
  • R 42 is hydrogen, Ci .galkyl, aryl, CN, CONR 4 8R49 ; c ⁇ 2 R 50 , trifluoromethyl, NHCO2R ⁇ 1 , hydroxy, C ⁇ _galkoxy, benzyloxy, OCH2CO2CX. galkyl, OCF3, S(O) s R 52 , SO 2 NR 53 R 5 , or halogen;
  • R47 is hydrogen, C ⁇ .galkyl, or 03.7 cycloalkyl;
  • R51 and R ⁇ 2 are independently C .galkyl;
  • l is O, 1, 2, or 3;
  • m is 1 or 2;
  • n is O, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3;
  • r is 0,1, 2, or 3;
  • s is O, 1, or 2;
  • t is 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONH, NHCO, or CH 2 NH, alternatively, E represents a group (f):
  • R ⁇ 7 and R ⁇ 8 are independently hydrogen or O ⁇ .galkyl;
  • R ⁇ 9 and R ⁇ O are independently hydrogen, C .galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ .galkyl, aryl, CONR 61 R 62 , NR 61 R 62 , hydroxy, OCOR 63 , NHCOCF3, NHSO 2 R 64 , NHCO 2 R 65 , or NHCOC 0 .galkyl wherein the alkyl of NHCOCQ.galkyl is optionally substituted by OH;
  • T is -(CR 66 R 67 ) V - or -O(CR 66 R 67 ) w -;
  • R 61 , R 62 , R 63 , R 66 , R 67 R 68 , R 69 , and R 70 are independently hydrogen or
  • R64 and R65 are independently O ⁇ .galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46' 5 NHCO, or CH2NH, wherein R4 ' ⁇ s hydrogen or C ⁇ .galkyl, alternatively, E represents a group (g):
  • R 71 is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R 7i is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of O .galkyl and optionally substituted on nitrogen with hydrogen, C ⁇ _ galkyl or C3_7cycloalkyl;
  • R 72 is hydrogen, C ⁇ _galkyl, aryl, CN, CONR 74 R 75 , c ⁇ 2 R 76 , trifluoromethyl, NHCO2R 77 , hydroxy, C ⁇ .galkoxy, benzyloxy, OCH2CO 2 C ⁇ . galkyl, OCF3, S(O) z R 78 , SO 2 NR 79 R 80 , or halogen;
  • R 77 and R 7 are independently C ⁇ _galkyl; y is 1 or 2; z is O, l, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR 4 ⁇ ', NHCO, or CH2NH, wherein R 4 "' is hydrogen or C ⁇ .galkyl, alternatively, E represents a group (h):
  • R 83 and R 84 are independently hydrogen or C ⁇ _galkyl;
  • R * and R 8 ° are independently hydrogen, C ⁇ _galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ _galkyl, aryl, CONR 88 R 89 , NR 90 R 91 , hydroxy, OCOR 92 , NHCOCF3, NHSO 2 R 93 , NHCO 2 R 94 , or NHCOC 0 .galkyl wherein the alkyl of NHCOCo-galkyl is optionally substituted by OH;
  • Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
  • R 88 , R 89 , R 90 , R 91 , R 92 , R 95 , and R 96 are independently hydrogen or C ⁇ _ galkyl;
  • R 93 and R 9 4 are independently C ⁇ .galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, or CH2NH, wherein R 4 6' is hydrogen or Cx .galkyl, alternatively, E represents a group (i): wherein:
  • R 97 and R 98 are independently hydrogen, C ⁇ .galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ .galkyl, aryl, CONR 102 R 103 , NR 104 R 105 , hydroxy, OCOR 106 , NHCOCF3, NHSO 2 R 107 , NHCO 2 R 108 , or NHCOC 0 -galkyl wherein the alkyl of NHCOCQ-galkyl is optionally substituted by OH; R 99 and R l00 are independently hydrogen or C ⁇ _ga ky ⁇ ;
  • AC is oxygen, CR 1 1 ⁇ R 112 or NR 113 or AC is a group S(O)ak;
  • RlO 2 Rl03 , R104 R 105, R 106, R 109 R110, R l 11, R l 12 an d Rl I 3 are independently hydrogen or O ⁇ .galkyl;
  • Rl07 and R ⁇ 0 are independently C _ga ky ⁇ ; afis O, 1, 2, 3, or 4; ag is 1, 2, or 3; ah is 1, 2, 3 or 4; ai is 2, 3 or 4; aj is O, 1, 2, or 3; and ak is 0, 1 or 2.
  • Ar is (i),(ii), or (iii).
  • Ar is (i) or (ii).
  • the terminal phenyl group in (i) and (ii) can be attached to the phenyl group bearing group A in any position.
  • the terminal phenyl ring is attached to the phenyl bearing group A in a position meta or para to group A.
  • R 1 ' and R 2 ' are independently one or more of hydrogen, C ⁇ _galkyl, C 2 _ galkenyl, C2_galkynyl, C3_7cycloalkyl, C3_gcycloalkenyl, aryl, (CH2) a NR 7 'R 8 ', (CH 2 ) a 'NR 7 'COR 9 ', (CH2) a 'NR 7 'CO2R 10 ', (CH2)a'NR 7 'SO2R n ', (CH 2 ) a !
  • R 1 ' and R 2 ' are independently one or more of hydrogen, C ⁇ _ galkyl, hydroxyC ⁇ .galkyl, COR 17 ', CONR 12 'R 13 ', CO 2 R 22 ', cyano, trifluoromethyl, NR 7 'R 8 ', NR 7 'COR 9 ', NR 2 3'C0NR 23 'R 24 ', NR 7 'SO2R n ', nitro, hydroxy, C ⁇ .galkoxy, SO2R 28 ', SO2NR 25 'R 26 ', or halogen.
  • R3' and R 4 ' are independently one or more of hydrogen, C ⁇ .galkyl, C3_7cycloalkyl, C3_gcycloalkenyl, hydroxyC ⁇ .galkyl, C ⁇ _galkylOC ⁇ . alkyl, CONR 29 'R30', CO 2 R 31 ', cyano, aryl, trifluoromethyl, NR 29 'R30', nitro, hydroxy, C ⁇ _galkoxy, acyloxy, or halogen.
  • R ⁇ ' is one or more of hydrogen, C ⁇ .galkyl, C ⁇ _galkoxy or halogen.
  • R 7 ' and R 8 ' are independently hydrogen or C ⁇ .galkyl, or together with the nitrogen to which they are attached, R 7 ' and R 8 ' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
  • R 9 ' is hydrogen, C ⁇ _galkyl or C _4alkoxy alkyl.
  • R 10 ' is C ⁇ .galkyl.
  • R 11 ' is C ⁇ _galkyl or phenyl.
  • R 12 ' and R* 3 ' are independently hydrogen or C ⁇ _galkyl, or together with the nitrogen to which they are attached, R 12 ' and R 13 ' form a 5- to 6- membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
  • R 14 ' is C ⁇ _4alkyl, optionally substituted by C ⁇ _galkoxy.
  • R ⁇ ' and R 16 ' are independently hydrogen or C ⁇ _galkyl.
  • R 1 ⁇ is hydrogen or C ⁇ _galkyl.
  • R 18 ' is hydrogen or C ⁇ _galkyl.
  • R 19 ' and R 20 ' are independently hydrogen or C ⁇ _galkyl.
  • R 21 ' is hydrogen or C ⁇ .galkyl.
  • R 22 ' is hydrogen or C ⁇ .galkyl optionally substituted with one or two substituents selected from C ⁇ _galkyl, C ⁇ _galkoxy, hydroxy, or NR 7 'R 8 '.
  • R 23 ' and R 24 ' are independently hydrogen or O ⁇ .galkyl.
  • R 2 ⁇ ' and R 26 ' are independently hydrogen or C ⁇ _galkyl, or together with the nitrogen to which they are attached, R ⁇ ' and R 26 ' form a 5- to 6- membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
  • R 27 ' is hydrogen or C ⁇ _galkyl.
  • R 28 ' is Cx .galkyl.
  • R 29 ', R 30 ' and R 31 ' are independently hydrogen or C ⁇ _galkyl.
  • R 32 ' is C x .galkyl, hydroxyC x .galkyl, or C x _4alkanoyl.
  • R 33 ' is hydrogen or C ⁇ _galkyl.
  • R34' is hydrogen or C ⁇ .galkyl.
  • R35' is hydrogen or C .galkyl.
  • R36' and R37' are independently hydrogen or C ⁇ .galkyl or together with the nitrogen to which they are attached, R36' and R37' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 3', wherein R4 ' is O ⁇ .galkyl, COR44' or CO2R45', wherein R 44 ' and R 4 ⁇ ' are independently hydrogen or O ⁇ .galkyl.
  • R3 ' is hydrogen or C x .galkyl.
  • R 9 ' is C ⁇ _galkoxy, CO 2 H, CO 2 C ⁇ .galkyl or CONR 36 R 37 '.
  • R4 1 ' and R 42 ' are independently hydrogen or C ⁇ .galkyl.
  • P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur
  • suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl.
  • Saturated and partially saturated rings are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams.
  • the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom.
  • Suitable substituents for these rings include one or more of R4 .
  • P is l,2,4-oxadiazol-3-yl wherein R 4 'is 5-methyl, or tetrazol-5-yl.
  • a' is 1, 2, 3 or 4.
  • b' is 0, 1, 2 or 3.
  • c' is 1, 2 or 3.
  • d' is 0, 1, 2, 3, 4, 5, or 6.
  • e' is 1, 2, 3, 4, 5 or 6.
  • substituent E is selected from the following groups:
  • Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, -NHCH 2 , or CH2NH, wherein R46' i s hydrogen or C ⁇ .galkyl, E suitably represents a group (a):
  • B is preferably CR 7 R 8 , or oxygen.
  • R 1 and R 2 are suitably independently hydrogen or C ⁇ _galkyl.
  • R 1 and R 2 are hydrogen.
  • B(CR 1 R 2 ) a is OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 .
  • B(CR!R 2 ) a is OCRiR ⁇ R ⁇ O ⁇ CRiR 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2
  • R 1 and R 2 are hydrogen.
  • R3 and R 4 are suitably independently hydrogen, C ⁇ .galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ .galkyl, aryl, CONR ⁇ R 11 , NR 10 R n , hydroxy, OCOR 12 , NHCOCF3, NHSO 2 R 13 , NHCO2R 14 , or NHCOCo-galkyl wherein the alkyl of NHCOCo-galkyl is optionally substituted by OH.
  • R 3 and R 4 are both Cx .galkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur.
  • B-(CR 1 R 2 ) a -NR 3 R 4 is ortho to R 5 , meta to A and para to R 6 , and R ⁇ is para to A.
  • R 5 is suitably hydrogen, C ⁇ _galkyl, aryl, CN, CONR 15 R 16 , CO2R 17 , trifluoromethyl, NHCO2R 18 , hydroxy, C ⁇ _galkoxy, benzyloxy, OCH2CO 2 C ⁇ _ galkyl, OCF3, S(O)dR 19 , SO2NR 20 R 21 , or halogen.
  • R 5 is preferably C ⁇ .galkoxy, SC ⁇ _galkyl or halogen.
  • R 6 is hydrogen.
  • R 7 , R 8 , RlO, Rll, R 12 , Rl5, Rl6, R17, R20, R 21, R 22, and R 2 3 are suitably independently hydrogen or O ⁇ .galkyl.
  • R 9 is suitably hydrogen, C ⁇ .galkyl, or phenylC ⁇ . galkyl.
  • R13, R14, R18, and R 19 are suitably independently C ⁇ . galkyl.
  • a is suitably 1, 2, 3, or 4.
  • b is suitably 1 or 2.
  • b is 1.
  • c and d are suitably independently 0, 1, or 2.
  • e is suitably 2, 3, or 4.
  • f is suitably 0, 1, 2, or 3.
  • Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, or CH2NH, wherein R 46 ' is hydrogen or C .galkyl, E suitably represents a group (b):
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are suitably independently hydrogen or C ⁇ .galkyl.
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , and R 32 are preferably hydrogen.
  • R 0 is suitably hydrogen, O ⁇ .galkyl, or C3_7cycloalkyl.
  • R30 is Cx .galkyl or C3_7cycloalkyl.
  • R3 is suitably hydrogen, C ⁇ _galkyl, trifluoromethyl, hydroxy or halogen, or R33 and R 46 ' together form a group -K- where K is (CR 34 R35) i or K is (CR34R35)J .
  • R33 is hydrogen.
  • J is suitably oxygen, CR36R37, or NR3 8 , or J is a group S(O) ⁇ ⁇ .
  • J is oxygen.
  • J is para to A.
  • R 4, R 5, R36, R37, R38 are suitably independently hydrogen or C ⁇ _galkyl.
  • g is suitably 1, 2, or 3.
  • h is suitably 1, 2, or 3.
  • h is 1.
  • i is suitably 2, 3, or 4.
  • j is suitably 0, 1, 2, or 3.
  • k is suitably 0, 1 or 2.
  • Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, -
  • E suitably represents a group (f):
  • R ⁇ 7 and R ⁇ 8 are independently hydrogen or O ⁇ .galkyl; suitably R ⁇ 9 and R 60 are independently hydrogen, C ⁇ _galkyl, C3_7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C ⁇ .galkyl, aryl, CONR 61 R 62 , NR 61 R 62 , hydroxy, OCOR 63 , NHCOCF3, NHSO 2 R 64 , NHCO R 65 or NHCOC 0 .galkyl wherein the alkyl of NHCOCo-galkyl is optionally substituted by OH, and wherein R 61 , R 62 , and R 63 are independently hydrogen or Cx .galkyl, and R 6 4 and R 6 ⁇ are independently C .galkyl; suitably, T is -(
  • R 71 is an optionally substituted 5- to 7-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and optionally a further one or two heteroatoms selected from nitrogen, oxygen or sulfur, or R 7 is an optionally substituted 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of C .galkyl, and substituted on nitrogen with hydrogen, C .galkyl, or C3_7cycloalkyl.
  • R 71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and is substituted on nitrogen with C ⁇ _ galkyl or C3_7cycloalkyl.
  • R 1 is preferably located meta to A, ortho to R 72 and para to R 73 , and R 72 is located para to A.
  • R 72 is hydrogen, C ⁇ .galkyl, aryl, CN, CONR 74 R 75 , CO 2 R 76 , trifluoromethyl, NHCO2R 77 , hydroxy, C ⁇ .galkoxy, benzyloxy, OCH2C ⁇ 2C ⁇ _ galkyl, OCF3, S(O) z R 78 , SO 2 NR 79 R 80 , or halogen wherein R 74 , R 75 , R 76 , R 79 and R 80 are independently hydrogen or C ⁇ .galkyl, R 77 and R 78 are C ⁇ _galkyl, and z is 0, 1, or 2.
  • R 72 is preferably C ⁇ _galkoxy, SO ⁇ .galkyl or halogen.
  • R 73 is hydrogen.
  • y is an integer from 1-2. Preferably, y is 1.
  • Ar is (i), (ii) or (iii), and A is CONR 6 ', NHCO, or CH2NH, wherein R4 6 ' is hydrogen or C ⁇ .galkyl
  • E suitably represents a group (h):
  • Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, or CH 2 NH, wherein R 46 ' is hydrogen or C ⁇ .galkyl, E suitably represents a group (i):
  • OCOR 106 NHCOCF3, NHSO 2 R 107 , NHCO 2 R 108 , or NHCOC 0 .galkyl wherein the alkyl of NHCOCo-galkyl is optionally substituted by OH, and wherein R 102 , R103, R104 R105 and R 106 are independently hydrogen or C ⁇ _galkyl, and R 107 and R 108 are independently Cl-6alkyl; suitably, R 99 and R 00 are independently hydrogen or C ⁇ .galkyl; suitably, AC is oxygen, CR 1 !
  • R111 , R112 a d R 113 are independently hydrogen or C ⁇ _galkyl or AC is a group S(O)ak wherein ak is 0, 1 or 2; suitably, ag is an integer from 1-3, ah is an integer from 1-4, and af is 0-4.
  • A is CONR 46 ', NHCO, or CH 2 NH, wherein R 46 ' is hydrogen. More preferably, A is CONR4 6 ' or NHCO, wherein R4 ' is hydrogen. Most preferably, A is CONR 46 ', wherein R 46 ' is hydrogen.
  • Ar is (i), (ii), or (iii)
  • E represents group (a), (b), or (g). More preferably, when Ar is (i), (ii) or (iii), E represents group (g).
  • E represents group (g). More preferably, when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A.
  • R 1 ' and R 2 ' are independently one or more of hydrogen, methyl, hydroxymethyl, acetyl, carbamoyl, ethoxycarbonyl, cyano, trifluoromethyl, amino, methylamino, butylamino, dimethylamino, acetamido, uriedo, (dimethylamino)carbonylamino, methanesulfonamido, nitro, hydroxy, methoxy, ethoxy, isopropoxy, methanesulfonyl, sulfamoyl, chloro or fluoro.
  • A is attached to group (a) meta to B- (CR 1 R 2 ) a -NR 3 R 4 and para to (R 5 )b, wherein B is oxygen or CR 7 R 8 , R 1 and R 2 are hydrogen, R ⁇ is methoxy, methylthio or iodo, R3 and R 4 are independently C3_ galkyl, or R3 and R 4 taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted with one or more of O ⁇ .galkyl and acetamido or hydroxyl, R 6 is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, and b is 1.
  • A is attached to group (a) meta to B- (CR 1 R 2 ) a -NR 3 R 4 and para to (R 5 )b, wherein B is oxygen or CH2, R 1 and R 2 are hydrogen, R is methoxy, R3 and R 4 are independently isopropyl or tert-butyl, or R3 and R 4 taken together with the nitrogen to which they are attached are 1 -(2,2,6,6- tetramethylpiperidinyl), l-(4-acetamido-2,2,6,6-tetramethyl piperidinyl), l-(4- hydroxy-2,2,6,6-tetramethyl piperidinyl) or l-(4-hydroxy-2,2,4,6,6- (pentamethyl)piperidinyl), R 6 is hydrogen, a is 2 when B is oxygen, and b is 1.
  • E is group (b) A is attached to group (b) para to J, J is oxygen, R 33 is hydrogen, R 24 , R 5, R26, R27, R28, R29, R31 and R 32 are hydrogen, R 30 is C3_galkyl, g is 2 and h is 1.
  • R 3 3 is hydrogen, R 24 , R 2 5, R26, R27, R28, R29, R31 and R 32 are hydrogen, R3° is isopropyl, g is 2 and h is 1.
  • R 71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_galkyl or C3_7cycloalkyl
  • R 72 is methoxy, methylthio or iodo
  • y is 1
  • R 7 3 is hydrogen.
  • E is group (g)
  • A is attached to group (g) meta to R 71 and para to R 72 wherein R 71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, or cyclopentyl, R 72 is methoxy, y is 1, and R 7 3 is hydrogen.
  • a particularly effective subgenus of compounds of formula (I) is wherein: Ar is (i) or (ii), E is group (g), and A is CONR4 6 ' and R4 ' is hydrogen, and further wherein, A is attached to group (g) meta to R 71 and para to R 72 , and wherein R 71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, or cyclopentyl, R 72 is methoxy, y is 1, and R 7 3 is hydrogen.
  • acyloxy is used herein at all occurrences to mean a moiety -O-C(O)-R, wherein R is hydrogen or C ⁇ _galkyl as defined below.
  • C ⁇ _4alkanoyl is used herein at all occurrences to mean a - C(O)C ⁇ -4alkyl group wherein the alkyl portion is as defined below.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl, and the like.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • C ⁇ .galkoxyC ⁇ .galkoxy is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
  • C ⁇ _4alkoxy alkyl is used herein at all occurrences to mean a C ⁇ _
  • C ⁇ .galkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
  • aralkyl is used herein at all occurrences to mean an aryl moiety as defined above, which is connected to an alkyl moiety as defined below, including, but not limited to, benzyl or phenethyl, and the like.
  • aryl is used herein at all occurrences to mean a 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to, phenyl, naphthalenyl, biphenyl, phenanthryl, anthracenyl, and the like.
  • 6,6 or 6,5 bicyclic ring is used herein at all occurrences to mean a 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen, or sulfur, which ring system may be optionally substituted with C ⁇ _galkyl.
  • ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings.
  • cycloalkenyl is used herein at all occurrences to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkyl and “cyclic alkyl” are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4- tetrahydronaphthalenyl, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • heteroaryl is used herein at all occurrences to mean a 5-14- membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like.
  • hydroxyC ⁇ _galkoxy is used herein at all occurrences to mean an hydroxyl group bonded to an alkoxy group as defined above, including, but not limited to, -O-CH 2 -CH(OH)CH 3 and the like.
  • hydroxyC ⁇ .galkyl and "hydroxyalkyl” are used herein interchangeably to mean an hydroxyl group bonded to a C .galkyl group as defined above, including, but not limited to, methanol, ethanol, n-propanol, isopropanol, n- butanol, sec-butanol, isobutanol, tert-butanol, and the like.
  • heterocyclic ring is used herein at all occurrences to mean a saturated or, wholly or partially saturated, 5-10-membered ring system (unless the cyclic ring system is otherwise limited) wherein the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with C ⁇ _ galkyl.
  • examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine, pyrrolidine, piperidine, morpholine, imidazolidine, pyrazolidine, hexahydroazepine, tropane, isoquinuclidine, granatane, and the like.
  • heterocyclic ring When the heterocyclic ring is fused to a phenyl group, as when E is the group (h), the term "heterocyclic ring", together with the phenyl ring to which it is fused, forms a ring which includes, but is not limited to, dihydro-l,4-benzoxazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,6-tetrahydropyridine, and hexahydroazepine, which may be optionally substituted by O ⁇ .galkyl or oxo.
  • heteroatom is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom. It will be recognized that when the heteroatom is nitrogen, it may form an NR a or NR a b moiety, wherein R a and Rb are, independently, hydrogen or Ci to Cg alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • optionally substituted is used herein at all occurrences to mean an optionally substituted 5- to 7-membered heterocyclic ring wherein the optional substituents are one or more of C .galkyl.
  • CCR5 mediated disease state is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
  • pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate, and stearate.
  • inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate
  • an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate, and stearate.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms.
  • the stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention.
  • the preferred compounds of the invention are the following compounds:
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient”) in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, ("CCR5-mediated disease states”) with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art.
  • atopic disorders for example, atopic dermatitis and allergies
  • sarcoidosis for example, atopic dermatitis and allergies
  • idiopathic pulmonary fibrosis and other fibrotic diseases for example, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCR5 mediated disease states.
  • the amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician.
  • a suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
  • topical administration non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • the topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the active ingredient may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
  • this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound as depicted in formula (I).
  • treating is meant either prophylactic or therapeutic therapy.
  • Such formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the formula (I) compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, in an amount sufficient to decrease symptoms associated with these disease states.
  • the route of administration may be oral or parenteral.
  • the invention relates to a method for modulating factors which exacerbate the symptoms of the CCR5-mediated diseases described herein.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient.
  • the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a formula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques.
  • the compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
  • compounds of formula (I) wherein A is NR 46 ' are synthesized from an appropriately substituted benzoic acid, for example 1-1, and an appropriately substituted aniline 1-2 by treatment with a suitable coupling reagent, for example benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate, and a suitable base, for example dusopropylethylamine, in a suitable solvent, for example acetonitrile, to afford the title compound 1-3.
  • a suitable coupling reagent for example benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • a suitable base for example dusopropylethylamine
  • a suitable solvent for example acetonitrile
  • E is a group of formula (i) are prepared according to the methods of international application publication number WO 97/19070 published 29 May 1997.
  • Nitric acid (70%, 3.1 mL) was added portionwise to a solution of the compound of Preparation 1(d) (5.0 g, 17 mmol) in acetic anhydride (17 mL) at 0°C.
  • the mixture was maintained at 0°C for an additional 30 min, combined with an identical concurrently run reaction, and poured into water (600 mL).
  • the pH of the resultant mixture was adjusted to >9 by the addition of aqueous sodium carbonate followed by 10% sodium hydroxide.
  • Preparation 6 Preparation of 3-r 2,3,6-Tetrahydro-l-(l-methylethyl)-4-pyridinyl]-4- methoxyaniline a) l,2,3,6-tetrahydro-4-(2-methoxyphenyl)-l-(trifluoroacetyl)piperidine Following the general procedure of Preparation 1(d), except substituting the compound of Preparation 1(b) for the compound of Preparation 1(c), gave the title compound. b) 1 ,2,3,6-tetrahydro-4-(2-methoxy-5-nitrophenyl)-l- (trifluoroacetyl)piperidine
  • Preparation 7 Preparation of 3-lT-(l -Methylethy l)-3 -pyrrolidinyll -4-methoxyaniline a) l-benzyl-3-hydroxy-3-(2-methoxyphenyl)pyrrolidine Following the general procedure of Preparation 1(a), except substituting 1- benzyl-3-pyrrolidinone for tert-butyl 4-oxo-l-piperidinecarboxylate, gave the title compound. MS(ES) m/e 284.2 [M+H]+.
  • Examples 10-53 A mixture of a solution of the compound of Preparation 2 in dimethylformamide (0.188M, 0.8 mL, 0.15 mmol), a solution of an appropriately substituted aryl bromide in dimethylformamide (IM, 0.3 mL.
  • CCR5 Receptor Binding Assay CHO cell membranes (0.25 xlO 6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125 I-RANTES in a 96 well plate for 45 min. at room temperature (final reaction volume 200 ul). The reaction was terminated by filtration and the filters (GF/C) were washed twelve times with a solution of phosphate buffered saline containing 0.1 % bovine serum albumin and 0.05 % NaN3. The radioactivity bound to filters was measured by liquid scintillation spectrometry. Non-specific binding was determined in the presence of unlabelled RANTES (10 or 30 nM) and averages 30-50% of total binding.
  • CCR5 Receptor Functional Assay CHO cell membranes (0.25 xlO 6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125 I-RANTES in a 96 well plate for 45 min
  • the cellular functional assay used to assess antagonist activity of compounds was RANTES -induced Ca 2+ mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5).
  • Agonist activity is determined by Ca 2 + mobilization in the same cells which is inhibitable by a selective CCR5 antagonist.
  • Cells were grown to 80-100% confluency in T-150 flasks and washed with phosphate-buffered saline. Cells were lifted from the flasks by treating with 3 mL of 1 mM EDTA for 3 min.
  • the percent of maximal RANTES -induced Ca + was determined for each concentration of antagonist and the IC50 defined as the concentration of test compound that inhibits 50% of the maximal 33 nM RANTES response, obtained from the concentration-response curves (5-7 concentrations of antagonists).
  • the compounds of this invention show CCR5 receptor modulator activity having IC50 values in the range of 0.0001 to 100 ⁇ M.
  • the full structure/activity relationship has not yet been established for the compounds of this invention.
  • one of ordinary skill in the art can utilize the present assays in order to determine which compounds of formula (I) are modulators of the CCR5 receptor and which bind thereto with an IC50 value in the range of 0.0001 to 100 ⁇ M.
  • All publications, including, but not limited to, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof.

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Abstract

La présente invention concerne des benzanilides substitués qui sont des modulateurs, des agonistes ou des antagonistes, du récepteur CCR5. Par ailleurs, la présente invention concerne également le traitement et la prévention d'états pathologiques induits par CCR5, y compris, sans en exclure d'autres, les troubles asthmatiques et atopiques (tels que les dermatites et les allergies atopiques), la polyarthrite rhumatoïde, la sarcoïdose et d'autres maladies fibrotiques, l'athérosclérose, le psoriasis, les maladies auto-immunes, telles que la sclérose en plaques, et l'affection abdominale inflammatoire, chez des mammifères, ces traitements consistant à utiliser des benzanilides substitués qui sont des antagonistes du récepteur CCR5. De plus, du fait que des lymphocytes T CD8+ ont été impliqués dans la BPCO (bronchopneumopathie chronique obstructive), CCR5 peut avoir un rôle dans leur recrutement et, ainsi, les antagonistes de CCR5 pourraient fournir un effet thérapeutique potentiel dans le traitement de la BPCO. Par ailleurs, du fait que CCR5 est un co-récepteur pour l'entrée du VIH dans les cellules, les modulateurs des récepteurs sélectifs peuvent être utiles dans le traitement d'une infection par le VIH.
PCT/US2003/023524 2002-07-31 2003-07-28 Benzanilides substitues utilises comme modulateurs du recepteur ccr5 Ceased WO2004010943A2 (fr)

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