EP1313477A1 - Compounds and methods - Google Patents

Compounds and methods

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Publication number
EP1313477A1
EP1313477A1 EP01958995A EP01958995A EP1313477A1 EP 1313477 A1 EP1313477 A1 EP 1313477A1 EP 01958995 A EP01958995 A EP 01958995A EP 01958995 A EP01958995 A EP 01958995A EP 1313477 A1 EP1313477 A1 EP 1313477A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
methoxyphenyl
methoxy
diisopropylamino
methylethyl
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.)
Withdrawn
Application number
EP01958995A
Other languages
German (de)
French (fr)
Other versions
EP1313477A4 (en
Inventor
William E. Bondinell
Michael J. Neeb
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1313477A1 publication Critical patent/EP1313477A1/en
Publication of EP1313477A4 publication Critical patent/EP1313477A4/en
Withdrawn legal-status Critical Current

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    • 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
    • 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
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • 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
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    • 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
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    • 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
    • C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • 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
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    • 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
    • C07D211/70—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/20—Nitrogen atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
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    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—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 chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to substituted heterocyclic compounds 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 (MJ. 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, Grit. 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 TNF « .
  • RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P. J. Nelson, and A.M. Krensky, Clin. Immunofher. 4: 1-8, 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.
  • 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 which are important in the maintenance of a chronic inflammatory reaction.
  • CCR5 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 activity 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.
  • the present invention is to compounds of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, 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.
  • 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 p
  • 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 dermatitis and allergies
  • sarcoidosis for example, atopic dermatitis and allergies
  • idiopathic pulmonary fibrosis and other fibrotic diseases
  • 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 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, whether 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 heterocycles 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 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
  • autoimmune diseases such as multiple
  • 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 HIV infection.
  • CCR5 modulators include those compounds as described in FR 2758328, published 17 July 1998, FR 2761069, published 25 September 1998, WO 94/07496, published 14 April 1994, WO 95/25443, published 28 September 1995, and PCT/USOO/01908, filed January 25, 2000. Each of these references is incorporated herein in their entirety.
  • 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:
  • A' is aryl or heteroaryl, each of which is optionally substituted with one or more of R! '; or A' is aryl or heteroaryl fused to a saturated or partly unsaturated 5-7- membered ring to form a higher order ring moiety, which ring moiety optionally contains 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein nitrogen may be optionally substituted with hydrogen, Ci.gaikyl or C3_7cycloalkyl; wherein the higher order ring moiety is optionally substituted with one or more of R! ;
  • Rl' is hydrogen, Cj.galkyl, C2_6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3_ 6 cycloalkenyl, CH 2 CF 3 , aryl, aralkyl, (CH 2 ) a 'NR 2 'R 3 ', (CH2) a 'N 2 'COR4', (CH2)a'NR 2 'CO 2 R 5 ', (CH 2 ) a 'NR 2 'SO2R 6 ', (CH 2 ) a €ONR 7 'R 8 ', hydroxyC 1 _ 6 alkyl, C ⁇ _4alkoxyalkyl (optionally substituted by a C j ⁇ alkoxy or hydroxy group), (CH 2 ) a CO 2 C ⁇ .
  • R 1 ' is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, C ⁇ . ⁇ alkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxyCi ⁇ galkyl, (C _ 6a ⁇ kyl)C ⁇ _6alkyl, C0NR 7 'R 8 ', CO2R 17 ', cyano, aryl, trifluoromethyl, nitro, hydroxy, C ⁇ _galkoxy, acyloxy, or halogen; a' is 1, 2, 3 or 4; b' is 0, 1, 2 or 3; c'is 1, 2 or 3;
  • R 2 ' and R 3 ' are independently hydrogen or C ⁇ _6alkyl, or R 2 ' and R 3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
  • R4' is hydrogen, C ⁇ galkyl or C ⁇ alkoxy alkyl, or, when Rl'is NR 'C0R4', R4' is (CH2) ⁇ _3 and forms a ring with A';
  • R 5 ' is C ⁇ _6alkyl;
  • R ⁇ ' is C ⁇ _6alkyl or phenyl;
  • R 7 ' and R 8 ' are independently hydrogen or C ⁇ _6alkyl, or R 7 ' and R 8 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
  • R ⁇ ' is C j ⁇ alkyl, optionally substituted by a C ⁇ _6alkoxy;
  • RlO' and R* 1 are independently hydrogen or Chalky!;
  • R l2 ' is hydrogen or Ci. ⁇ aikyi;
  • R ⁇ - 3 ' is hydrogen or C ⁇ _6alkyl;
  • Rl4' and R ⁇ ' are independently hydrogen or Chalky!
  • R 1 ⁇ ' is hydrogen or Ci.galkyl
  • R* 7 ' is hydrogen or C ⁇ _6alkyl optionally substituted with one or more substituents selected from C j _galkyl, C j ⁇ alkoxy, hydroxy, or NR 2 R 3 ';
  • R i8 ' and R ⁇ 9 are independently hydrogen or C ⁇ alkyl;
  • R 0' and R 2x ' are independently hydrogen or C j .galkyl, or R 2 ⁇ ' and R 21 ' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom.
  • R 22 ' is hydrogen or C ⁇ .galkyl;
  • CR 4 ' CR 24 CO, C ⁇ CCO, (C(R 24 ') 2 ) c "SO 2 , SO 2 [C(R 24 ') 2 ] a » , NR 2 5 , [C(R 2 4 , ) 2 ] a --SO2, NR 2 5'sO 2 [C(R 24 ') 2 ] a -'SO 2 , O[C(R 24 ') 2 ] a "SO 2 , SO 2 NR 2 5'[C(R 4') 2 ] 1 _ 2 , [C(R 24 ') 2 ] b »COO[C(R 24 ') 2 ] 2 , [C(R 2 4') 2 ] b HCONR 2 5'[C(R 2 4') 2 ] 1 .
  • D' may further be O, NR 25 ', CONR 25 ', SO 2 NR 25 ', OCONR 25 ', NR25'C00, NR 25 'CONR 25 ', [C(R 2 4') 2 ] a "NR 25 '[C(R 2 4') 2 ] b .., [C(R 2 4')2] a --O[C(R 24 ')2]b", CO[C(R 4')2] a »NR 2 5', NR 5'[C(R 2 4') 2 ] a »O, NR 25' [C( R24' )2]aêt NR 25' j O[C(R 4') 2 ] a »O, CO[C(R 24 ') 2 ] a »O, SO 2 [C(R 24 ') 2 ] a ->NR 2 5
  • R 24 ' is hydrogen or C ⁇ galkyl;
  • R 2 ⁇ ' is hydrogen or Cj.galkyl;
  • R 2 ⁇ ' is hydrogen or Cj ⁇ galkyl
  • R 27 ' is hydrogen, OR 28 ', NHR 28 ', CN, NO 2 , R 28 ', SR 29 ', COR 28 ', CHOHR 28 ', CO 2 R 28 ', NHCOR 28 ', NHCO 2 R 29 ', NHSO 2 R 29 ', or OCONHR 28 ';
  • R 2 ' is hydrogen, C ⁇ _5alkyl, aryl or aralkyl
  • R 29 is C ⁇ _5alkyl, aryl or aralkyl
  • R' is one or more of hydrogen or Cj_6alkyl, or R' is oxo;
  • J' is CO or SO 2 ;
  • L' is NR 3 0', O or C(R 30 ') 2 ;
  • R 3 ⁇ is hydrogen or C ⁇ galkyl; E represents a group (a):
  • R 1 and R 2 are independently hydrogen or C ⁇ _6alkyl; alternatively B(CR i R 2 ) a is OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR 1 R2CR 1 (OCOCH 3 )CR 1 R2;
  • R 3 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 ⁇ _ 6 alkyl, aryl, CONR 1 ⁇ 11 , NR 10 R n , hydroxy, OCOR 12 , NHCOCF3,
  • NHCOC 0 -6alkyl wherein the alkyl of NHCOC 0 -6alkyl is optionally substituted by OH;
  • R 5 is hydrogen, Chalky!, aryl, CN, CONR 15 R 16 , CO 2 R 17 , trifluoromethyl, NHCO 2 R 18 , hydroxy, Ci.galkoxy, benzyloxy, OCH ⁇ O ⁇ .galkyl, OCF3, S(O) d R 19 , SO 2 NR 20 R 21 or halogen;
  • R 9 is hydrogen, Ci.gaikyl, or phenyrC ⁇ _6alkyl
  • R 13 , R 14 , R 18 , and R 19 are independently Ci ⁇ 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; alternatively, E represents a group (b):
  • R 3 ⁇ is hydrogen, C ⁇ galkyl, or C3_7cycloalkyl
  • J is oxygen, CR 36 R 37 , or NR 38 , or J is a group
  • R 34 , R 35 , R 36 , R 37 , and R 38 are independently hydrogen or Cj.galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents a group (c):
  • R 39 and R 4 ⁇ are independently hydrogen or Cj.galkyl;
  • R 41 is a group of formula (d):
  • R 4i is a group of formula (e):
  • R 42 is hydrogen, Cx.galkyl, aryl, CN, CONR 48 R 49 , CO 2 R 50 , trifluoromethyl, NHCO 2 R 51 , hydroxy, C ⁇ _ 6 alkoxy, benzyloxy, OCF 3 , S(O) s R 52 , SO 2 NR 53 R 54 , or halogen;
  • R 47 is hydrogen, C ⁇ galkyl, or C3_7 cycloalkyl
  • R ⁇ l and R ⁇ 2 are independently C ⁇ _6alkyl; 1 is 0, 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 0, 1, or 2; t is 2 or 3; alternatively, E represents a group (f):
  • R ⁇ 7 and R ⁇ 8 are independently hydrogen or C ⁇ _galkyl;
  • R ⁇ 9 and R ⁇ 0 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 ⁇ alkyl, aryl, CONR 61 R 62 , NR 61 R 62 , hydroxy, OCOR 63 , NHCOCF3, NHSO 2 R 64 NHCO 2 R 65 , or NHCOC 0 -6alkyl wherein the alkyl of NHCOC 0 -6alkyl is optionally substituted by OH;
  • T is -(CR66 R 67) V . or -0(CR66R67) W . ;
  • R ⁇ 4 and R ⁇ 5 ⁇ e independently C ⁇ _6alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):
  • R 7i 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 7 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 C ⁇ alkyl and optionally substituted on nitrogen with hydrogen, Cj.galkyl or C3_ 7cycloalkyl;
  • R 72 is hydrogen, C ⁇ alkyl, aryl, CN, CONR 74 R 7 5, CO2R 76 , trifluoromethyl, NHCO 2 R 77 , hydroxy, Cj ⁇ alkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _6alkyl, OCF3, S(O) z R 78 , SO 2 NR 79 R 80 , or halogen;
  • R 74 , R 75 , R 76 , R 79 , R 80 , R 81 , and R 82 are independently hydrogen or Cj_ g ⁇ kyl;
  • R 77 and R 78 are independently C ⁇ alkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents a group (h):
  • R 83 and R 84 are independently hydrogen or C j .galkyl;
  • R ⁇ nd 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 ⁇ _ 6 alkyl, aryl, CONR 8 R 89 , NR 90 R 91 , hydroxy, OCOR 92 , NHCOCF3, NHSO 2 R 93 , NHCO 2 R 94 , or NHCOC 0 _6alkyl wherein the alkyl of NHCOC 0 _6alkyl 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 Ci _ ⁇ alkyl;
  • R 93 and R 94 are independently Ci.galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E
  • R 97 and R 98 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 ⁇ _ 6 alkyl, aryl, CONR 102 R 103 , NR 104 R 105 , hydroxy, OCOR 106 , NHCOCF3, NHSO 2 R 107 , NHCO 2 R 108 , or NHCOC 0 _6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH;
  • R 99 and RIOO ⁇ e independently hydrogen or C ⁇ galkyl;
  • AC is oxygen, CR 1 1 ⁇ R 112 or NR 113 or AC is a group SfO) ⁇ ;
  • R 104 R 105, R 106, R 109, R 110, R lll, R112, and R 113 m independently hydrogen or C ⁇ _gal yl;
  • R 107 and R 108 are independently Ci.galkyl; af is O, l, 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.
  • af is O, l, 2, 3, or 4
  • ag is 1, 2, or 3
  • ah is 1, 2, 3 or 4
  • ai 2, 3 or 4
  • aj is O, 1, 2, or 3
  • ak is 0, 1 or 2.
  • E may be optionally quatemized with C ⁇ _ ⁇ alkyl or is optionally present as the N-oxide.
  • A' is aryl or heteroaryl, each of which is optionally substituted with one or more of R*'.
  • A' is suitably aryl or heteroaryl fused to a saturated or partly unsaturated 5-7-membered ring to form a higher order ring moiety, which ring moiety optionally contains 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein nitrogen may be optionally substituted with hydrogen, C ⁇ galkyl or C3_ 7cycloalkyl; wherein the higher order ring moiety is optionally substituted with one or more of R 1 '.
  • A' is phenyl, 5,6,7,8-tetrahydro-l-naphthalenyl, lH-indol-4-yl, or 2-benzothiazolyl.
  • Rl' is hydrogen, Cj_6alkyl, C 2 _6alkenyl, C _galkynyl, C3. 7 cycloalkyl, C 3 _6cycloalkenyl, CH 2 CF 3 , aryl, aralkyl, (CH 2 ) a 'NR 2 'R 3 ', (CH 2 ) a 'NR 2 'COR 4 ', (CH 2 ) a NR 2 CO 2 R5', (CH 2 ) a 'NR 2 SO R6', (CH ) a CONR 7 'R 8 ', hydroxyC ⁇ _6alkyl, C ⁇ alkoxy alkyl (optionally substituted by a C ⁇ _4alkoxy or hydroxy group), (CH 2 ) a CO 2 C ⁇ _ 6 alkyl, (CH 2 ) b C(O)R 9 ', CRlO ⁇ NOR 11 ', CNRiO ⁇ NORll', COR 12
  • NR 18 'CONR 18 'R 19 ', NR 2 'CO 2 R 5 ', NR 2 'SO 2 R 6 ', N CNR 1 'NRl 'Rl 9 ', nitro, hydroxy, C ⁇ .galkoxy, OCF3, hydroxyC ⁇ _6a ⁇ koxy, C ⁇ _6alkoxyC ⁇ _6a ⁇ ko y, OC(O)NR 20 'R 21 ', SR 22 ', SOR 23 ', SO R 23 ', SO 2 NR 20 R 21 ' or halogen, or suitably R!
  • heterocyclic ring 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.
  • these rings may be optionally substituted with one or more of hydrogen, Cj.galkyl, C3_7cycloalkyl, C3., 6cycloalkenyl, CONR 7 R 8 ', CO 2 R 17 ', cyano, aryl, trifluoromethyl, nitro, hydroxy, Cj.galkoxy, acyloxy, or halogen.
  • R 1 ' is one or more of C .galkyl, (CH 2 ) a NR 2 COR 4 , CF3, CO2C!.6alkyl, Cj.gaikoxy, halogen, or cyano.
  • R 2 and R 3 are independently hydrogen or C ⁇ alkyl, or suitably, R 2 ' and R 3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring.
  • the ring may be optionally substituted by an oxo group, or, when R 2 ' and R 3 form a 6-membered ring, the ring may optionally contain one oxygen or one sulfur atom.
  • the oxygen or sulfur atom are preferably in the 4-position.
  • R 4 ' is hydrogen, or, when Rl' is
  • R 5 ' is C ⁇ galkyl.
  • R ⁇ ' is Ci.gal yl or phenyl.
  • R 7 ' and R 8 are independently hydrogen or C ⁇ .galkyl, or suitably, R 7 and R 8 ' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring.
  • the ring may optionally contain one oxygen or one sulfur atom.
  • R 9 ' is Ci ⁇ alkyl, wherein the C ⁇ galkyl is optionally substituted by a
  • R 1 ⁇ ' and R* 1 ' are independently hydrogen or C ⁇ galkyl.
  • R i2 ' is hydrogen or Cj.galkyl.
  • Rl ' is hydrogen or C ⁇ alkyl.
  • R* 4 ' and R 1 ⁇ ' are independently hydrogen or Cj.galkyl.
  • R ⁇ ' is hydrogen or C ⁇ .galkyl.
  • R l7 ' is hydrogen or Ci ⁇ alkyl, wherein the C ⁇ .galkyl is optionally substituted with one or more substituents selected from Cj.galkyl, Cj.galkoxy, hydroxy, or NR 2 'R 3 .
  • substituents selected from Cj.galkyl, Cj.galkoxy, hydroxy, or NR 2 'R 3 .
  • there is more than one substituent there are two substituents.
  • R i8 ' and R are independently hydrogen or C ⁇ alkyl.
  • R 2 ⁇ ' and R 21 ' are independently hydrogen or Ci ⁇ alkyl, or suitably,
  • R20' an d R 2i ' together with the nitrogen to which they are attached form a 5- to 6- membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom.
  • R 2 ' is hydrogen or C ⁇ galkyl.
  • R 23 ' is Ci _6alkyl.
  • D' is either a bond or represents [C(R 24 ') 2 ] a » [C(R 2 ')2] a "CO, SO 2 ,
  • CR2 4 ' CR 4 'CO, C ⁇ CCO, (C(R 24 ') 2 ) c "SO 2 , SO 2 [C(R 24 ') 2 ] a ",
  • D' may further be O, NR25', C0NR25', SO 2 NR 2 5', OCONR 2 5' ; NR25 COO, NR25 CO NR 5', [C(R 24 ') 2 ] a "NR 2 5 '[C(R 24 ') 2 ] b » [C(R 24 '
  • D' is a bond, CO or SO 2 .
  • R2 4 ' is hydrogen or C ⁇ galkyl.
  • R25' is hydrogen or C ⁇ alkyl.
  • E' and G' together are NC(R 26 ) 2 .
  • R 2 ⁇ ' is hydrogen or Cj.galkyl.
  • R 2 " is hydrogen.
  • R 27 ' is hydrogen, OR 28 ', NHR 28 ', CN, NO 2 , R 28 ', SR 29 ', COR 29 ',
  • R 28 is hydrogen, C ⁇ alkyl, aryl or aralkyl.
  • R 29 ' is C ⁇ _5alkyl, aryl or aralkyl.
  • R' is one or more of hydrogen or C ⁇ _6alkyl, or R' is oxo.
  • R' is hydrogen.
  • J' is CO or SO2.
  • J' is CO.
  • L' is NR 30 ', O, or C(R 30 ') 2 .
  • L' is NR 30 '.
  • R 30 ' is hydrogen or C .galkyl.
  • R 30 ' is hydrogen.
  • substituent E is selected from the following groups:
  • E suitably represents a group (a):
  • B is preferably CR 7 R 8 , or oxygen.
  • R 1 and R2 are suitably independently hydrogen or Ci ⁇ alkyl.
  • R 1 and R2 are each hydrogen.
  • B(CRiR 2 ) a is OCR 1 R 2 CR 1 (OH)CR 1 R2 or
  • B(CRlR 2 ) a is OCR 1 R 2 CR 1 (OH)CR1R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 , Rl and R 2 are hydrogen.
  • R 3 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 ⁇ R 11 , hydroxy, OCOR 12 , NHCOCF3, NHSO 2 R 13 , NHCO 2 R 14 , or NHCOCo-6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH.
  • R 3 and R 4 are independently Ci ⁇ galkyl, C3_7cycloalkyl, 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!R 2 ) a -NR 3 R 4 is ortho to R 5 , meta to L' and para to R 6 , and R5 is para to L'.
  • R 5 is suitably hydrogen, Ci ⁇ alkyl, aryl, CN, CONR 15 R 16 , CO2R 17 , trifluoromethyl, NHCO 2 R 18 , hydroxy, Cj ⁇ galkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _6alkyl, OCF3, S(O) d R 19 , SO 2 NR 2 °R 21 , or halogen.
  • R 5 is preferably SC ⁇ _ galkyl or halogen.
  • R 6 is hydrogen.
  • R 7 , R 8 , Rl°, RU, Rl2, R15, R16 ; R 17, R 20, R 21 ; R 22 5 an R 23 ⁇ suitably independently hydrogen or C ⁇ . ⁇ alkyl.
  • R 9 is suitably hydrogen, R 13 , R l4 R 18 , 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.
  • E suitably represents a group (b):
  • R 24 , R25 5 R 26 5 R 27 ; R 28 ; R 29 ⁇ R 31 ; and R 32 ⁇ Q suitably independently hydrogen or C ⁇ alkyl.
  • R 30 is suitably hydrogen, C ⁇ _galkyl, or C3_7cycloalkyl.
  • R 30 is C _
  • R 33 is hydrogen.
  • J is suitably oxygen, CR 3o R 37 , or NR 38 , or J is a group 8(0) ⁇ .
  • J is oxygen.
  • J is para to L ⁇
  • R 34 , R 3 ⁇ , R 3 °, R 37 , R 38 are suitably independently hydrogen or C j _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.
  • E suitably represents a group (c):
  • E suitably represents a group (f):
  • R ⁇ 7 and R ⁇ 8 are independently hydrogen or Cj.galkyl; suitably R ⁇ 9 and R6° are independently hydrogen, Ci. ⁇ alkyl, 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, OCOR6 3 , NHCOCF3, NHSO R 64 , NHCO 2 R65 or NHCOCo_6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH, and wherein R°l, R62 ; anc ⁇ R 63 ⁇ g independently hydrogen or C j .galkyl, and R ⁇ 4 and R65 are independently Cj.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
  • R x 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 substituted on nitrogen with Cj.galkyl or C3_7cycloalkyl.
  • R 7 i is preferably located meta to L', ortho to R 72 and para to R 73 , and R 72 is located para to L'.
  • R 72 is hydrogen, C ⁇ _ 6 alkyl, aryl, CN, CONR 74 R 75 , CO 2 R 76 , trifluoromethyl, NHCO 2 R 77 , hydroxy, C ⁇ galkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _galkyl, OCF 3 , 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 ⁇ alkyl, R 77 and R 78 are C ⁇ galkyl, and z is 0, 1, or 2.
  • R 72 is preferably C ⁇ alkoxy, SC ⁇ galkyl or halogen.
  • R 73 is hydrogen.
  • y is an integer from 1-2. Preferably, y is 1.
  • E suitably represents a group (h):
  • R ⁇ 01 is hydrogen or C ⁇ .galkyl or R i i and R 30 ' together form a group -AD- wherein AD is (CR i09 R i l0 )ai wherein ai is 2, 3 or 4 or AD is (CR 109 R! 10 ) a j-AE wherein aj is 0, 1, 2 or 3 and AE is oxygen, sulfur or
  • R 109 CR! 10
  • R 109 and R 110 are independently hydrogen or C galkyl; suitably, R 97 and R 98 are independently hydrogen, 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 j .galkyl, aryl, CONR1°2R1° 3 , NR i04 R 10 5, hydroxy, OCOR 106 , NHCOCF3, NHSO 2 R 107 , NHCO 2 R 108 , or NHCOC 0 -6alkyl wherein the alkyl of NHCOC 0 _6alkyl is optionally substituted by OH, and wherein R 102 , Rl° 3 , R1° 4 R 105 and Rl°6 are independently hydrogen or C ⁇ galkyl, and R 107 and R 108 are independently
  • AC is oxygen, CRI HR 1 * 2 G r NR 113 wherein R 111 , R 112 and 113 are independently hydrogen or Cj.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 phenyl, 5,6,7,8-tetrahydro-l-naphthalenyl, lH-indol-4-yl, or 2- benzothiazolyl
  • R 1 ' is one or more of C ⁇ galkyl, (CH 2 ) a NR 2 COR 4 CF 3 , CO 2 C ⁇ _ ⁇ alkyl, C ⁇ galkoxy, halogen, or cyano
  • D' is a bond
  • E' and G' together are NC(R 2 6) 2
  • R' is hydrogen
  • J' is CO
  • L' is NR 30
  • E is group (a), (b), (c), (f), (g), (h), or (i).
  • A' is phenyl, 5,6,7,8-tetrahydro-l-napthalenyl, lH-indol-4-yl, or 6-chloro-2-benzothiazolyl; and when A' is phenyl, R 1 ' is one or more of Cj.galkyl, CF3, CO 2 CH 2 CH3, C ⁇ _6alkoxy, halogen, or cyano substituted at the 2,3-, 2,4-, 2,5-, 2- , 3-, 4-, 3,4-, and 3,5- positions, D' is a bond, E' and G' together are NCH 2 , R' is hydrogen, J' is CO, L' is NH, and E is a group (a), (b), or (g). Preferably, E is selected from group (a), (b) and (g).
  • E is group (a)
  • L' 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!
  • R 2 are hydrogen, R ⁇ is methoxy, methylthio or iodo, R 3 and R 4 are independently C3_6alkyl, or R 3 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 Cj.galkyl and acetamido or hydroxyl, R" is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CR 7 R 8 , and b is l.
  • L' is attached to group (a) meta to B- (CR!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, R 3 and R 4 are independently isopropyl or tert-butyl, or R 3 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 ⁇ is hydrogen, a is 2 when B is oxygen, and b is 1.
  • E is group (b)
  • L' is attached to group (b) para to J
  • J is oxygen
  • R 33 is hydrogen
  • R 24 R 25 , R 26 , R 27 , R 28 , R 29 , R 31 and R 32 are hydrogen
  • R 30 is C3_6alkyl
  • g is 2 and h is 1.
  • E is group (b)
  • L' is attached to group (b) para to J
  • J is oxygen
  • R 33 is hydrogen
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 and R 32 are hydrogen
  • R 30 is isopropyl
  • g is 2
  • h is 1.
  • R x is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom substituted on nitrogen with C3_galkyl or C3_7cycloalkyl, R 72 is methoxy, methylthio or iodo, y is 1, and R 73 is hydrogen.
  • L' is attached to group (g) meta to R 7 * and para to R 72 wherein R 7i is piperidin-4-yl substituted on nitrogen with isopropyl, R 72 is methoxy, y is 1, and R 73 is hydrogen.
  • a particularly effective subgenus of compounds of formula (I) is wherein, A' is phenyl, 5,6,7,8-tetrahydro-l-naphthalenyl, or lH-indol-4-yl; and when A' is phenyl, R 1 ' is methyl, chloro or trifluoromethyl substituted at the 2 and/or 3-positions, or R 1 ' is 2,4- dimethyl, 2-methoxy-5-chloro, 2-methyl, 3-ethoxycarbonyl, or 3,5-dichloro, D' is a bond, E' and G' together are NCH2, R' is hydrogen, J' is CO, L' is NH, and E is group
  • acyloxy is used herein at all occurrences to mean a moiety
  • 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 ⁇ _5alkoxyC ⁇ _6alkoxy is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
  • C]i _6a ⁇ kyl 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 U ited 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]i _5alkyl.
  • 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.
  • hydroxyCi.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.
  • hydroxyalkyl are used herein interchangeably to mean an hydroxyl group bonded to a C ⁇ _6alkyl 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 partially saturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with Cj.galkyl.
  • examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, piperazine, pyrrolidine, morpholine, imidazolidine, pyrazolidine, hexahydroazepine, 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- 1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by C ⁇ gal yl 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 R b moiety, wherein R a and R b are, independently, hydrogen or C 1 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.
  • 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.
  • 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. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • 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.
  • topical formulations of the present invention 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. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • 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).
  • 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
  • autoimmune diseases such as multiple sclerosis
  • 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) where L' is NR 30 are prepared by treating a suitably substituted aniline 1-1 with suitable reagent, for example triphosgene, and a suitable base, for example triethylamine, in a suitable solvent, for example dichloromethane, followed by treatment with a suitably substituted amine 1-2, e.g., l-(5,6,7,8-tetrahydro-l-naphthalenyl)piperazine, ethyl 3-(l-piperazinyl)benzoate, 4- (phenyl)piperidine, l-(phenyl)piperazine, 4-phenyl-2,3,4,6-tetrahydropyrdine, hexahydro- l-phenyl-lH-l,4-diazepine, etc., to afford the title compound 1-3.
  • suitable reagent for example triphosgene
  • a suitable base for example triethylamine
  • a suitable solvent for example dichlor
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (b) are prepared according to the methods of international application publication number WO 95/11934, published 25 April 1995, and WO 95/19477, published 27 June 1995.
  • Four other applications relate to the spiro compounds WO 97/17350 published 15 May 1997; WO 97/34900 published 25 September 1997; WO 97/34901 published 25 September 1997; WO 97/35862 published 2 October 1997.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (c) are prepared according to the methods of international application publication number WO 95/30675, published 16 November 1995.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (f) are prepared according to the methods of international application publication number WO 95/17401, published 29 June 1995.
  • Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (h) are prepared according to the methods of international application publication number WO 95/32967, published 7 December 1995 and WO 97/07120, published 27 February 1997, WO 97/07120, published 27 February 1997.
  • Suitably substituted anilines used to prepare compounds of formula (I) where 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.
  • Nitration of the resulting N-acylated phenylpiperidine with a suitable nitrating agent for example 70% nitric acid in acetic anhydride, at a suitable temperature, for example 0°C, for a suitable time, for example 30 minutes, yields 2-2.
  • a suitable reagent for example potassium carbonate
  • a suitable solvent for example aqueous methanol
  • R is H with a suitable alkylating agent RX where R is C ⁇ galkyl or C3_7cycloalkyl, for example isopropyl, and X is a suitable leaving group, for example iodo, bromo, methanesulfonyloxy, trifluoromefhysulfonyloxy, etc., and with a suitable base, for example potassium carbonate, in a suitable solvent, for example dimethylformamide and acetonitrile, at a suitable temperature, for example 70°C, for a suitable time, for example 20 hours gives 2-3 where R is C ⁇ _galkyl or C3_7cycloalkyl.
  • RX is a suitable alkylating agent
  • RX is C ⁇ galkyl or C3_7cycloalkyl, for example isopropyl
  • X is a suitable leaving group, for example iodo, bromo, methanesulfonyloxy, trifluoromefhysulf
  • 2-3 where R is H may be reductively alkylated on the piperidine nitrogen by treatment with a C _galdehyde, C3. gketone, or a C3_7cyclic ketone, for example, cyclopentanone, and a suitable reducing agent, for example sodium cyanoborohydride, in a suitable solvent, for example, acetic acid and methanol, for a suitable time, for example 16 hours, to afford 2-3 where R is Cx.galkyl or C3_7cycloalkyl.
  • a suitable solvent for example, acetic acid and methanol
  • Particularly useful intermediates for preparing compounds of formula (I) are: 4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]benzenamine; 4-methoxy-3 - [ 1 -cyclopentyl-4-piperidinyl]benzenamine; and 4-methoxy-3-[l-(3-pentyl)-4-piperidinyl]benzenamine.
  • the invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In the Examples, mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated.
  • the mixture was maintained at 0°C for an additional 30 rnin, 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.
  • the resulting mixture was extracted with dichloromethane (2 x 400 mL) and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 12 g (>100%) of a 2.2: 1 mixture of the title compound and its 3-nitro isomer.
  • the crude product was recrystallized from methanol (30 mL) to give 5.9 g (54%) of the title compound as off-white crystals.
  • Triphosgene (74 mg, 0.25 mmol) was added to a solution of 3-(2- diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954)(200 mg, 0.75 mmol) and dichloromethane (3 mL) and maintained at RT for 30 rnin.
  • Triethylamine (0.30 g, 0.42 mL, 3.0 mmol) was added and the resulting mixture was stirred for 1 h, treated with l-(2,3-dimethylphenyl)piperazine (0.11 g, 0.60 mmol), and the mixture stirred at RT for 16 h. The mixture was washed with water, dried (MgSO4) and concentrated in vacuo.
  • Examples 3-22 Following the procedure of Example 2, except substituting 1-phenylpiperazine, l-(2-methylphenyl)piperazine, l-[2-(acetamidomethyl)phenyl]-piperazine(GB 2309458), l-[3-(trifluoromethyl)phenyl]piperazine, l-(2-methoxyphenyl)piperazine, 1- (2-chlorophenyl)piperazine, l-(3-chlorophenyl)piperazine, l-(4- chlorophenyl)piperazine, l-(2,6-dimethylphenyl)piperazine, l-(2,3- dichlorophenyl)piperazine, and l-(3,4-dichlorophenyl)piperazine for l-(2,3- dimethylphenyl)piperazine, gave the following compounds:
  • Examples 25-46 Following the procedure of Example 2, except substituting l-(3- methyipheny piperazine, l-(4-methylphenyl)piperazine, l-(2,5- dimethylphenyl)piperazine, 1 -(3 ,4-dimethylphenyl)piperazine, 1 -(3 ,5- dichlorophenyl)piperazine, l-(3-methoxyphenyl)piperazine, l-(3,5- dimethoxyphenyl)piperazine, l-[3-(ethoxycarbonyl)phenyl]piperazine, l-(2- cyanophenyl)piperazine, l-(4-cyanophenyl)piperazine, l-(2-pyridinyl)piperazine, l-(4- pyridinyl)piperazine, l-[4-chloro-3-(trifluoromethyl)phenyl]piperazine, l-[2-
  • Triphosgene (12.2 mg, 0.041 mmol) was added to a solution of the compound of Preparation 1(e) (31 mg, 0.125 mmol) in dichloromethane (1 mL). The mixture was , Pj stirred for 30 rnin and then triethylamine ( 0.07 mL, 0.5 mmol) was added. The mixture was stirred an additional 1 h, treated with l-(2,3-dimethylphenyl)piperazine (31.0 mg, 0.125 mmol), and the mixture stirred at RT overnight.
  • Example 48 Preparation of 4-(2.3-Dichlorophenyl)-N-r4-methoxy-3-ri-(l-methylethy -4- piperidinyllphenyl1-l-pi ⁇ erazinecarboxamide Following the procedure of Example 47, except substituting l-(2,3- dichlorophenyl)piperazine for l-(2,3-dimethylphenyl)piperazine, gave the title compound. MS(ES) m/e 505.4 [M+H]+.
  • Example 49 Preparation of N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyn-4-(3- carboxyphenyDpiperazine- 1 -carboxamide To a flask containing the compound of Example 32 (5.5 mg, 0.01 mmol) was added 0.5 ml ethanol and 0.3 N sodium hydroxide (0.1 ml, 0.03 mmol.). The mixture was stirred at RT overnight.
  • Example 97 Preparation of 4-r3-(Ethoxycarbonyl)phenyll-N-r3-r3-rbis(l- methylethyl amino1propoxy1-4-methoxyphenyl1-l-piperazinecarboxamide Following the procedure of Example 2, except substituting 3-(3- diisopropylamino)propoxy-4-methoxy aniline (WO 99/01127) for 3-(2- diisopropylamino)ethoxy-4-methoxyaniline and substituting the compound of Preparation 3 for l-(2,3-dimethylphenyl)piperazine, gave the title compound. MS(ES) m/e 541.4 [M+H]+.
  • Example 98-99 Preparation of 4-(2.3-Dimethylphenyl -N-[4-methoxy-3-[l-cvclopentyl-4- piperidinyl]phenyl]-l-piperazinecarboxamide and 4-(2.3-Dimethylphenyl)-N-ri-(3- pentyl)-4-methoxy-3-[l-cvclopentyl-4-piperidinyl1phenyl1-l-piperazinecarboxamide
  • Example 47 except substituting the compounds of Preparation 4(b) and Preparation 5 for the compound of Preparation 1(e), gives the title compounds.
  • 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.
  • 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 IC5Q ; 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.

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Abstract

This invention relates to substituted heterocyclic compounds which are modulators, agonists or antagonists, of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5, 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, by the use of substituted heterocyclic compounds which are CCR5 receptor antagonists. Furthermore, since CD8+ T cells have been implicated in COPD, 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.

Description

COMPOUNDS AND METHODS
FIELD OF THE INVENTION This invention relates to substituted heterocyclic compounds which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.
BACKGROUND OF THE INVENTION
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 (MJ. 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, Grit. Rev. Clin. Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (J.L. Jones, J. Berth- Jone, A. Fletcher and P.E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791-804, 1995).
T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are 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. Immunol. 154: 1870-1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, T J. Schall, et al., J. Biol. Chem. 268: 5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F. Koltrowitz, E. Bornscheuer, et al., (J. Invest. Dermatol. 105: 585-591, 1995), mesangial cells (G. Wolf, S. Aberle, F. Thaiss, et al., Kidney Int. 44: 795-804, 1994) and platelets (Y. Koameyoshi, A. Dorschner, A.I. Mallet, E. Christophers, et al., J. Exp. Med. 176: 587-592, 1992). In these cells, RANTES mRNA is rapidly upregulated in response to IL-1 or TNF«. Although RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P. J. Nelson, and A.M. Krensky, Clin. Immunofher. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, 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. 4: 1-8, 1995; and K.C. Nadeau, H. Azuma and N.I. Tilney, Proc. Natl. Acad. USA 92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med. 181: 2153-2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant (J.M. Pattison, P.J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-8, 1995). Further, increased immunoreactive protein for RANTES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum from asthmatic individuals (CM. Gelder, P.S. Thomas, D.H. Yates, I.M. Adcock, et al., Thorax 50: 1033-1037, 1995).
Several receptors have been identified that bind RANTES. In particular, 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 which 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.
Since 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. Furthermore, since CD8+ T cells have been implicated in chronic obstructive pulmonary disease (COPD), CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic activity 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.
Compounds formula (I) having 5-WTID/I receptor antagonist activity have been reported in FR 2758328, published July 17, 1998; FR 2761069, published September 25, 1998; Matzen et al, J. Med. Chem. 2000, 43, 1149-1157; DE 197 56 036 Al, published June 24, 1999; WO 96/02525, published February 1, 1996; WO
97/28140, published August 7, 1997; WO 97/28141, published August 7, 1997; WO 98/31677, published July 23, 1998; U.S. Patent 5,789,412, issued August 4, 1998; WO 95/29907, published November 9, 1995; or compounds which inhibit leukotriene synthesis have been reported in WO 97/24328, published July 10, 1997; or compounds which antagonize tocolytic oxytocin receptor antagonist activity have been reported in WO 94/07496, published 14 April 1994, and WO 95/25443, published 28 September 1995.
Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted heterocyclic compounds of formula (I), function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.
SUMMARY OF THE INVENTION
The present invention is to compounds of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, 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. In addition, 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. Further, 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.
Yet further, 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. Still further, 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.
The present invention is also directed to combined therapy to 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. 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 antivirals, immunomodulators, anti-infectives, or vaccines known to the skilled artisan.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that substituted heterocycles 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 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. Furthermore, since CD8+ T cells have been implicated in COPD, 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 HIV infection.
Compounds of formula (I) for use herein as CCR5 modulators include those compounds as described in FR 2758328, published 17 July 1998, FR 2761069, published 25 September 1998, WO 94/07496, published 14 April 1994, WO 95/25443, published 28 September 1995, and PCT/USOO/01908, filed January 25, 2000. Each of these references is incorporated herein in their entirety.
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:
Formula (I) in which: the basic nitrogen in moiety E may be optionally quaternized with C^galkyl or is optionally present as the N-oxide;
A' is aryl or heteroaryl, each of which is optionally substituted with one or more of R! '; or A' is aryl or heteroaryl fused to a saturated or partly unsaturated 5-7- membered ring to form a higher order ring moiety, which ring moiety optionally contains 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein nitrogen may be optionally substituted with hydrogen, Ci.gaikyl or C3_7cycloalkyl; wherein the higher order ring moiety is optionally substituted with one or more of R! ;
Rl'is hydrogen, Cj.galkyl, C2_6alkenyl, C2-6alkynyl, C3_7cycloalkyl, C3_ 6cycloalkenyl, CH2CF3, aryl, aralkyl, (CH2)a'NR2'R3', (CH2)a'N 2'COR4', (CH2)a'NR2'CO2R5', (CH2)a'NR2'SO2R6', (CH2)a€ONR7'R8', hydroxyC1_6alkyl, Cι_4alkoxyalkyl (optionally substituted by a Cj^alkoxy or hydroxy group), (CH2)aCO2Cι.6alkyl, (CH2)bOC(O)R9', CRl0 =NORH', CNRiO^NOR1!', CORl2', CONR7R8', CONR7'(CH2)c C1.4alkyl, CONR7'(CH2)a'CO2R13', CONHNR14'R15', CONR7'SO2R16', CO2R17', cyano, trifluoromethyl, NR2R3', NR2'C0R4', NRl8'C0(CH2)a'NRl8 Rl9', NR1B'C0NR18'R19', NR2'CO2R5', NR2 SO2R6', N=CNR18'NR18'R19', nitro, hydroxy, C^alkoxy, OCF3, hydroxyCi. galkoxy, C^alkoxyC ^alkoxy, OC(O)NR20'R21', SR22', SOR23', SO2R23', Sθ2NR20'R i' or halogen, or R1' is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, C^.^alkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxyCi^galkyl, (C _ 6aιkyl)Cι_6alkyl, C0NR7'R8', CO2R17', cyano, aryl, trifluoromethyl, nitro, hydroxy, Cι_galkoxy, acyloxy, or halogen; a' is 1, 2, 3 or 4; b' is 0, 1, 2 or 3; c'is 1, 2 or 3;
R2' and R3' are independently hydrogen or Cι_6alkyl, or R2' and R3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
R4'is hydrogen, C^galkyl or C^alkoxy alkyl, or, when Rl'is NR 'C0R4', R4' is (CH2)ι_3 and forms a ring with A'; R5' is Cι_6alkyl; R^'is Cι_6alkyl or phenyl; R7' and R8' are independently hydrogen or Cι_6alkyl, or R7' and R8 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
R^'is Cj^alkyl, optionally substituted by a Cι_6alkoxy; RlO' and R* 1 are independently hydrogen or Chalky!;
Rl2' is hydrogen or Ci.βaikyi; RΪ-3' is hydrogen or Cι_6alkyl;
Rl4' and R^' are independently hydrogen or Chalky!;
R1^' is hydrogen or Ci.galkyl; R*7' is hydrogen or Cι_6alkyl optionally substituted with one or more substituents selected from Cj_galkyl, Cj^alkoxy, hydroxy, or NR2R3';
Ri8' and R^9 are independently hydrogen or C^alkyl; R 0' and R2x ' are independently hydrogen or C j.galkyl, or R2^' and R21 ' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom. R22' is hydrogen or C^.galkyl;
R23'is Cι_6al yl;
D'is either a bond or represents [C(R24')2]a", [C(R24')2]a"CO, CO, SO2, CO[C(R24')2]a», OrC(R24')2]a », S[C(R24')2]a", O[C(R24')2]a »CO, [C(R24')2]c»OCO, NR25'[C(R24')2]a„> NR25'[C(R24')2]a--CO, [C(R24')2]C»NR25'C0, NR25"C0[C(R24)2]a-., NR25'sO2[C(R24')2]a.., [C(R24 )2]C"NR25'S02,
CR 4'=CR24 CO, C≡CCO, (C(R24')2)c"SO2, SO2[C(R24')2]a », NR25,[C(R24,)2]a--SO2, NR25'sO2[C(R24')2]a-'SO2, O[C(R24')2]a"SO2, SO2NR25'[C(R 4')2]1_2, [C(R24')2]b»COO[C(R24')2]2, [C(R24')2]bHCONR25'[C(R24')2]1.2; and when E' and G' together are CR27'-C(R26')2, then D'may further be O, NR25', CONR25', SO2NR25', OCONR25', NR25'C00, NR25'CONR25', [C(R24')2]a"NR25'[C(R24')2]b.., [C(R24')2]a--O[C(R24')2]b", CO[C(R 4')2]a»NR25', NR 5'[C(R24')2]a»O, NR25'[C(R24')2]a„NR25'j O[C(R 4')2]a»O, CO[C(R24')2]a»O, SO2[C(R24')2]a->NR25', SO2[C(R 4')2]a..O, [C(R24')2]a»SO2NR25', [C(R24')2]a..CONR25', O[C(R24')2]a"SO2NR25', O[C(R24')2]a"CONR 5', NR25'[C(R24')2]a"SO2NR25', NR25'[C(R2 ')2]a»CONR25',
NR 5'C0[C(R24')2]aπNR25', NR25'S02[C(R24')2]a,,NR25', (C(R24')2)aMS(C(R24')2)b„, COO, CR2 'OH, C(R24')a"CR24OH; and when E' and G' together are CR27 -C(R26')2 or C=CR26', D' may further be CR24 =CR24' or C≡C; and a» is 1-6, b» is 0-1, c- is 0-2; R24' is hydrogen or C^galkyl; R2^' is hydrogen or Cj.galkyl;
E' and G' together are NC(R26)2, NC(R26')2C(R26')2, CR27'C(R26')2 or C=CR26';
R2^' is hydrogen or Cj^galkyl;
R27'is hydrogen, OR28', NHR28', CN, NO2, R28', SR29', COR28', CHOHR28', CO2R28', NHCOR28', NHCO2R29', NHSO2R29', or OCONHR28';
R2 'is hydrogen, Cι_5alkyl, aryl or aralkyl;
R29 is Cι_5alkyl, aryl or aralkyl;
R' is one or more of hydrogen or Cj_6alkyl, or R' is oxo;
J'is CO or SO2; L' is NR30', O or C(R30')2;
R3^ is hydrogen or C^galkyl; E represents a group (a):
R6 (a); in which
B is oxygen, C≡C, S(O)c, CR =CR8, or CR7R8, or B is NR9; R1 and R2 are independently hydrogen or Cι_6alkyl; alternatively B(CRiR2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, Cχ_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 Cι _6alkyl, aryl, CONR1^11, NR10Rn, hydroxy, OCOR12, NHCOCF3,
NHSO2R13, NHCO2R14, or NHCOC0-6alkyl wherein the alkyl of NHCOC0-6alkyl is optionally substituted by OH;
R5 is hydrogen, Chalky!, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, Ci.galkoxy, benzyloxy, OCH^O^.galkyl, OCF3, S(O)dR19, SO2NR20R21 or halogen;
R6 is hydrogen, C^.^alkyl, aryl, trifluoromethyl, hydroxy, C^alkoxy or halogen, or R" taken together with R ^' forms a group D where D is (CR22R23)e or D is (CR22R23)f_G where G is oxygen, sulfur or CR22=CR23, CR2 =N, =CR22O, =CR22S , or =CR22-NR23 ; R7, R8, RlO, Rll, R12 R15, R16, R17, R20, R21, R22, and R23 ^ independently hydrogen or Cj.galkyl;
R9 is hydrogen, Ci.gaikyl, or phenyrCι_6alkyl;
R13, R14, R18, and R19 are independently Ci^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; alternatively, E represents a group (b):
R24, R 5, R26; R275 R28; R295 R315 and R32 3^ independently hydrogen or Cι_6alkyl;
R3^ is hydrogen, C^galkyl, or C3_7cycloalkyl;
R33 ls hydrogen, Cj.galkyl, trifluoromethyl, hydroxy or halogen, or R33 and R30' together form a group -K- where K is (CR34R35)i or K is (CR3 R35)j -M and M is oxygen, sulfur, CR3 =CR35, CR34=N, orN=N;
J is oxygen, CR36R37, or NR38, or J is a group
R34, R35, R36, R37, and R38 are independently hydrogen or Cj.galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents a group (c):
in which:
Q is oxygen, S(O)n, CR44=CR45, CR44R45, or Q is NR46; R39 and R4^ are independently hydrogen or Cj.galkyl; R41 is a group of formula (d):
or R4i is a group of formula (e):
R42 is hydrogen, Cx.galkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO2R51, hydroxy, Cι_6alkoxy, benzyloxy, OCF3, S(O)sR52, SO2NR53R54, or halogen;
R43 is hydrogen or R43 together with R3^' forms a group R where R is CR55=CR5 , CR55=CR56CR55R565 or (CR55R56)t; R44 R45, R46, R48, R49, R50, R53, R54 R55, and R56 are independently hydrogen or C _6alkyl;
R47 is hydrogen, C^galkyl, or C3_7 cycloalkyl;
R^l and R^2 are independently Cι_6alkyl; 1 is 0, 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 0, 1, or 2; t is 2 or 3; alternatively, E represents a group (f):
R^7 and R^8 are independently hydrogen or Cι_galkyl; R^9 and R^0 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^alkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOCF3, NHSO2R64 NHCO2R65, or NHCOC0-6alkyl wherein the alkyl of NHCOC0-6alkyl is optionally substituted by OH;
T is -(CR66R67)V. or -0(CR66R67)W.;
W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70;
R61, R62, R63, R66, R67 R68; R69; and R70 ^e independently hydrogen or C^alkyl;
R^4 and R^5 ^e independently Cι_6alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):
R7i 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 R7 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 C^alkyl and optionally substituted on nitrogen with hydrogen, Cj.galkyl or C3_ 7cycloalkyl;
R72 is hydrogen, C^alkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, Cj^alkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R73 is hydrogen, Cj_6alkyl, hydroxy, C^galkoxy or halogen, or R73 and R3^ taken together from a group -X- where X is (CR81R82)aa or X is (CR81R82)ab-Y and Y is oxygen, sulfur or CR8 i=CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or Cj_ g^kyl;
R77 and R78 are independently C^alkyl; y is 1 or 2; z is 0, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents a group (h):
— j Z H- (CR83R84)ac RS5R86
R87 ( );
R83 and R84 are independently hydrogen or Cj.galkyl; R ^ nd R8^ 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 Cι _6alkyl, aryl, CONR8 R89, NR90R91, hydroxy, OCOR92, NHCOCF3, NHSO2R93, NHCO2R94, or NHCOC0_6alkyl wherein the alkyl of NHCOC0_6alkyl is optionally substituted by OH;
R87 is hydrogen or Ci^alkyl, Cj.βalkoxy, or halogen, or R87 together with R30' forms a group -AA- where AA is (CR95R96)ad or AA is (CR95=CR96)ae-AB and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR95NR96 or N=N;
Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R88, R89, R90, R91, R92, R95, and R96 are independently hydrogen or Ci _ βalkyl;
R93 and R94 are independently Ci.galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E
R97 and R98 are independently hydrogen, Cι_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 Cι_6alkyl, aryl, CONR102R103, NR104R105, hydroxy, OCOR106, NHCOCF3, NHSO2 R107, NHCO2R108, or NHCOC0_6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH;
R99 and RIOO ^e independently hydrogen or C^galkyl; RlOl is hydrogen or C^.galkyl or RlOl and R3^' together form a group -AD- where AD is (CR109R110)ai or AD is (CR109R110)aj-AE and AE is oxygen, sulfur or CRl09=CRllO; AC is oxygen, CR11 ΪR112 or NR113 or AC is a group SfO)^;
R102 R103? R104 R105, R106, R109, R110, Rlll, R112, and R113 m independently hydrogen or Cι_gal yl;
R107 and R108 are independently Ci.galkyl; af is O, l, 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. For compounds of formula (I) various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quatemized with Cι_ βalkyl or is optionally present as the N-oxide.
Suitably, A' is aryl or heteroaryl, each of which is optionally substituted with one or more of R*'. Alternatively, A' is suitably aryl or heteroaryl fused to a saturated or partly unsaturated 5-7-membered ring to form a higher order ring moiety, which ring moiety optionally contains 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein nitrogen may be optionally substituted with hydrogen, C^galkyl or C3_ 7cycloalkyl; wherein the higher order ring moiety is optionally substituted with one or more of R1'. Preferably A' is phenyl, 5,6,7,8-tetrahydro-l-naphthalenyl, lH-indol-4-yl, or 2-benzothiazolyl.
Suitably, Rl'is hydrogen, Cj_6alkyl, C2_6alkenyl, C _galkynyl, C3. 7cycloalkyl, C3_6cycloalkenyl, CH2CF3, aryl, aralkyl, (CH2)a'NR2'R3', (CH2)a'NR2'COR4', (CH2)aNR2 CO2R5', (CH2)a'NR2 SO R6', (CH )aCONR7'R8', hydroxyCι_6alkyl, C^alkoxy alkyl (optionally substituted by a Cι_4alkoxy or hydroxy group), (CH2)aCO2Cι_6alkyl, (CH2)b C(O)R9', CRlO^NOR11', CNRiO^NORll', COR12', CONR7 R8', CONR7'(CH2)c C1.4alkyl, CONR7'(CH2)aCO2R13', CONHNR14!^', CONR7'SO2R16', CO2R17', cyano, trifluoromethyl, NR2'R3', NR2'COR4', NR18'CO(CH2)a'NR18'Rl9',
NR18'CONR18'R19', NR2'CO2R5', NR2'SO2R6', N=CNR1 'NRl 'Rl9', nitro, hydroxy, C^.galkoxy, OCF3, hydroxyCι_6aιkoxy, Cι_6alkoxyCι_6aιko y, OC(O)NR20'R21', SR22', SOR23', SO R23', SO2NR20R21' or halogen, or suitably R! 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. Suitably, the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom. Suitably these rings may be optionally substituted with one or more of hydrogen, Cj.galkyl, C3_7cycloalkyl, C3., 6cycloalkenyl, CONR7 R8', CO2R17', cyano, aryl, trifluoromethyl, nitro, hydroxy, Cj.galkoxy, acyloxy, or halogen. Preferably, R1 ' is one or more of C .galkyl, (CH2)aNR2COR4, CF3, CO2C!.6alkyl, Cj.gaikoxy, halogen, or cyano.
Suitably, a' is 1, 2, 3 or 4; b' is 0, 1, 2 or 3; and c' is 1, 2 or 3. Suitably, R2 and R3 are independently hydrogen or C όalkyl, or suitably, R2' and R3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring. Suitably, the ring may be optionally substituted by an oxo group, or, when R2' and R3 form a 6-membered ring, the ring may optionally contain one oxygen or one sulfur atom. When the ring is a 6-membered ring substituted by an oxygen or sulfur atom, the oxygen or sulfur atom are preferably in the 4-position.
Suitably, R4'is hydrogen, or, when Rl' is
NR2'COR4', R4'is (CH2)i-3 and forms a ring with A'.
Suitably R5'is C^galkyl. Suitably, R^' is Ci.gal yl or phenyl.
Suitably, R7' and R8 are independently hydrogen or C^.galkyl, or suitably, R7 and R8' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring. Suitably, when the ring is 6-membered, the ring may optionally contain one oxygen or one sulfur atom. Suitably, R9' is Ci^alkyl, wherein the C^galkyl is optionally substituted by a
Cι_6alkoxy.
Suitably, R1^' and R*1' are independently hydrogen or C^galkyl.
Suitably, Ri2'is hydrogen or Cj.galkyl.
Suitably, Rl 'is hydrogen or C^alkyl. Suitably, R*4' and R1^' are independently hydrogen or Cj.galkyl.
Suitably, R^'is hydrogen or C^.galkyl.
Suitably, Rl7'is hydrogen or Ci^alkyl, wherein the C^.galkyl is optionally substituted with one or more substituents selected from Cj.galkyl, Cj.galkoxy, hydroxy, or NR2'R3 . Preferably, when there is more than one substituent, there are two substituents.
Suitably, Ri8' and R are independently hydrogen or C^alkyl.
Suitably, R2^' and R21' are independently hydrogen or Ci^alkyl, or suitably,
R20' and R2i' together with the nitrogen to which they are attached form a 5- to 6- membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom.
Suitably, R 2'is hydrogen or C^galkyl.
Suitably, R23' is Ci _6alkyl.
Suitably, D' is either a bond or represents [C(R24')2]a», [C(R2 ')2]a"CO, SO2,
CO, CO[C(R2 ')2]a", O[C(R24')2]a", S[C(R 4')2]a", O[C(R24')2]a"CO, [C(R24')2]c-oCO, NR25'[C(R24')2]a.-, NR25'[C(R24')2]a"CO, [C(R24')2]C.-NR25'C0,
NR25'C0[C(R2 ')2]a», NR25'SO2[C(R24')2]a-, [C(R 4')2]C»NR25'S02,
CR24'=CR 4'CO, C≡CCO, (C(R24')2)c"SO2, SO2[C(R24')2]a",
NR25'[C(R ')2]a »SO2, NR25'sO2[C(R2 ')2]a"SO2, O[C(R24')2]a"SO2, SO2NR25'[C(R24')2]l_2j [C(R24')2]b)>COO[C(R24')2]25 [C(R24')2]b"CONR25'[C(R24')2] ι_2; and when E' and G' together are CR27'_ C(R26')2J then D' may further be O, NR25', C0NR25', SO2NR25', OCONR25'; NR25 COO, NR25CONR 5', [C(R24')2]a"NR25 '[C(R24')2]b», [C(R24')2]a»O[C(R24')2]b", CO[C(R24')2]a"NR25', NR25'[C(R24')2]a"O, NR25'[C(R24')2]a„NR25') θ[C(R24')2)]a"NR25', O[C(R24')2]a"0, CO[C(R24')2]a"O, SO2[C(R24')2]a»NR25', SO2[C(R 4')2]a"O, [C(R24')2]a»SO2NR25', [C(R24')2]a"CONR25', O[C(R24')2]a"SO2NR25', O[C(R24')2]a"CONR25', NR25'[C(R24')2]a„sO2NR25', NR25'[C(R24')2]a"CONR25';
NR25'cO[C(R24')2]a»NR25', NR25 SO2[C(R24')2]a»NR25',
(C(R24')2)a»S(C(R24')2)b», COO, CR24'OH, C(R24')a--CR24'θH; and when E' and G' together are CR27'-C(R26')2 or C=CR26', D' may further be CR24=CR24 or C≡C; and a" is 1-6, b" is 0-1, c» is 0-2. Preferably, D'is a bond, CO or SO2. Suitably, R24' is hydrogen or C^galkyl.
Suitably, R25'is hydrogen or C^alkyl.
Suitably, E' and G' together are NC(R26')2, NC(R 6')2C(R26')2) CR27'C(R26')2 or C=CR26'. Preferably, E' and G' together are NC(R26)2.
Suitably, R2^' is hydrogen or Cj.galkyl. Preferably, R2" is hydrogen. Suitably, R27' is hydrogen, OR28', NHR28', CN, NO2, R28', SR29', COR29',
CHOHR29', CO2R29', NHCOR29', NHCO2R29', NHSO2R29', or OCONHR29'.
Suitably, R28 is hydrogen, C^alkyl, aryl or aralkyl.
Suitably, R29'is Cι_5alkyl, aryl or aralkyl.
Suitably, R' is one or more of hydrogen or Cι_6alkyl, or R' is oxo. Preferably, R' is hydrogen.
Suitably, J' is CO or SO2. Preferably, J' is CO.
Suitably, L' is NR30', O, or C(R30')2. Preferably, L' is NR30'.
Suitably, R30' is hydrogen or C .galkyl. Preferably, R30' is hydrogen.
Suitably, substituent E is selected from the following groups:
E suitably represents a group (a):
R6 (a).
B is suitably oxygen, C≡C, S(O)c, CR7=CR8> or CR7R8, or B is NR9. B is preferably CR7R8, or oxygen.
R1 and R2 are suitably independently hydrogen or Ci^alkyl. Preferably, R1 and R2 are each hydrogen. Alternatively, B(CRiR2)a is OCR1R2CR1(OH)CR1R2 or
OCR1R2CR1(OCOCH3)CR1R2. Preferably, when B(CRlR2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2, Rl and R2 are hydrogen.
R3 and R4 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^R11, NR^R11, hydroxy, OCOR12, NHCOCF3, NHSO2 R13, NHCO2R14, or NHCOCo-6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH. Preferably R3 and R4 are independently Ci^galkyl, C3_7cycloalkyl, 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.
Preferably, B-(CR!R2)a-NR3R4 is ortho to R5, meta to L' and para to R6, and R5 is para to L'. R5 is suitably hydrogen, Ci^alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, Cj^galkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)dR19, SO2NR2°R21, or halogen. R5 is preferably SCι_ galkyl or halogen. R6 is suitably hydrogen, Cj.galkyl, aryl, trifluoromethyl, hydroxy, C _ galkoxy, or halogen, or R^ taken together with R30' forms a group D where D is (CR22R23)C or D is (CR22R23)f_Q where G is oxygen, sulfur, or CR22=CR23, CR22=N, =CR22O, =CR22s, or =CR22_NR23. Preferably, R6 is hydrogen. R7, R8, Rl°, RU, Rl2, R15, R16; R17, R20, R21; R225 an R23 ^ suitably independently hydrogen or C^.^alkyl.
R9 is suitably hydrogen, R13, Rl4 R18, and R19 are suitably independently C^galkyl. a is suitably 1, 2, 3, or 4. Preferably, a is 2 or 3. b is suitably 1 or 2. Preferably, 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.
Alternatively, E suitably represents a group (b):
R24, R255 R265 R27; R28; R29^ R31; and R32 ^Q suitably independently hydrogen or C^alkyl. R24, R25, R26, R27, R28, R 9? R31? and R32 ^ preferably hydrogen. R30 is suitably hydrogen, Cι_galkyl, or C3_7cycloalkyl. Preferably, R30 is C _
5alkyl or C3_7cycloalkyl.
R33 is suitably hydrogen, Cj.galkyl, trifluoromethyl, hydroxy or halogen, or R33 and R30' together form a group -K- where K is (CR34R35)i or K is (CR34R35)j - M and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N. Preferably, R33 is hydrogen.
J is suitably oxygen, CR3oR37, or NR38, or J is a group 8(0)^. Preferably, J is oxygen. Preferably, J is para to L\
R34, R3^, R3°, R37, R38 are suitably independently hydrogen or Cj_galkyl. g is suitably 1, 2, or 3. Preferably, g is 2 or 3. h is suitably 1, 2, or 3. Preferably, 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.
Alternatively, E suitably represents a group (c):
Suitably, Q is oxygen, S(O)n, CR44=CR 5, C=C , or CR44R45, wherein n is 0, 1 or 2, and R44 and R ^ are independently hydrogen or Cj.galkyl, or suitably, Q is NR46 wherein R4^ is hydrogen or alkyl; suitably, R39 and R40 are independently hydrogen or C ^alkyl; suitably, R42 is hydrogen, C^alkyl, aryl, CN, CONR48R49, CO R5°, trifluoromethyl, NHCO2R51, hydroxy, Ci.galkoxy, benzyloxy, OCH2CO2C1.6alkyl, OCF3, S(O)sR52, SO2NR53R54 or halogen, wherein R48, R49, R50, R53; an R54 arg hydrogen or C^galkyl, and R^1 and R^ are C^alkyl; suitably, R43 is hydrogen or R43 together with R30' forms a group R where R is CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t wherein R55 and R56 are independently hydrogen or C^galkyl and t is 2 or 3; suitably, R4i is selected from a group of formula (d) or (e); suitably R47 is hydrogen, Cj_6alkyl, or 03. 7 cycloalkyl; suitably, 1 is 0, 1, 2 or 3, m is 1 or 2, n and s are independently 0, 1 or 2, o, p and q are independently 1, 2 or 3, and r is 0, 1, 2 or 3. Alternatively, E suitably represents a group (f):
Suitably, R^7 and R^8 are independently hydrogen or Cj.galkyl; suitably R^9 and R6° are independently hydrogen, Ci.βalkyl, 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, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOCF3, NHSO R64, NHCO2R65 or NHCOCo_6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH, and wherein R°l, R62; ancι R63 ^g independently hydrogen or Cj.galkyl, and R^4 and R65 are independently Cj.galkyl; suitably, T is -(CR66R67)V- or -O(CR66R67)w-, wherein R°o and R^7 are independently hydrogen or C^alkyl, wherein v is 2 or 3, and w is 1, 2 or 3; suitably, W is oxygen, S(O)x, wherein x is 0, 1 or 2, or W is NR^8, wherein R68 is hydrogen or C galkyl, or W is CR69=CR70, C=C, or CR69R70, wherein R"9 and R70 are independently hydrogen or C^.galkyl; and suitably, u is an integer from 1-4. Alternatively, E suitably represents a group (g):
Suitably, R71 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 x 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. Examples of such ring systems include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, 1,2,3,6-tetrahydropyridine, hexahydroazepine, tropane, isoquinuclidine and granatane rings. Preferably, R71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with Cj.galkyl or C3_7cycloalkyl.
R7 i is preferably located meta to L', ortho to R72 and para to R73, and R72 is located para to L'.
Suitably, R72 is hydrogen, Cι_6alkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, C^galkoxy, benzyloxy, OCH2CO2Cι_galkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen wherein R74, R75, R76, R79 and R80 are independently hydrogen or C^alkyl, R77 and R78 are C^galkyl, and z is 0, 1, or 2. R72 is preferably C^alkoxy, SC^galkyl or halogen.
R73 is hydrogen, Cj^aikyl, hydroxy, Cj.galkoxy or halogen, or R73 and R30' taken together from a group -X- where X is (CR8 iR82)aa, wherein aa is 2, 3 or 4, and R8 ! and R82 are independently hydrogen or C \ _6alkyl, or X is (CR81R82)ab- Y, wherein ab is 0, 1, 2 or 3, and Y is oxygen, sulfur or CR8i=CR 2 wherein R8 and R82 ar independently hydrogen or C^galkyl. Preferably, R73 is hydrogen.
Suitably, y is an integer from 1-2. Preferably, y is 1.
Alternatively, E suitably represents a group (h):
Suitably, R87 is hydrogen, C^galkyl, C^galkoxy or halogen, or R87 together with R30' form a group -AA-, wherein AA is (CR95R88)ad, wherein ad is 1, 2 or 3, and R95 and R88 are independently hydrogen or C^galkyl, or AA is (CR95CR96)ae-AB, wherein ae is 0, 1 or 2, and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR95NR96 or N=N wherein R9^ and R9^ are independently hydrogen or C^galkyl; suitably, R83 and R84 are independently hydrogen or Cj.galkyl; suitably, R8^ and R8^ are independently hydrogen, Cj.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^alkyl, aryl, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOCF3, NHSO2R93, NHCO2R94, or NHCOCo_6alkyl wherein the alkyl of the NHCOCo_6alkyl is optionally substituted by OH, and wherein R88, R89, R90, R91 and R92 are independently hydrogen or Cj_ galkyl, and R93 and R94 are independently C^galkyl; suitably Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; suitably ac is 0-4. Alternatively, E suitably represents a group (i):
Suitably, R^01 is hydrogen or C^.galkyl or Ri i and R30' together form a group -AD- wherein AD is (CRi09Ri l0)ai wherein ai is 2, 3 or 4 or AD is (CR109R! 10)aj-AE wherein aj is 0, 1, 2 or 3 and AE is oxygen, sulfur or
CR109=CR! 10 , and R109 and R110 are independently hydrogen or C galkyl; suitably, R97 and R98 are independently hydrogen, 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 Cj.galkyl, aryl, CONR1°2R1°3, NRi04R105, hydroxy, OCOR106, NHCOCF3, NHSO2 R107, NHCO2R108, or NHCOC0-6alkyl wherein the alkyl of NHCOC0_6alkyl is optionally substituted by OH, and wherein R102, Rl°3, R1°4 R105 and Rl°6 are independently hydrogen or C^galkyl, and R107 and R108 are independently Cj.galkyl; suitably, R99 and R!°° are independently hydrogen or C\. βalkyl; suitably, AC is oxygen, CRI HR1 *2 Gr NR113 wherein R111, R112 and 113 are independently hydrogen or Cj.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. Suitably, A' is phenyl, 5,6,7,8-tetrahydro-l-naphthalenyl, lH-indol-4-yl, or 2- benzothiazolyl, R1' is one or more of C^galkyl, (CH2)aNR2COR4 CF3, CO2Cι_ βalkyl, C^galkoxy, halogen, or cyano, D' is a bond, E' and G' together are NC(R26)2, R' is hydrogen, J' is CO, L' is NR30, and E is group (a), (b), (c), (f), (g), (h), or (i). More preferably, A' is phenyl, 5,6,7,8-tetrahydro-l-napthalenyl, lH-indol-4-yl, or 6-chloro-2-benzothiazolyl; and when A' is phenyl, R1' is one or more of Cj.galkyl, CF3, CO2CH2CH3, Cι_6alkoxy, halogen, or cyano substituted at the 2,3-, 2,4-, 2,5-, 2- , 3-, 4-, 3,4-, and 3,5- positions, D' is a bond, E' and G' together are NCH2, R' is hydrogen, J' is CO, L' is NH, and E is a group (a), (b), or (g). Preferably, E is selected from group (a), (b) and (g).
More preferably, when E is group (a), L'is attached to group (a) meta to B- (CR1R2)a-NR3R4 and para to (R5)b, wherein B is oxygen or CR7R8, R! and R 2 are hydrogen, R^ is methoxy, methylthio or iodo, R3 and R4 are independently C3_6alkyl, or R3 and R4 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 Cj.galkyl and acetamido or hydroxyl, R" is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CR7R8, and b is l.
Most preferably, when E is group (a), L' is attached to group (a) meta to B- (CR!R2)a-NR3R4 and para to (R5)b, wherein B is oxygen or CH2, R1 and R 2 are hydrogen, R^ is methoxy, R3 and R4 are independently isopropyl or tert-butyl, or R3 and R4 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^ is hydrogen, a is 2 when B is oxygen, and b is 1. More preferably, when E is group (b), L' is attached to group (b) para to J, J is oxygen, R33 is hydrogen, R24 R25, R26, R27, R28, R29, R31 and R32 are hydrogen, R30 is C3_6alkyl, g is 2 and h is 1.
Most preferably, when E is group (b), L' is attached to group (b) para to J, J is oxygen, R33 is hydrogen, R24, R25, R26, R27, R28, R29, R31 and R32 are hydrogen, R30 is isopropyl, g is 2, and h is 1.
More preferably, when E is group (g), L'is attached to group (g) meta to R7* and para to R72, R x is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom substituted on nitrogen with C3_galkyl or C3_7cycloalkyl, R72 is methoxy, methylthio or iodo, y is 1, and R73 is hydrogen.
Most preferably, when E is group (g), L' is attached to group (g) meta to R7* and para to R72 wherein R7i is piperidin-4-yl substituted on nitrogen with isopropyl, R72 is methoxy, y is 1, and R73 is hydrogen.
A particularly effective subgenus of compounds of formula (I) is wherein, A' is phenyl, 5,6,7,8-tetrahydro-l-naphthalenyl, or lH-indol-4-yl; and when A' is phenyl, R1' is methyl, chloro or trifluoromethyl substituted at the 2 and/or 3-positions, or R1' is 2,4- dimethyl, 2-methoxy-5-chloro, 2-methyl, 3-ethoxycarbonyl, or 3,5-dichloro, D' is a bond, E' and G' together are NCH2, R' is hydrogen, J' is CO, L' is NH, and E is group
(g)-
The term "acyloxy" is used herein at all occurrences to mean a moiety
-O-C(O)-R, wherein R is hydrogen or Ci^alkyl as defined below. The term " C^alkanoyl " is used herein at all occurrences to mean a -C(O)Ci-
4alkyl group wherein the alkyl portion is as defined below.
The term "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.
The term "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.
The term "Cι_5alkoxyCι_6alkoxy" is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
The term is used herein at all occurrences to mean a Cj_
4alkoxy group as defined above bonded to an alkyl group as defined below, including, but not limited to, -CH2-CH2-O-CH2-CH2-CH3 and the like.
The term "C]i _6aιkyl" 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. The term "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 U ited 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.
The term "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.
The term "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.
The term "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]i _5alkyl. Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings.
The term "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.
The terms "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.
The terms "halo" or "halogen" are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
The term "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.
The term "hydroxyCi.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-CH2-CH(OH)CH3 and the like. The terms and "hydroxyalkyl" are used herein interchangeably to mean an hydroxyl group bonded to a Cι_6alkyl group as defined above, including, but not limited to, methanol, ethanol, n-propanol, isopropanol, n- butanol, sec-butanol, isobutanol, tert-butanol, and the like.
The term "heterocyclic ring" is used herein at all occurrences to mean a saturated or partially saturated 5-10-membered ring system (unless the cyclic ring system is otherwise limited) in which the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with Cj.galkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, piperazine, pyrrolidine, morpholine, imidazolidine, pyrazolidine, hexahydroazepine, and the like. 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- 1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by C^gal yl or oxo.
The term "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 NRa or NRaRb moiety, wherein Ra and Rb are, independently, hydrogen or C1 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. The term "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.
The term "oxo" is used herein at all occurrences to mean a double bonded oxygen atom attached to a chemical moiety as a substituent. The term "CCR5 mediated disease state" is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
Suitably, 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.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, 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. Among the preferred compounds of the invention are the following compounds:
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenyl-l,2,3,6- tetrahydropyridine-1-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine-l- carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide;
N-[3-(2-DiisopiOpylamino)ethoxy-4-methoxyphenyl]- 4-(3 -trifluoromethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(2-chlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(4-chlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3 ,4-dichlorophenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine-l -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4- phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro-2(lH)- quinolinone-6-yl)piperazine- 1 -carboxamide ; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piρerazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- cyanophenyl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- [4- (ethoxycarbonyl)phenyl]ρiperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2- (ethoxycarbonyl)ρhenyl]piρerazine-l-carboxamide;
N-[2,3-dihydro- -isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl ] -4-(3 - methylphenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,5- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dichlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- methoxyphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethoxyphenyl)piperazine-l-carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- [3 - (ethoxycarbonyl)phenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- cyanophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- cyanophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-pyridinyl)piperazine- 1-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4-pyridinyl)piperazine-
1-carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxypheny 1] -4- [4-chloro-3 - (trifluoromethyl)phenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl jpiperazine- 1 -carboxamide ;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-( 1 - naphthalenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(lH-indol-4- yl)piperazine- 1 -carboxamide ; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4-methoxyphenyl)-3- methylpiperazine-1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methoxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- hy droxyphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3-chloro-2- methylphenyl)piperazine-l-carboxamide; 4-(2,3-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,3-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl]- 1 -piperazinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- carboxyphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- carboxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dimethoxyphenyl)- 1-piperazinecarboxamide; 4-(2-Benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide;
4-(2-Benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
4-(lH-Indol-2-yl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide;
4-(lH-Indol-2-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperidinecarboxamide;
4-(4-Chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxypheny]-4- hydroxy- 1 -piperidinecarboxamide ; 4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-
4-hydroxy- 1 -piperidinecarboxamide;
4-Acetyl-4-(4-chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l-piρeridmecarboxamide;
4-Acetyl-4-(4-chloroρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
4-(4-Chlorophenyl)-4-cyano-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l-piperidinecarboxamide;
4-(4-Chlorophenyl)-4-cyano-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxypheny]-4-(4-hydroxyphenyl)~l- piperidinecarboxamide; 4-(4-Hydroxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
4-(6-Chloro-2-benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxyphenyl]-l-piperazinecarboxamide;
4-(6-Chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl]- 1 -piperazinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-pyrazinyl)-l- piperazinecarboxamide;
N- [4-Methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -4-(2-pyrazinyl)- 1 - piperazinecarboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[5-(trifluoromethyl)-2- pyridinyl] - 1 -piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[5- (trifluoromethyl)-2-pyridinyl]-l-piperazinecarboxamide;
4-(3,4-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide;
4-(3 -Chlorophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide; 4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-
1-piperazinecarboxamide;
4-(3,4-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dichloroρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,6-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(2,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(3-methylphenyl)-
1-piperazinecarboxamide;
4-(2,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl]- 1 -piperazinecarboxamide;
4-(3,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l -piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro-l-naphthalenyl)-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2-methylphenyl)- 1 -piperazinecarboxamide; 4-(5-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[3- (trifluoromethyl)phenyl]l-piperazinecarboxamide;
4-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3-
(trifluoromethyl)phenyl]-l-piperazinecarboxamide;
4-(3-Methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- ρiperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Cy anophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1-piperazinecarboxamide;
4-(4-Cyanophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide; 4-[3-(Ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[3-(3-diisopropylamino)propoxy-4- methoxyphenyl]-l-piperazinecarboxamide; and
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(4- carboxyphenyl)piperazine- 1 -carboxamide.
Among the more preferred compounds of the invention are the following compounds:
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine-l-carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(2,3 - dichlorophenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine- 1 -carboxamide; N-[2,3-Dihydro- -isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[3- (ethoxycarbonyl)phenyl]piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- [2-methyl-3 - (trifluoromethyl)phenyl]piperazine- 1-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methoxyphenyl)piperazine-l-carboxamide; 4-(6-Chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(3-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide;
4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(3 ,4-Dichlorophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(3,5-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl]- 1 -piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(3-methylρhenyl)- 1 -piperazinecarboxamide;
4-(2,5-Dimethylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1 -piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro-l-naphthalenyl)-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2-methylphenyl)- 1 -piperazinecarboxamide ;
4-(5-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(3-Chloro-2-methylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[3-
(trifluoromethyl)phenyl]l-piperazinecarboxamide;
4-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piρeridinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl]-l-piperazinecarboxamide;
4-(3-Methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(2-Cyanophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -
1-piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-ρiperidinyl]ρhenyl]-l- piperazinecarboxamide;
N-[4-Methoxy-3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro- 1 -naphthalenyl)- 1 -piperazinecarboxamide; 4-[3-(Ethoxycarbonyl)phenyl]-N-[3-(3-diisopropylamino)propoxy-4- methoxyphenyl]-l-piperazinecarboxamide; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3-chloro-2- methylphenyl)piρerazine- 1 -carboxamide.
Among the most preferred compounds of the invention are the following compounds:
4-(3,5-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro- 1 -naphthalenyl)- 1 -piperazinecarboxamide ;
4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl] - 1 -piperazinecarboxamide ;
4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyljpiperazine- 1 -carboxamide.
Formulation of Pharmaceutical Compositions
The pharmaceutically effective compounds of this invention (and the pharmaceutically acceptable salts thereof) 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. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, 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.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, 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. When a liquid carrier is used, 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.
By topical administration is meant 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. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
While it is possible for an active ingredient to 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. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of 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. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. 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. 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. By "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. In one aspect, 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).
By the term "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.
In another aspect, the invention relates to a method for modulating factors which exacerbate the symptoms of the CCR5-mediated diseases described herein.
The term 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. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. Methods of Preparation
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.
For example, as shown in Scheme 1, compounds of formula (I) where L' is NR30 are prepared by treating a suitably substituted aniline 1-1 with suitable reagent, for example triphosgene, and a suitable base, for example triethylamine, in a suitable solvent, for example dichloromethane, followed by treatment with a suitably substituted amine 1-2, e.g., l-(5,6,7,8-tetrahydro-l-naphthalenyl)piperazine, ethyl 3-(l-piperazinyl)benzoate, 4- (phenyl)piperidine, l-(phenyl)piperazine, 4-phenyl-2,3,4,6-tetrahydropyrdine, hexahydro- l-phenyl-lH-l,4-diazepine, etc., to afford the title compound 1-3.
Scheme 1
R30'
H J'— — E
1-2 Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (a) are prepared according to the methods of international application publication number WO 95/15954, published 15 June 1995, international application publication number WO 95/17398, published 29 June 1995, international application publication number WO 95/26328, published 5 October 1995, and international application publication number WO 96/06079, published 29 February 1996.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (b) are prepared according to the methods of international application publication number WO 95/11934, published 25 April 1995, and WO 95/19477, published 27 June 1995. Four other applications relate to the spiro compounds WO 97/17350 published 15 May 1997; WO 97/34900 published 25 September 1997; WO 97/34901 published 25 September 1997; WO 97/35862 published 2 October 1997.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (c) are prepared according to the methods of international application publication number WO 95/30675, published 16 November 1995. Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (f) are prepared according to the methods of international application publication number WO 95/17401, published 29 June 1995.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group or formula (g) are prepared according to the methods of international application publication number WO 96/31508 published 10 October 1996.
Suitably substituted anilines used to prepare compounds of formula (I) where E is a group of formula (h) are prepared according to the methods of international application publication number WO 95/32967, published 7 December 1995 and WO 97/07120, published 27 February 1997, WO 97/07120, published 27 February 1997. Suitably substituted anilines used to prepare compounds of formula (I) where 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.
Novel intermediates useful in preparing compounds of formula (I) are also included in the scope of this invention. For example, as shown in Scheme 2, certain anilines wherein E is a group (g) are prepared from commercially available 4-(2- methoxyphenyl)piperidine, 2-1 by treatment with a suitable acylating agent, for example trifiuoroacetic anhydride, and suitable base, for example triethylamine, in a suitable solvent, for example dichloromethane. Nitration of the resulting N-acylated phenylpiperidine with a suitable nitrating agent, for example 70% nitric acid in acetic anhydride, at a suitable temperature, for example 0°C, for a suitable time, for example 30 minutes, yields 2-2. Removal of the piperidine nitrogen protecting group from 2-2 with a suitable reagent, for example potassium carbonate, in a suitable solvent, for example aqueous methanol, at a suitable temperature, for example room temperature, gives 2-3 where R is H. Treatment of 2-3 where R is H with a suitable alkylating agent RX where R is C^galkyl or C3_7cycloalkyl, for example isopropyl, and X is a suitable leaving group, for example iodo, bromo, methanesulfonyloxy, trifluoromefhysulfonyloxy, etc., and with a suitable base, for example potassium carbonate, in a suitable solvent, for example dimethylformamide and acetonitrile, at a suitable temperature, for example 70°C, for a suitable time, for example 20 hours gives 2-3 where R is Cχ_galkyl or C3_7cycloalkyl. Alternatively, 2-3 where R is H may be reductively alkylated on the piperidine nitrogen by treatment with a C _galdehyde, C3. gketone, or a C3_7cyclic ketone, for example, cyclopentanone, and a suitable reducing agent, for example sodium cyanoborohydride, in a suitable solvent, for example, acetic acid and methanol, for a suitable time, for example 16 hours, to afford 2-3 where R is Cx.galkyl or C3_7cycloalkyl. Reduction of the nitro group in 2-3 where R is Cχ_ galkyl or C3_7cycloalkyl with a suitable reagent, for example hydrogen, in the presence of a suitable catalyst, for example palladium hydroxide, in a suitable solvent, for example ethanol, for a suitable time, for example 4 hours, affords 2-4. Compounds 2-4 are examples of 1-1 in Scheme 1 and are converted to 1-3, which are compounds of formula (I)
Scheme 2
2-1 2-2
2-3 2-4
(a) TFAA, Et3N, CH2C12, 16 h; (b) HNO3, Ac2O, 0°C, 30 min; (c) K2CO3, MeOH, H2O, 40 h; (d) K2CO3, RX, DMF, MeCN, 70°C, 20 h or RCHO/RRCO, NaBH3CN, AcOH, MeOH, Δ, 16 h; (e) H2, Pd(OH)2, EtOH, 4 h.
Particularly useful intermediates for preparing compounds of formula (I) are: 4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]benzenamine; 4-methoxy-3 - [ 1 -cyclopentyl-4-piperidinyl]benzenamine; and 4-methoxy-3-[l-(3-pentyl)-4-piperidinyl]benzenamine. The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In the Examples, mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated.
EXAMPLES
Preparation 1 Preparation of 4-Methoxy-3 - r 1 -(1 -methylethyl)-4-piperidinyl)benzenamine a) 4-(2-methoxyphenyl)-l-(trifluoroacetyl)piperidine Trifluoroacetic anhydride (8.1 g, 39 mmol) was added portionwise over 10 rnin to a solution of commercially available 4-(2-methoxyphenyl)piperidine (6.7 g, 35 mmol), triethylamine (7.8 g, 77 mmol), and dichloromethane (100 mL) at RT. The reaction was maintained at RT for 16 h. The resultant mixture was washed with saturated sodium bicarbonate, saturated ammonium chloride, and with brine, dried (MgSO4), and concentrated in vacuo to afford 10 g (99%) of the title compound as an amber oil. MS(ES) m/e 288.1 [M+H] +. b) 4-(2-methoxy-5-nitrophenyl)-l-(trifluoroacetyl)piperidine Nitric acid (70%, 3.1 mL) was added portionwise to a solution of the compound of Preparation 1(a) (5.0 g, 17 mmol) in acetic anhydride (17 mL) at 0°C. The mixture was maintained at 0°C for an additional 30 rnin, 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. The resulting mixture was extracted with dichloromethane (2 x 400 mL) and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 12 g (>100%) of a 2.2: 1 mixture of the title compound and its 3-nitro isomer. The crude product was recrystallized from methanol (30 mL) to give 5.9 g (54%) of the title compound as off-white crystals. MS(ES) m/e 333.1 [M+H] +. c) 4-(2-methoxy-5-nitrophenyl)piperidine Potassium carbonate (10 g, 74 mmol) was added to a solution of the compound of Preparation 1(b) (4.9 g, 15 mmol), methanol (100 mL) and water (7.5 mL). The resultant mixture was stirred at RT for 40 h, concentrated in vacuo, and the residue partitioned between water and dichloromethane. The layers were separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSU4), and concentrated in vacuo to give 3.7 g (>100%) of the title compound as an off-white solid. MS(ES) m/e 237.2 [M+H] +. d) 4-(2-methoxy-5-nitrophenyl)- 1 -(1 -mefhylefhyl)piperidine Potassium carbonate (8.6 g, 62 mmol) and isopropyl iodide (8.0 g, 47 mmol) were added to a solution of the compound of Preparation 1(c) (3.7 g, 16 mmol), dimethylformamide (10 mL) and acetonitrile (50 mL). The resultant mixture was heated at 70°C for 20 h, concentrated in vacuo, and the residue partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with water (3 x 100 mL) and with brine, dried (MgSO4), and concentrated in vacuo to provide 4.0 g (90%) of the title compound as a yellow solid. MS(ES) m/e 279.2 [M+H] +. e) 4-methoxy-3- [ 1 -( 1 -methylethyl)-4-piperidinyl)benzenamine Palladium hydroxide on carbon (1.2 g, 20% dry weight) was added to a solution of the compound of Preparation 1(d) (4.0 g, 14 mmol) in ethanol (100 mL). The mixture was hydrogenated at 50 psi for 4 h, filtered through Celite®, and concentrated in vacuo. The residue was dissolved in ether (200 mL) and washed with 10% sodium carbonate and with water (2 x 100 mL). The ether solution was dried (MgSO4) and concentrated in vacuo to provide 3.0 g (84%) of the title compound as a tan solid. MS(ES) m/e 249.2 [M+H] +.
Preparation 2 Preparation of l-(5.6,7.8-Tetrahydro-l-naphthalenyl)piperazine Following the general procedure of Kuipers, et. al., J. Med. Chem., 1995, 38,
1942-1954, bis(chloroethyl)amine hydrochloride (2 g, 11.2 mmol) was added to a solution of 5,6,7,8-tetrahydro-l-naphthylamine (1.65 g, 11.2 mmol) in chlorobenzene (15 mL) and the mixture was heated to 135°C for 2 days. The mixture was cooled, concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 5% methanol/dichloromethane) to give the title compound as a tan solid which was further purified by HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A:0.1% trifluoroacetic acid in acetonitrile B:0.1% aqueous trifluoroacetic acid, A: 10 to 90% during 10 rnin, UV detection at 254 nm) to give the title compound as a tan solid (0.25 g).
Preparation 3 Preparation of Ethyl 3-(T-piperazinyl benzoate
Following the general procedure of Kato et. al., WO 9802432 and of Preparation 2, except substituting ethyl 3-aminobenzoate for 5,6,7,8-tetrahydro-l- naphthylamine, gave the title compound. MS(ES) m/e 235.2 [M+H]+. Preparation 4 Preparation of 4-Methoxy-3-ri-cyclopentyl-4-piperidinyl1benzenamine a) 4-(2-methoxy-5-nitrophenyl)- 1 -(cyclopentyl)piperidine A solution of the compound of Preparation 1(c) (3.4 g, 14.4 mmol) in methanol (21 mL) was treated with acetic acid (8.5 g, 0.14 mol), cyclopentanone (6.12 g, 71.4 mmol) and sodium cyanoborohydride (3.74 g, 57.8 mmol). The resulting mixture was heated to reflux for 16 h, concentrated in vacuo, and the residue was partitioned between dichloromethane and 2N sodium hydroxide. The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound. b) 4-methoxy-3-[l-cyclopentyl-4-piperidinyl]benzenamine
Following the general procedure of Preparation 1(e), except substituting the compound of Preparation 4(a) for the compound of Preparation 1(d), gave the title compound.
Preparation 5
Preparation of 4-Methoxy-3-[l-(3-pentyl)-4-piperidinyl1benzenamine
The title compound is prepared following the procedure of Preparation 4(a)- 4(b), except substituting 3-pentanone for cyclopentanone.
Example 1
Preparation of N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyn-4-phenyl-1.2,3,6- tetrahydropyridine- 1 -carboxamide
A solution of triphosgene (0.23 g, 0.77 mmol) in dichloromethane (25 mL) was stirred in an ice bath and treated with a solution of 4-phenyl-l,2,3,6-tetrahydropyridine hydrochloride (0.5 g, 2.6 mmol) and triethylamine (1 g, 10.2 mmol) in dichloromethane added dropwise. The ice bath was removed and the mixture was stirred for 30 rnin, treated with 3-(2-diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954)(0.68 g, 2.55 mmol), and stirred for 16 h. The mixture was diluted with dichloromethane (50 mL), extracted with 5% sodium carbonate, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed (silica gel, 8% methanol/dichloromethane saturated with ammonia) to give the title compound. MS(ES) m/e 452.0 [M+H]+.
Example 2 Preparation of N-r3-('2-Diisopropylamino ethoxy-4-methoxyphenyll-4-(2.3- dimethylρhenv piρerazine-1-carboxamide;
Triphosgene (74 mg, 0.25 mmol) was added to a solution of 3-(2- diisopropylamino)ethoxy-4-methoxyaniline (WO 95/15954)(200 mg, 0.75 mmol) and dichloromethane (3 mL) and maintained at RT for 30 rnin. Triethylamine (0.30 g, 0.42 mL, 3.0 mmol) was added and the resulting mixture was stirred for 1 h, treated with l-(2,3-dimethylphenyl)piperazine (0.11 g, 0.60 mmol), and the mixture stirred at RT for 16 h. The mixture was washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 20:1:0.04 dichloromethane:methanol:triethylamine) to give 205 mg (70%) of the title compound as an off-white powder. MS(ES) m/e 483.1 [M+H] +.
Examples 3-22 Following the procedure of Example 2, except substituting 1-phenylpiperazine, l-(2-methylphenyl)piperazine, l-[2-(acetamidomethyl)phenyl]-piperazine(GB 2309458), l-[3-(trifluoromethyl)phenyl]piperazine, l-(2-methoxyphenyl)piperazine, 1- (2-chlorophenyl)piperazine, l-(3-chlorophenyl)piperazine, l-(4- chlorophenyl)piperazine, l-(2,6-dimethylphenyl)piperazine, l-(2,3- dichlorophenyl)piperazine, and l-(3,4-dichlorophenyl)piperazine for l-(2,3- dimethylphenyl)piperazine, gave the following compounds:
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine-l- carboxamide: MS(ES) m/e 454. 9 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine-l -carboxamide: MS(ES) m/e 469.1 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide: MS(ES) m/e 525.9 [M+H] +;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-trifluoromethylphenyl)piperazine-l-carboxamide: MS(ES) m/e 522.8 [M+H]+; N-[3-(2-diisopiOpylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine-l-carboxamide: MS(ES) m/e 485.0 [M+H]+;
N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -
4-(2-chlorophenyl)piperazme-l-carboxamide: MS(ES) m/e 488.9 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine-l-carboxamide: MS(ES) m/e 488.8 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(4-chlorophenyl)piperazine-l-carboxamide: MS(ES) m/e 488.8 [M+H]+;
N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine-l-carboxamide: MS(ES) m/e 483.1 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine-l-carboxamide: MS(ES) m/e 522.9 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3,4-dichlorophenyl)piperazine-l-carboxamide: MS(ES) m/e 522.7 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine-l-carboxamide: MS(ES) m/e 483.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine-l -carboxamide: MS(ES) m/e 499.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine-l-carboxamide: MS(ES) m/e 483.2 [M+H]+; N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -3 -methyl-4- phenylpiperazine-1-carboxamide: MS(ES) m/e 469.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro-2(lH)- quinolinone-6-yl)piperazine-l -carboxamide: MS(ES) m/e 524.2 [M+H]+;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine-l-carboxamide: MS(ES) m/e 483.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- cyanophenyl)piperazine-l -carboxamide: MS(ES) m/e 480.2 [M+H]+; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[4- (ethoxycarbonyl)phenyl]piperazine-l -carboxamide: MS(ES) m/e 527.2 [M+H]+; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2- (ethoxycarbonyl)phenyl]piperazine-l -carboxamide: MS(ES) m/e 527.2 [M+H]+.
Example 23 Preparation of 1 '-(l-Methylethyl)spirorbenzofuran-3(2H),4'-piperidin1-5-amine a) 5- and 7-nitrospiro[benzofuran-3(2H .4 '-piperidine]
A solution of l'-methyl-5- and 7-nitrospiro[benzofuran-3(2H),4'-piperidine] (WO 96/11934) (3 g, 12 mmol) and diisopropylethylamine (2.5 g, 19 mmol) in 1,2- dichloroethane (80 mL) was treated with 1-chloroethyl chloroformate (2.3 g, 16 mmol) at RT, stirred for 1 h, and heated to reflux for 20 rnin. The mixture was cooled, concentrated in vacuo, and the residue was dissolved in methanol and heated to reflux for 2 h, concentrated in vacuo, and the residue was partitioned between dichloromethane (250 mL) and 5% sodium bicarbonate (50 mL). The organic phase was washed with 5% sodium bicarbonate (50 mL) and the combined aqueous phase was extracted with dichloromethane (2 X 50 mL). The combined organic phase was dried (Na2SO4) and concentrated to afford the title compound (2.65 g). b) -(tert-butoxycarbonyl)-5-nitrospirorbenzofuran-3(2H').4'-piperidine] A solution of the compound of Preparation 2(a) (2.65 g, 1.13 mmol) in tetrahydrofuran (300 mL) was treated with di-tert-butyl dicarbonate (2.6 g, 12 mmol) and stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was crystallized from methanol to afford the title compound (2.1 g). c) 5-nitrospiro[benzofuran-3(2H14 '-piperidine] A solution of the compound of Preparation 2(b)(2.1 g, 6.3 mmol) in dichloromethane (50 mL) and trifluoroacetic acid (10 mL) was kept at RT for 5 h, concentrated in vacuo, and the residue was partitioned between dichloromethane (300 mL) and 5% sodium bicarbonate. The organic phase was washed with 5% sodium bicarbonate and the combined aqueous washes were extracted with dichloromethane. The combined organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (1.45 g). MS(ES) m/e 235.1 [+H]+. d) 1 '-( 1 -methylethyl)-5-nitrospiro Fbenzofuran-3 (2H) .4 -piperidine]
A mixture of the compound of Preparation 2(c) (1.45 g, 6.2 mmol), powdered potassium carbonate (0.86 g, 6.2 mmol) and dimethylformamide (50 mL) containing 2- iodopropane (1.1 g, 6.4 mmol) was stirred and heated to 50°C for 4 h, treated with 2- iodopropane (0.17 g, 1 mmol) at 50°C for 90 rnin, and treated with 2-iodopropane (0.1 g, 1 mmol) at 50°C for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed, dried (MgSO4), concentrated in vacuo, and the residue was chromatographed (silica gel, 5% methanol: dichloromethane) to give the title compound (0.85 g). e) r-(l-methylethyl)spiro[benzofuran-3(2H .4'-piperidin]-5-amine A solution of the compound of Preparation 2(d) (0.78 g, 2.8 mmol) in methanol
(250 mL) containing 10% palladium-on-carbon (0.375 g) was shaken in a hydrogen atmosphere (40 psi) for 40 rnin, filtered, and concentrated in vacuo to afford the title compound (0.6 g).
Example 24
Following the procedure of Example 2, except substituting the compound of Example 23(e) for 3-(2-diisopropylamino)ethoxy-4-methoxyaniline, gave the following compound:
N-[2,3-dihydro-r-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine-l -carboxamide: MS(ES) m/e 463.1 [M+H]+.
Examples 25-46 Following the procedure of Example 2, except substituting l-(3- methyipheny piperazine, l-(4-methylphenyl)piperazine, l-(2,5- dimethylphenyl)piperazine, 1 -(3 ,4-dimethylphenyl)piperazine, 1 -(3 ,5- dichlorophenyl)piperazine, l-(3-methoxyphenyl)piperazine, l-(3,5- dimethoxyphenyl)piperazine, l-[3-(ethoxycarbonyl)phenyl]piperazine, l-(2- cyanophenyl)piperazine, l-(4-cyanophenyl)piperazine, l-(2-pyridinyl)piperazine, l-(4- pyridinyl)piperazine, l-[4-chloro-3-(trifluoromethyl)phenyl]piperazine, l-[2-methyl-3- (trifluoromethyl)phenyl]piperazine, 1 -( 1 -naphthalenyl)piperazine, 1 - [ 1 -(5 ,6 ,7 , 8- tetrahydronaphthalenyljpiperazine, l-(lH-indol-4-yl)piperazine, l-(4-methoxyphenyl)- 3-methylpiperazine, l-(5-chloro-2-methoxyphenyl)piperazine, l-(3- hydroxyphenyl)piperazine, l-(5-chloro-2-methylphenyl)piperazine, and l-(3-chloro-2- methylphenyl)piperazine for l-(2,3-dimethylphenyl)piperazine, gave the title compounds: N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4-(3 - methylphenyl)piperazine-l-carboxamide: MS(ES) m/e 469.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-mefhoxyphenyl]-4-(4- methylphenyl)piperazine-l-carboxamide: MS(ES) m/e 469.4 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,5- dimethylphenyl)piperazine-l-carboxamide: MS(ES) m/e 483.4 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4- dimethylphenyl)piperazine-l -carboxamide: MS(ES) m/e 483.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dichlorophenyl)piperazine-l-carboxamide: MS(ES) m/e 523.4 [M+H]+; N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4-(3 - methoxyphenyl)piperazine-l-carboxamide: MS(ES) m/e 485.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethoxyphenyl)piperazine-l-carboxamide: MS(ES) m/e 515.4 [M+H]+; N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4- [3- (ethoxycarbonyl)phenyl]piperazine-l -carboxamide: MS(ES) m/e 527.4 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- cyanophenyl)piperazine-l-carboxamide: MS(ES) m/e 480.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- cyanophenyl)piperazine-l-carboxamide: MS(ES) m/e 480.4 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-pyridinyl)piperazine-
1-carboxamide: MS(ES) m/e 456.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4-pyridinyl)piperazine- 1-carboxamide: MS(ES) m/e 456.4 [M+H]+;
N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4- [4-chloro-3- (trifluoiOmethyl)phenyl]piperazine-l-carboxamide: MS(ES) m/e 557.2 [M+H]+; N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4- [2-methyl-3 - (trifluoromethyl)phenyl]piρerazine-l-carboxamide: MS(ES) m e 537.4 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(l- naphthalenyl)piρerazine-l -carboxamide: MS(ES) m/e 505.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine-l -carboxamide: MS(ES) m/e 509.6 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(lH-indol-4- yl)piperazine-l -carboxamide: MS(ES) m/e 494.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4-methoxyphenyl)-3- methylpiperazine-1 -carboxamide: MS(ES) m/e 499.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methoxyphenyl)piperazine-l -carboxamide: MS(ES) m/e 519.4 [M+H]+; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- hydroxyphenyl)piperazine-l -carboxamide: MS(ES) m/e 471.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methylphenyl)piperazine-l -carboxamide: MS(ES) m/e 503.4 [M+H]+; and N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4-(3 -chloro-2- methylphenyl)piperazine-l -carboxamide: MS(ES) m/e 503.4 [M+H]+.
Example 47 Preparation of 4-(2.3-Dimethylphenyl -N-[4-methoxy-3-ri-(l-methylethyl)-4- piperidinyllphenyl] - 1 -piperazinecarboxamide
Triphosgene (12.2 mg, 0.041 mmol) was added to a solution of the compound of Preparation 1(e) (31 mg, 0.125 mmol) in dichloromethane (1 mL). The mixture was ,Pj stirred for 30 rnin and then triethylamine ( 0.07 mL, 0.5 mmol) was added. The mixture was stirred an additional 1 h, treated with l-(2,3-dimethylphenyl)piperazine (31.0 mg, 0.125 mmol), and the mixture stirred at RT overnight. The resultant mixture was concentrated in vacuo and the residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A:0.1% trifluoroacetic acid in acetonitrile B:0.1% aqueous trifluoroacetic acid, A: 10 to 90% during 10 rnin, UV detection at 254 nm) to give 30 mg (52%) of the title compound as a yellow oil. MS(ES) m/e 465.4 [M+H] +.
Example 48 Preparation of 4-(2.3-Dichlorophenyl)-N-r4-methoxy-3-ri-(l-methylethy -4- piperidinyllphenyl1-l-piρerazinecarboxamide Following the procedure of Example 47, except substituting l-(2,3- dichlorophenyl)piperazine for l-(2,3-dimethylphenyl)piperazine, gave the title compound. MS(ES) m/e 505.4 [M+H]+. Example 49 Preparation of N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyn-4-(3- carboxyphenyDpiperazine- 1 -carboxamide To a flask containing the compound of Example 32 (5.5 mg, 0.01 mmol) was added 0.5 ml ethanol and 0.3 N sodium hydroxide (0.1 ml, 0.03 mmol.). The mixture was stirred at RT overnight. The resultant mixture was concentrated in vacuo and the residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 rnL/min, A:0.1% trifluoroacetic acid in acetonitrile B:0.1% aqueous trifluoroacetic acid, A:10 to 90% during 10 rnin, UV detection at 254 nm) to give 1.0 mg (19%) of the title compound as a yellow oil. MS(ES) m/e 499.4 [M+H] +.
Examples 50-51 Following the procedure of Example 49, except substituting the compounds of Examples 22 and 21 for the compound of Example 32 gave the title compounds: N- [3 -(2-diisopropylamino)ethoxy-4-methoxyphenyl] -4-(2- carboxyphenyl)piperazine-l-carboxamide: MS(ES) m/e 499.4 [M+H]+; and
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- carboxyphenyl)piperazine-l-carboxamide: MS(ES) m/e 499.4 [M+H]+.
Examples 52-61 Following the procedure of Example 2, except substituting l-(3,4- dimethoxyphenyl)piperazine, 4-(2-benzothiazolyl)piperidine, 4-(lH-indol-2-yl)-l- piperidine, 4-(4-chlorophenyl)-4-hydroxy-l-piperidine, 4-acetyl-4-(4-chlorophenyl)-l- piperidine, 4-(4-chlorophenyl)-4-cyano-l -piperidine, 4-(4-hydroxyphenyl)-l -piperidine, l-(6-chloro-2-benzothiazolyl)piperazine, l-(2-pyrazinyl)piperazine, and l-[5- (trifluoromethyl)-2-pyridinyl]piperazine for l-(2,3-dimethylphenyl)piperazine, gave the following compounds:
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dimethoxyphenyl)- 1 -piperazinecarboxamide: MS(ES) m/e 515.4 [M+H]+;
4-(2-benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide: MS(ES) m/e 511.4 [M+H]+;
4-(lH-indol-2-yl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide: MS(ES) m/e 493.4 [M+H]+; 4-(4-chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxypheny]-4- hydroxy-1 -piperidinecarboxamide: MS(ES) m e 504.4 [M+H]+;
4-acetyl-4-(4-chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l-piperidinecarboxamide: MS(ES) m/e 496.4 [M+H]+; 4-(4-chlorophenyl)-4-cyano-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l -piperidinecarboxamide: MS(ES) m/e 479.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxypheny]-4-(4-hydroxyphenyl)-l- piperidinecarboxamide: MS(ES) m/e 470.4 [M+H]+;
4-(6-chloro-2-benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxyphenyl]-l-piperazinecarboxamide: MS(ES) m/e 546.4 [M+H]+;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-pyrazinyl)-l- piperazinecarboxamide: MS(ES) m/e 457.4 [M+H]+; and N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazinecarboxamide: MS(ES) m/e 524.4 [M+H]+.
Examples 62-96 Following the procedure of Example 47, except substituting 4-(2-benzothiazolyl)-l- piperidine, 4-(lH-indol-2-yl)-l-piperidine, 4-(4-chlorophenyl)-4-hydroxy-l -piperidine, 4- acetyl-4-(4-chlorophenyl)- 1 -piperidine, 4-(4-chlorophenyl)-4-cyano- 1 -piperidine, 4-(4- hydroxyphenyl)-l-piperidine, l-(6-chloro-2-benzothiazolyl)piperazine, l-(2- pyrazinyl)piperazine, l-[5-(trifluoromethyl)-2-pyridinyl]piperazine, l-(3,4- dimethoxyphenyl)piperazine, l-(2-chlorophenyl)piperazine, l-(3-chlorophenyl)-piperazine, 1- (4-chlorophenyl)piperazine, l-(3,4-dichlorophenyl)piperazine, l-(3,5- dichlorophenyl)piperazine, l-(2,6-dimethylphenyl)piperazine, l-(2,4-dimethylphenyl)- piperazine, l-(3,5-dimethylphenyl)piperazine, l-(3-methylphenyl)piperazine, l-(2,5- dimethylphenyl)piperazine, l-(3,4-dimethylphenyl)piperazine, l-(5,6,7,8-tetrahydro-l- naphthalenyl)piperazine, l-(2-methylphenyl)piperazine, l-(5-chloro-2-methylphenyl- piperazine, l-(3-chloro-2-methylphenyl)piperazine, l-(3-chloro-2-methoxyphenyl)- piperazine, l-[3-(trifluoromethyl)phenyl]piρerazine, l-[4-chloro-3-(trifluoromethyl)- phenyl]piperazine, 1 - [2-methyl-3-(trifluoromethyl)phenyl]piperazine, 1 -(3- methoxyphenyl)piperazine, l-(3,5-dimethoxyphenyl)piperazine, l-(2-cyanophenyl)piperazine l-(4-cyanophenyl)piperazine, the compound of Preparation 3, and l-(lH-indol-4- yl)piperazine for l-(2,3-dimethylphenyl)piperazine, gave the following compounds:
4-(2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1 -piperidinecarboxamide: MS(ES) m/e 493.4 [M+H]+;
4-(lH-indol-2-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperidinecarboxamide: MS(ES) m/e 475.4 [M+H]+; 4-(4-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-
4-hydroxy-l -piperidinecarboxamide: MS(ES) m/e 486.4 [M+H]+;
4-acetyl-4-(4-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide: MS(ES) m/e 478.4 [M+H]+; 4-(4-chlorophenyl)-4-cyano-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]ρhenyl]-l-piperidinecarboxamide: MS(ES) m/e 461.4 [M+H]+; 4-(4-hydroxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxarnide: MS(ES) m/e 452.2 [M+H]+; 4-(6-chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 528.2 [M+H]+;
N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -4-(2-pyrazinyl)- 1 - piperazinecarboxamide: MS(ES) m/e 439.2 [M+H]+; N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[5-
(trifluoromethyl)-2-pyridinyl]-l-piperazinecarboxamide: MS(ES) m/e 506.4 [M+H]+;
4-(3,4-dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS (ES) m/e 497.4 [M+H]+;
4-(2-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide: MS(ES) m/e 471.4 [M+H]+;
4-(3-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide: MS(ES) m/e 471.4 [M+H]+;
4-(4-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide: MS(ES) m/e 471.4 [M+H]+; 4-(3,4-dichloroρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m e 505.4 [M+H]+;
4-(3 ,5-dichlorophenyl)-N-[4-methoxy-3- [ 1 -(1 -methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 505.4 [M+H]+; 4-(2,6-dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 465.4 [M+EQ+; 4-(2,4-dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 465.4 [M+H]+;
4-(3,5-dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1-piperazinecarboxamide: MS(ES) m/e 465.4 [M+H]+; N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(3-methylphenyl)-
1-piperazinecarboxamide: MS(ES) m/e 451.4 [M+H]+;
4-(2,5-dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 465.4 [M+H]+; 4-(3,4-dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 465.4 [M+H]+; N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]ρhenyl]-4-(5,6,7,8- tetrahydro-l-naphthalenyl)-l-piperazinecarboxamide: MS(ES) m/e 491.4 [M+H]+; N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2- methylphenyl)-l-piperazinecarboxamide: MS(ES) m/e 451.4 [M+H]+;
4-(5-chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 485.4 [M+H]+; 4-(3-chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 485.4 [M+H]+;
4-(3-chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m e 501.4 [M+H]+; N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[3- (trifluoromethyl)phenyl] 1-piperazinecarboxamide: MS(ES) m/e 505.4 [M+H]+;
4- [4-chloro-3 -(trifluoromethyl)phenyl] -N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m/e 539.4 [M+H]+;
N- [4-methoxy-3 - [ 1 -(1 -methylethyl)-4-piperidinyl]phenyl]-4- [2-methyl-3 - (trifluoromethyl)phenyl]-l-piperazinecarboxamide: MS(ES) m/e 519.4 [M+H]+; 4-(3-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide: MS(ES) m e 467.4 [M+H]+;
4-(3,5-dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl]- 1-piperazinecarboxamide: MS(ES) m/e 497.4 [M+H]+;
4-(2-cy anophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1 - piperazinecarboxamide: MS(ES) m/e 462.4 [M+H]+;
4-(4-cy anophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1 - piperazinecarboxamide: MS(ES) m/e 462.4 [M+H]+;
4-[3-(ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1-piperazinecarboxamide: MS(ES) m/e 509.4 [M+H]+; and 4-(lH-indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide: MS(ES) m/e 476.4 [M+H]+.
Example 97 Preparation of 4-r3-(Ethoxycarbonyl)phenyll-N-r3-r3-rbis(l- methylethyl amino1propoxy1-4-methoxyphenyl1-l-piperazinecarboxamide Following the procedure of Example 2, except substituting 3-(3- diisopropylamino)propoxy-4-methoxy aniline (WO 99/01127) for 3-(2- diisopropylamino)ethoxy-4-methoxyaniline and substituting the compound of Preparation 3 for l-(2,3-dimethylphenyl)piperazine, gave the title compound. MS(ES) m/e 541.4 [M+H]+. Example 98-99 Preparation of 4-(2.3-Dimethylphenyl -N-[4-methoxy-3-[l-cvclopentyl-4- piperidinyl]phenyl]-l-piperazinecarboxamide and 4-(2.3-Dimethylphenyl)-N-ri-(3- pentyl)-4-methoxy-3-[l-cvclopentyl-4-piperidinyl1phenyl1-l-piperazinecarboxamide Following the general procedure of Example 47, except substituting the compounds of Preparation 4(b) and Preparation 5 for the compound of Preparation 1(e), gives the title compounds.
Biological Data: CCR5 Receptor Binding Assay
CHO cell membranes (0.25 xlO6 cell equivalents) derived from CHO cells stably transfected with CCR5 were incubated with 0.3 125I-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
The cellular functional assay used to assess antagonist activity of compounds was RANTES-induced Ca2+ mobilization in RBL 2H3 cells stably expressing the hCCR5 receptor (RBL 2H3 hCCR5). Agonist activity is determined by Ca2+ 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. at room temperature and diluting to 2 X 10^ cells/mL with Krebs Ringer Henseleit buffer (KRH; 118 mM NaCl, 4.6 mM KCl, 25 mM NaHCO3, 1 mM KH2PO4 and 11 mM glucose) containing 5 mM HEPES (pH 7.4), 1 mM CaCl2, 1 mM MgCl2 and 0.1% BSA and centrifuged at 200g for 3 min. Cells were resuspended at 2 X 10^ cells/mL in the same buffer with 2 μM Fura-2AM, and incubated for 35 min. at 37° C. Cells were centrifuged at 200 x g for 3 min. and resuspended in the same buffer without Fura- 2AM, then incubated for 15 min. at 37° C to complete the hydrolysis of intracellular Fura-2AM, and then centrifuged as before. Cells (10^ cells/mL) were resuspended in cold KRH with 5 mM HEPES (pH 7.4), 1 mM CaCl2, 1 mM MgCl2 and 0.1% gelatin and maintained on ice until assayed. For antagonist studies, aliquots (2 mL) of cells were pre-warmed at 37° C for 5 min. in 3 mL plastic cuvettes and fluorescence measured in a fluorometer (Johnson Foundation Biomedical Group, Philadelphia, PA, USA) with magnetic stirring and temperature maintained at 37° C. Excitation was set at 340 nm and emission set at 510 nm. Various concentrations of antagonists or vehicle were added and fluorescence monitored for -15 sec to ensure that there was no change in baseline fluorescence, followed by the addition of 33 nM RANTES. Maximal Ca2+ attained after 33 nM RANTES stimulation was calculated as described by Grynkiewicz et al., (1985). The percent of maximal RANTES -induced Ca + was determined for each concentration of antagonist and the IC5Q; 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 μM. The full structure/activity relationship has not yet been established for the compounds of this invention. However, given the disclosure herein, 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 μM.
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. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:
1. A method of treating a CCR5-mediated disease state in mammals which comprises administering to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
Formula I in which: the basic nitrogen in moiety E may be optionally quatemized with Cχ_galkyl or is optionally present as the N-oxide;
A' is aryl or heteroaryl, each of which is optionally substituted with one or more of R1'; or A' is aryl or heteroaryl fused to a saturated or partly unsaturated 5-7- membered ring to form a higher order ring moiety, which ring moiety optionally contains 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein nitrogen may be optionally substituted with hydrogen, C _galkyl or C3_7cycloalkyl; wherein the higher order ring moiety is optionally substituted with one or more of R*';
Rl' is hydrogen, Ci^alkyl, C2_6 l enyl, C2_6alkynyl, C3_7cycloalkyl, C3. gcycloalkenyl, CH2CF3, aryl, aralkyl, (CH2)a'NR2'R3', (CH2)a'NR2'COR4', (CH2)a'NR2'CO2R5', (CH2)a'NR2'SO2R6', (CH2)aCONR7 R8', Cχ_4alkoxy alkyl (optionally substituted by a Cχ_4alkoxy or hydroxy group), (CH2)aCO2C1.6alkyl, (CH2)b C(O)R9', 1', COR12', CONR7'R8', CONR7'(CH2)c C1.4alkyl, CONR7'(CH2)aCO2R13', CONHNR14'R15', C0NR7'S02R16', CO2R17', cyano, trifluoromethyl, NR2'R3', NR2'C0R4', NRl8'CO(CH2)a'NRl8 Rl9', NR18'CONR18'R19', NR2'CO2R5', NR2 SO R6', N=CNR18'NR18 RI ', nitro, hydroxy, C^alkoxy, OCF3, hydroxyCι_ 6alkoxy, Ci.ealkoxyCx.galkoxy, OC(O)NR20'R21', SR22', SOR23', SO2R23', SO NR20'R21 or halogen, or Rl' is a 5- to 7-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, optionally substituted with hydrogen, C _6alkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxyCχ_6alkyl, (Cχ_ 6alkyl)Cχ_6alkyl, C0NR7'R8', CO2R17', cyano, aryl, trifluoromethyl, nitro, hydroxy, C^.galkoxy, acyloxy, or halogen; a' is l, 2, 3 or 4; b' is O, 1, 2 or 3; c'is 1, 2 or 3; R2' and R3' are independently hydrogen or Cχ_6alkyl, or R2' and R3 together with the nitrogen to which they are attached, form a 5- to 6-membered heterocyclic ring which ring may be optionally substituted by an oxo group, or, when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom; R4' is hydrogen, Ci.gaikyl or Cχ_4alkoxyalkyl, or, when R1' is NR2'C0R4',
R4' is (CH2)i-3 and forms a ring with A'; R5'is Cι_6alkyl; R^'is C^.galkyl or phenyl;
R7' and R8 are independently hydrogen or Cχ_6alkyl, or R7' and R8' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring, wherein when there are 6 ring members, the ring may optionally contain one oxygen or one sulfur atom;
R9 is Cχ_4alkyl, optionally substituted by a Cj.βalkoxy; Rl0 and R11 ' are independently hydrogen or Cj^galkyl; Ri2 is hydrogen or Cχ_6alkyl;
Rl3' is hydrogen or Ci^galkyl;
Rl4 and R^' are independently hydrogen or C _galkyl; R16' JS hydrogen or Cj.galkyl;
Ri7 is hydrogen or Cj.galkyl optionally substituted with one or more substituents selected from C _galkyl, Cχ_6alkoxy, hydroxy, or NR2 R3'; Rl ' and R*9' are independently hydrogen or C^galkyl; R20' and R2i' are independently hydrogen or C _galkyl, or R20' and R i' together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when the ring is 6-membered, may optionally contain in the ring one oxygen or one sulfur atom. 22' is hydrogen or C^.galkyl; R23' is Cι_6alkyl;
D' is either a bond or represents [C(R24')2]a", [C(R24')2]a"CO, CO, SO2, CO[C(R24')2]a--, O[C(R 4')2]a-., S[C(R ')2]a-., O[C(R24')2]a--CO, [C(R2 ')2]C-OCO, NR25'[C(R24')2]a", NR25'[C(R2 ')2]a"CO, [C(R24')2]c"NR25'CO,
NR25"C0[C(R24)2]a", NR25'SO2[C(R24')2]a », [C(R24')2]c"NR25'SO2, CR24'=CR 4'CO, C≡CCO, (C(R2 ')2)c"SO , SO2[C(R24')2]a », NR25'[c(R24')2]a„so2, NR25'S02[C(R24')2]a"SO2, O[C(R2 ')2]a-SO2,
SO2NR25'[C(R2 ')2]i_2, [C(R24')2]b„cOO[C(R24')2]2, [C(R2 ')2]b"CONR25'[C(R24')2]ι.2; and when E' and G' together are CR27'-C(R26')2, then D' may further be O, NR25', CONR25', SO2NR25', OCONR25', NR25'COO, NR25'C0 25,, [C(R24')2]a"NR25'[C(R24')2]b", [C(R24')2]a-.0[C(R24')2]b--, CO[C(R24')2]a»NR25', NR 5'[C(R24')2]a"O, NR25'[C(R24')2]a"NR25',
O[C(R24')2)]a"NR25', O[C(R24')2]a"O, CO[C(R24')2]a--O, SO2[C(R24')2]a"NR25',
SO2[C(R24')2]a»O, [C(R2 ')2]a--SO2NR25', [C(R24')2]a"CONR25',
O[C(R2 ')2]a"SO2NR25', 0[C(R24')2]a"CONR25', NR 5'[C(R24')2]a"SO2NR25', NR25'[C(R24')2]a"CONR25', NR25'C0[C(R24')2]a"NR25',
NR25'so2[C(R2 ')2]a..NR25', (C(R24')2)a"S(C(R24')2)b", COO, CR24'OH,
C(R24')a"CR2 'OH; and when E' and G' together are CR27 -C(R26')2 0r C=CR26', then D' may further be CR2 '=CR24' or C≡C; wherein a" is 1-6, b" is 0-1, and c" is 0-2; R24' is hydrogen or Cχ_6alkyl;
R25' is hydrogen or Cj^alkyl;
E' and G' together are NC(R26')2, NC(R26')2C(R26')2, CR27 C(R26')2 or
C=CR26';
R2^' is hydrogen or Ci^alkyl; R27' is hydrogen, OR28', NHR28', CN, NO2, R28', SR29', COR28',
CHOHR28', CO2R28', NHCOR28', NHCO2R29', NHSO2R29', or OCONHR28';
R28' is hydrogen, Ci^alkyl, aryl or aralkyl;
R29 is C _5alkyl, aryl or aralkyl;
R' is one or more of hydrogen or Cχ_galkyl, or R' is oxo; J' is CO or SO2;
L' is NR30', O or C(R30')2;
R30 is hydrogen or C^.^alkyl;
E represents a group (a):
in which
B is oxygen, C≡C, S(O)c, CR7=CR8, or CR7R8, or B is NR9; R1 and R2 are independently hydrogen or C _galkyl; alternatively B(CRlR2)a is OCR1R2CRl(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, Cj.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 Cι_6alkyl, aryl, CONR^R11, NR10RU, hydroxy, OCOR12, NHCOCF3, NHSO2R13, NHCO2R14, or NHCOC0-6alkyl wherein the alkyl of NHCOC0_6alkyl is optionally substituted by OH;
R5 is hydrogen, Cj.galkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, Cι_6alkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)dR19, SO2NR2°R21 or halogen; R6 is hydrogen, C^alkyl, aryl, trifluoromethyl, hydroxy, C^alkoxy or halogen, or R^ taken together with R30' forms a group D where D is (CR22R23)e or D is (CR2 R23)f_o where G is oxygen, sulfur or CR22=CR23, CR22=N, =CR22O, =CR22S, or =CR22_NR23;
R7, R8, Rl°, RU, Rl , Rl5, Rl6, R17, R20, R21, R22; and R23 ^ independently hydrogen or Cχ_6alkyl;
R9 is hydrogen, Cχ_6alkyl, or phenylCi.galkyl;
R13, R14, R18, and R19 are independently Ci.galkyl; 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; alternatively, E represents a group (b):
R24, R25, R26, R27, R28, R29, R31, and R32 are independently hydrogen or
Cι_6alkyl;
R30 is hydrogen, Cχ_galkyl, or C3_7cycloalkyl;
R33 is hydrogen, Cχ_galkyl, trifluoromethyl, hydroxy or halogen, orR33 and R30' together form a group -K- where K is (CR34R35)i or K is (CR34R35)j -M and M is oxygen, sulfur, CR 4=CR35, CR34=N, or N=N;
J is oxygen, CR3^R37, or NR38, or J is a group 8(0)^;
R34, R35, R36, R37; and R38 aj-g independently hydrogen or C^galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; alternatively, E represents a group (c): in which:
Q is oxygen, S(O)n, CR44=CR45, CR44R45, or Q is NR46; R39 and R40 are independently hydrogen or Cχ_galkyl; R41 is a group of formula (d):
or R4i is a group of formula (e):
R42 is hydrogen, Cx.galkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl,
NHCO2R51, hydroxy, Ci^alkoxy, benzyloxy, OCH2CO2C1_6alkyl, OCF3, S(O)sR52, SO2NR53R54, or halogen;
R43 is hydrogen or R43 together with R30' forms a group R where R is CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t; R44, R45, R46, R48, R49, R50, R53, R54, R55, and R56 are independently hydrogen or Ci^alkyl;
R47 is hydrogen, Cχ_6alkyl, or 03.7 cycloalkyl; R51 and R52 are independently Cχ_galkyl; l is O, 1, 2, or 3; m is 1 or 2; n is O, l, 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; alternatively, E represents a group (f):
R57 and R58 are independently hydrogen or Cx.galkyl; R59 and R^0 are independently hydrogen, Cχ_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 Cχ_6alkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOCF3, NHSO2R64, NHCO2R65, or NHCOC0_6alkyl wherein the alkyl of NHCOC0-6alkyl is optionally substituted by OH; T is -(CR66R67)V- or -O(CR66R67)w-;
W is oxygen, S(O)x, NR°A or W is CR69=CR70 or CR69R70; R61, R62, R63, R66, R67 R68, R69, and R70 are independently hydrogen or Cx.galkyl;
R^ and R^5 are independently C _6alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; alternatively, E represents a group (g):
R71 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 R7i 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 Cχ_6alkyl and optionally substituted on nitrogen with hydrogen, Cχ_6alkyl or C^. 7cycloalkyl;
R72 is hydrogen, C^alkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, Ci^alkoxy, benzyloxy, OCH2CO2Ci_6alkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R73 is hydrogen, Cχ_6alkyl, hydroxy, Ci^alkoxy or halogen, or R73 and R30' taken together from a group -X- where X is (CR81R82)aa or X is (CR8lR82)ab-γ and Y is oxygen, sulfur or CR81=CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or Cι_ βal yl;
R77 and R78 are independently Cχ_6alkyl; ! y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; alternatively, E represents a group (h):
R87 (h);
R83 and R84 are independently hydrogen or Cχ_6alkyl;
R85 and R8^ are independently hydrogen, Cj.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 _6alkyl, aryl, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOCF3, NHSO2R93, NHCO2R94 or NHCOC0_6alkyl wherein the alkyl of NHCOC0-6alkyl is optionally substituted by OH;
R87 is hydrogen or Cχ_6alkyl, Cχ_6alkoxy, or halogen, or R87 together with R30' forms a group -AA- where AA is (CR95R96)ad 0r AA is (CR 5=CR96)ae-AB and AB is oxygen, sulfur, CR95=CR96, CR95=N, CR95NR96 or N=N;
Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R88, R89, R90 R91, R92, R95, and R96 are independently hydrogen or Cχ_ 6alky!;
R93 and R94 are independently Ci^aikyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; alternatively, E represents a group (i):
R97 and R98 are independently hydrogen, Cx.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^alkyl, aryl, CONR102R103, NR104R105, hydroxy, OCOR106,
NHCOCF3, NHSO2 R107, NHCO2R108, orNHCOC0-6alkyl wherein the alkyl of
NHCOCo-6alkyl is optionally substituted by OH;
R99 and R 0 are independently hydrogen or Cj.βalkyl;
R!°1 is hydrogen or Cχ_6alkyl or R!°1 and R30' together form a group -AD- where AD is (CR109R110)ai or AD is (CR109R110)aj-AE and AE is oxygen, sulfur or
CRl09=CRll°;
AC is oxygen, CR111!*.112 or NR113 or AC is a group S(O)ak;
R102 R1035 R104 R105, R106 R109 R110, RIII, R112 and R113 m independently hydrogen or Ci.galkyl; Rl°7 and R108 are independently Cj.galkyl; af is 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 0, 1, 2, or 3; and ak is 0, 1 or 2.
2. The method as claimed in claim 1 , wherein the compound of formula (I) is selected from: N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenyl-l,2,3,6- tetrahydropyridine-1-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine-l- carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine-l-carboxamide; N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] - 4-(3 -trifIuoromethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine- 1-carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] - 4-(2-chlorophenyl)piperazine-l-carboxamide;
N-[3~(2-Diisopropylamino)ethoxy-4-methoxyphenyl]~ 4-(3-chlorophenyl)piperazine-l-carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] - 4-(4-chlorophenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3,4-dichlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4- phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro-2(lH)- quinolinone-6-yl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine- 1 -carboxamide ;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(3 - cyanophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[4- (ethoxycarbonyl)phenyl]piperazine- 1 -carboxamide ; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2-
(ethoxycarbonyl)phenyl]piperazine-l-carboxamide;
N-[2,3-dihydro- -isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- methylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methylphenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,5- dimethylphenyl)ρiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4- dimethylphenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dichlorophenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 methoxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethoxyphenyl)piperazine-l -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- (ethoxycarbonyl)phenyl]piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- cyanophenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- cyanophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 2-pyridinyl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- 4-pyridinyl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- 4-chloro-3- (trifluoromethyl)phenyl]piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl]piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 naphthalenyl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- [ 1 -(5 ,6,7,8- tetrahydronaphthalenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(lH-indol-4- yl)ρiperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 4-methoxyphenyl)-3 - methylpiperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 5-chloro-2- methoxyphenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- hydroxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3-chloro-2- methylphenyl)piperazine- 1 -carboxamide;
4-(2,3-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,3-Dichloroρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- carboxyphenyl)piperazine- 1 -carboxamide; N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(2- carboxyphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dimethoxyphenyl)- 1 -piperazinecarboxamide;
4-(2-Benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide;
4-(2-Benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
4-(lH-Indol-2-yl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide; 4-(lH-Indol-2-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-ρiperidinyl]phenyl]-l- piperidinecarboxamide;
4-(4-Chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxypheny]-4- hydroxy-1 -piperidinecai-boxamide;
4-(4-Chlorophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl]- 4-hydroxy-l-piperidinecarboxamide;
4-Acetyl-4-(4-chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l-piperidinecarboxamide;
4-Acetyl-4-(4-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperidinecarboxamide ; 4-(4-Chlorophenyl)-4-cyano-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]- 1 -piperidinecarboxamide;
4-(4-Chlorophenyl)-4-cyano-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxypheny]-4-(4-hydroxyphenyl)~l- piperidinecarboxamide;
4-(4-Hydroxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide; 4-(6-Chloro-2-benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxyphenyl]-l-piperazinecarboxamide;
4-(6-Chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-pyrazinyl)-l- piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2-pyrazinyl)-l- piperazinecarboxamide;
N-[3-(2-DiisopiOpylamino)ethoxy-4-methoxyphenyl]-4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-mefhylethyl)-4-piperidinyl]phenyl]-4-[5- (trifluoromethyl)-2-pyridinyl]- 1 -piperazinecarboxamide;
4-(3,4-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(2-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-
1-piperazinecarboxamide;
4-(3-Chlorophenyl)-N- [4-methoxy-3- [1 -(1 -methylethyl)-4-piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide;
4-(3,4-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dichloroρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(2,6-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(3-methylphenyl)- 1 -piperazinecarboxamide ;
4-(2,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ; 4-(3,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro- 1 -naphthalenyl)- 1 -piperazinecarboxamide ;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2-methylρhenyl)- 1 -piperazinecarboxamide;
4-(5-Chloro-2-methylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[3-
(trifluoromethyl)phenyl] 1 -piperazinecarboxamide;
4-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl] - 1 -piperazinecarboxamide;
4-(3-Methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3 ,5 -Dimethoxyphenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4- piperidinyljphenyl]- 1 -piperazinecarboxamide; 4-(2-Cy anophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -
1-piperazinecarboxamide;
4-(4-Cy anophenyl)-N- [4-methoxy-3- [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1 -piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl]- 1 -piperazinecarboxamide;
4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[3-(3-diisopropylamino)propoxy-4- methoxyphenyl]-l-piperazinecarboxamide; and N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- carboxyphenyl)piperazine-l-carboxamide.
3. The method as claimed in claim 1, wherein the compound of formula (I) is selected from: N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine- 1 -carboxamide;
N-[2,3-Dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4 -piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- [3 - (ethoxycarbonyl)phenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl]piperazine- 1 -carboxamide ; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methoxyphenyl)piperazine- 1 -carboxamide;
4-(6-Chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(2-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(3 -Chlorophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1 -piperazinecarboxamide ; 4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-
1-piperazinecarboxamide;
4-(3,4-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ;
4-(2,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(3-methylphenyl)-
1 -piperazinecarboxamide;
4-(2,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ;
4-(3,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro-l-naphthalenyl)-l-piρerazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]ρhenyl]-4-(2- methylphenyl)- 1 -piperazinecarboxamide;
4-(5-Chloro-2-methylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1 -piperazinecarboxamide; 4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1 -piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[3- (trifluoromethyl)phenyl] 1 -piperazinecarboxamide;
4-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl]-l-piperazinecarboxamide; 4-(3-Methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Cy anophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1-piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l -(1 -methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide ; N-[4-Methoxy-3-[4-cyano-l-(l-methylethyl)-4-ρiperidinyl]phenyl]-4-(5,6,7,8- tetrahydro-l-naphthalenyl)-l-piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[3-(3-diisopropylamino)propoxy-4- methoxyphenyl]-l-piperazinecarboxamide; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3-chloro-2- methylphenyl)piperazine-l-carboxamide.
4. The method as claimed in claim 1, wherein the compound of formula (I) is selected from:
4-(3,5-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]- 1-ρiperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro- 1 -naphthalenyl)- 1-piperazinecarboxamide; 4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl]-l-piperazinecarboxamide; and 4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine-l-carboxamide.
5. The method as claimed in claim 1, wherein the disease is selected from
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.
6. The method as claimed in claim 1 , wherein A' is phenyl, 5,6,7,8- tetrahydro- 1-naphthalenyl, or lH-indol-4-yl; D' is a bond, E' and G' together are NCH2, R' is hydrogen, J' is CO, L' is NH, and E is group (g).
7. The method as claimed in claim 6, wherein A' is phenyl, and R1 is methyl, chloro or trifluoromethyl substituted at the 2 and/or 3-positions, or R1' is 2,4- dimethyl, 2-methoxy-5-chloro, 2-methyl, 3-ethoxycarbonyl, or 3,5-dichloro.
8. A compound or a pharmaceutically active salt or solvate thereof, selected from:
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenyl-l,2,3,6- tetrahydropyridine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-phenylpiperazine-l- carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine-l-carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-acetamido- methylphenyl) piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(3 - trifluoromethylphenyl)piperazine-l-carboxamide;
N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- methoxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(2-chlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3-chlorophenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-
4-(4-chlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,6- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]- 4-(3 ,4-dichlorophenyl)piperazine- 1-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4-(3- methylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methoxyphenyl)piperazine-l-carboxamide; N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(2,4- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-3-methyl-4- phenylpiperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dihydro-2(lH)- quinolinone-6-yl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,5- dimethylphenyl)piperazine-l-carboxamide;
N- [3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4-(3 - cyanophenyl)piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[4-
(ethoxycarbonyl)phenyl]ρiperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2- (ethoxycarbonyl)phenyl]piperazine-l-carboxamide;
N-[2,3-dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3- methylphenyl)piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- methylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 2,5- dimethylphenyl)piperazine-l-carboxamide; N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- 3,4- dimethylphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 3,5- dichlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- methoxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 3,5- dimethoxyphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 (ethoxycarbonyl)phenyl]piperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 cyanophenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 cyanophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- (2-pyridinyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 4-pyridinyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 4-chloro-3- (trifluoromethyl)phenyl]piperazine- 1 -carboxamide ; N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4- 2-methyl-3-
(trifluoromethyl)phenyl]piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 1- naphthalenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 l-(5,6,7,8- tetrahydronaphthalenyl]piρerazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4 lH-indol-4- yl)piperazine- 1 -carboxamide;
N- [3 -(2-Diisopropylamino)ethoxy-4-methoxyphenyl] -4 (4-methoxyphenyl)-3- methylpiperazine- 1 -carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- 5-chloro-2- methoxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4- hydroxyphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methylphenyl)piρerazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3-chloro-2- methylphenyl)piperazine- 1 -carboxamide;
4-(2,3-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,3-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]'-4-(3- carboxyphenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2- carboxyphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3,4-dimethoxyphenyl)- 1-piperazinecarboxamide;
4-(2-Benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide;
4-(2-Benzothiazolyl)-N- [4-methoxy-3- [ l-( 1 -methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide; 4-(lH-Indol-2-yl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxyphenyl]-l- piperidinecarboxamide;
4-(lH-Indol-2-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperidinecarboxamide;
4-(4-Chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4-methoxypheny]-4- hydroxy- 1 -piperidinecarboxamide;
4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 4-hydroxy- 1 -piperidinecarboxamide;
4-Acetyl-4-(4-chlorophenyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l-piperidinecarboxamide; 4-Acetyl-4-(4-chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperidinecarboxamide;
4-(4-Chlorophenyl)-4-cyano-N-[3-(2-diisopropylamino)ethoxy-4- methoxypheny]-l-piperidinecarboxamide;
4-(4-Chlorophenyl)-4-cyano-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-ρiperidinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxypheny]-4-(4-hydroxyphenyl)-l- piperidinecarboxamide; 4-(4-Hydroxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4~ piperidinyl]phenyl]-l-piperidinecarboxamide;
4-(6-Chloro-2-benzothiazolyl)-N-[3-(2-diisopropylamino)ethoxy-4- methoxyphenyl]-l-piperazinecarboxamide; 4-(6-Chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2-pyrazinyl)-l- piperazinecarboxamide;
N- [4-Methoxy-3 -[ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -4-(2-pyrazinyl)- 1 - piperazinecarboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[5-(trifluoromethyl)-2- pyridinyl] - 1 -piperazinecarboxamide ;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[5- (trifluoromethyl)-2-pyridinyl] - 1 -piperazinecarboxamide ; 4-(3,4-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1 -piperazinecarboxamide;
4-(3-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide;
4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-ρiperazinecarboxamide;
4-(3,4-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(3 ,5-Dichlorophenyl)-N- [4-methoxy-3- [1 -(1 -methylethyl)-4- piperidinyljphenyl] - 1 -piperazinecarboxamide ;
4-(2,6-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ;
4-(2,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]ρhenyl]-4-(3-methylphenyl)- 1 -piperazinecarboxamide; 4-(2,5-Dimethylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piρeridinyl]phenyl]- 1 -piperazinecarboxamide;
4-(3,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N- [4-Methoxy-3- [ 1 -( 1 -methylethyl)-4-piρeridinyl]phenyl]-4-(5 ,6,7,8- tetrahydro- 1-naphthalenyl)- 1 -piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2-methylphenyl)- 1-piperazinecarboxamide;
4-(5-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(3-Chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[3- (trifluoromethyl)phenyl]l-piperazinecarboxamide;
4-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-[2-methyl-3- (trifluoromethyl)phenyl]-l-piperazinecarboxarnide;
4-(3-Methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(3,5-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Cyanophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1-piperazinecarboxamide;
4-(4-Cy anophenyl)-N- [4-methoxy-3- [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1-piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(lH-Indol-4-yl)-N- [4-methoxy-3- [ 1 -( l-methylethyl)-4-piperidinyl]phenyl]- 1 - piperazinecarboxamide; 4-[3-(Ethoxycarbonyl)phenyl]-N-[3-(3-diisopropylamino)propoxy-4- methoxyphenyl] - 1 -piperazinecarboxamide ; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(4- carboxyphenyl)piperazine- 1 -carboxamide.
9. A compound or a pharmaceutically active salt or solvate thereof, selected from:
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide ;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,3- dichlorophenyl)piperazine-l-carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(2,4- dimethylphenyl)piperazine- 1 -carboxamide;
N-[2,3-Dihydro-l'-isopropyl-spiro[benzofuran-5-yl-3,4'-piperidine]]-4-(2,3- dimethylphenyl)piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[3- (ethoxycarbonyl)phenyl]piperazine-l-carboxamide; N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[2-methyl-3-
(trifluoromethyl)phenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine- 1 -carboxamide;
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(5-chloro-2- methoxyphenyl)piperazine- 1 -carboxamide ;
4-(6-Chloro-2-benzothiazolyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Chlorophenyl)-N- [4-methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1-piperazinecarboxamide; 4-(3-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-
1 -piperazinecarboxamide;
4-(4-Chlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]- 1-piperazinecarboxamide;
4-(3,4-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ;
4-(3 ,5-Dichlorophenyl)-N- [4-methoxy-3-[ 1 -(1 -methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2,4-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; 4-(3,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(3-methylphenyl)- 1 -piperazinecarboxamide;
4-(2,5-Dimethylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piρeridinyl]phenyl] - 1 -piperazinecarboxamide ;
4-(3,4-Dimethylρhenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro- 1 -naphthalenyl)- 1 -piperazinecarboxamide;
N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(2-methylphenyl)- 1 -piperazinecarboxamide; 4-(5-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3-Chloro-2-methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
N- [4-Methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -4- [3 - (trifluoromethyl)phenyl] 1 -piperazinecarboxamide;
4-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N- [4-Methoxy-3 - [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] -4- [2-methyl-3-
(trifluoromethyl)phenyl]-l-piperazinecarboxamide;
4-(3-Methoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(3,5-Dimethoxyphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide;
4-(2-Cy anophenyl)-N- [4-methoxy-3- [ 1 -( 1 -methylethyl)-4-piperidinyl]phenyl] - 1 -piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyljphenyl] - 1 -piperazinecarboxamide ; 4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide;
N-[4-Methoxy-3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro- 1 -naphthalenyl)- 1 -piperazinecarboxamide;
4-[3-(Ethoxycarbonyl)phenyl]-N-[3-(3-diisopropylamino)propoxy-4- methoxyphenyl]-l-piperazinecarboxamide; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-(3-chloro-2- methylphenyl)piperazine- 1 -carboxamide .
10. A compound or a pharmaceutically active salt or solvate thereof, selected from:
4-(3,5-Dichlorophenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl] - 1 -piperazinecarboxamide ; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-4-(5,6,7,8- tetrahydro-l-naphthalenyl)-l-piperazinecarboxamide;
4-(3-Chloro-2-methylphenyl)-N-[4-methoxy-3-[l-(l-methylethyl)-4- piperidinyl]phenyl]-l-piperazinecarboxamide; N-[4-Methoxy-3-[l-(l-methylethyl)-4-piperidinyl]ρhenyl]-4-[2-methyl-3-
(trifluoromethyl)phenyl]-l-piperazinecarboxamide; and
4-(lH-Indol-4-yl)-N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl]phenyl]-l- piperazinecarboxamide; and
N-[3-(2-Diisopropylamino)ethoxy-4-methoxyphenyl]-4-[l-(5,6,7,8- tetrahydronaphthalenyl]piperazine-l -carboxamide.
11. A pharmaceutical composition comprising a compound as claimed in claim 8, 9 or 10, and a pharmaceutically acceptable carrier.
12. A process for making a compound as claimed in claims 8, 9, or 10, comprising for compounds wherein L' is NR3 , a) treating a compound of formula (II):
R30'
H— N— E Formula (II)
wherein R30' is hydrogen or C .galkyl, with triphosgene under basic conditions to form a mixture; and b) adding to the mixture a compound of formula (III):
wherein A', D', E', G' and R' are as defined in claim 1.
13. A compound selected from: 4-methoxy-3- [ 1 -(1 -methylethyl)-4-piperidinyl]benzenamine;
4-methoxy-3 - [ 1 -cyclopentyl-4-piperidinyl]benzenamine; and 4-methoxy-3-[l-(3-pentyl)-4-piperidinyl]benzenamine.
EP01958995A 2000-07-15 2001-07-13 Compounds and methods Withdrawn EP1313477A4 (en)

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