WO2004011427A2 - Substituted benzanilides as modulators of the ccr5 receptor - Google Patents

Substituted benzanilides as modulators of the ccr5 receptor Download PDF

Info

Publication number
WO2004011427A2
WO2004011427A2 PCT/US2003/023343 US0323343W WO2004011427A2 WO 2004011427 A2 WO2004011427 A2 WO 2004011427A2 US 0323343 W US0323343 W US 0323343W WO 2004011427 A2 WO2004011427 A2 WO 2004011427A2
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
galkyl
group
6alkyl
carboxamide
Prior art date
Application number
PCT/US2003/023343
Other languages
French (fr)
Other versions
WO2004011427A3 (en
Inventor
William E. Bondinell
Michael J. Neeb
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Priority to AU2003254177A priority Critical patent/AU2003254177A1/en
Publication of WO2004011427A2 publication Critical patent/WO2004011427A2/en
Publication of WO2004011427A3 publication Critical patent/WO2004011427A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to substituted benzanilides which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature
  • this invention relates to the treatment and prevention of disease states mediated by CCR5.
  • T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases.
  • Increased numbers or enhanced activation state of T cells, especially CD4+ T cells have been demonstrated in the synovium of individuals with rheumatoid arthritis (M.J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial ucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci.
  • T cells as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors.
  • chemokines a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues.
  • R ANTES 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 LL-1 or TNF*.
  • RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate.
  • RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J.M. Pattison, P J. Nelson, and A.M. Krensky, Clin.
  • CCR5 when expressed in either HEK 293 cells or CHO cells, binds RANTES.
  • This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells that are important in the maintenance of a chronic inflammatory reaction.
  • 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 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 novel compounds of formula (I) and their use as CCR5 modulators for the 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, all in mammals, preferably humans.
  • the preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.
  • the present invention is directed to 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 ATDS.
  • 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 benzanilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt 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
  • 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 HJV infection.
  • 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
  • the basic nitrogen in moiety E may be optionally quaternized with Ci. ⁇ alkyl or is optionally present as the N-oxide;
  • CONRl2'(CH2) c OC 1 _4alkyl CONRl2'(CH 2 ) a 'C02R 18 ', CONHNR ⁇ O CONR 12 'SO2 21 ', C0 2 R 22 ', cyano, trifluoromethyl, NR 7 R 8 ', NR 7 'COR 9 ', NR23'cO(CH2) a 'NR2 'R 4' ; NR23'C0NR23'R24' ?
  • NR 7 'CO2R 10 ', NR 7 'SO2R 11 ', N CNR23'NR23'R24', nitro, hydroxy, C ⁇ _ 6 alkoxy, hydroxyC ⁇ _ 6 alkoxy, C ⁇ _6alkoxyC ⁇ _6 ⁇ dko y, OC(O)NR 2 5'R26' 3 SR 27' J SOR 28 ', S0 2 R 28 ' S ⁇ 2NR25'R 'or halogen;
  • R ' and R ⁇ ' are each independently one or more of hydrogen, C ⁇ _6alkyl, C ⁇ . j cycloalkyl, C3_gcycloalkenyl, hydroxyCi-galkyl, CONR29'R30', CO2R 31 ', cyano, aryl, trifluoromethyl, NR 2 9'R30' ) n i tro?
  • R5' is one or more of hydrogen, C ⁇ alkyl, C ⁇ _galkoxy or halogen
  • R ⁇ ' is one or more of hydrogen, Ci.galkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyCi .galkyl, hydroxyC3_6alkenyl, hydroxyC 3 _6alkynyl, (CH 2 )dOR. 32 ', (CH 2 )d !
  • R ⁇ ' is hydrogen, Cx.galkyl or C ⁇ _4alkoxyalkyl; RlO'is C ⁇ _ 6 alkyl;
  • Ri 1' is C ⁇ _6alkyl or phenyl
  • Rl ' and R ⁇ ' are independently hydrogen or C ⁇ _6alkyl, or together with the nitrogen to which they are attached, R l2 and R ⁇ form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • Rl4' is C ⁇ _4alkyl, optionally substituted by C ⁇ _galkoxy;
  • Rl5' and R 1 ⁇ ' are independently hydrogen or C ⁇ _6alkyl
  • R l7 ' is hydrogen or C ⁇ _6alkyl
  • R l8 is hydrogen or C ⁇ _ ⁇ alkyl
  • R l9 ' and R20' are independently hydrogen or C ⁇ _6alkyl
  • R ⁇ l' is hydrogen or C ⁇ _6alkyl
  • R22 is hydrogen or C ⁇ _5alkyl optionally substituted with one or two substituents selected from Ci.galkyl, Cx.galkoxy, hydroxy, or NR 7 R 8 ';
  • R23' and R24' are independently hydrogen or C ⁇ _6alkyl
  • R25' and R26' are independently hydrogen or Cx.galkyl, or together with the nitrogen to which they are attached, R ⁇ 5' and R26' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
  • R2 ' is hydrogen or C ⁇ . ⁇ alkyl;
  • R 28 ' is C ⁇ _6alkyl;
  • R29', R30' an( j R31' aj-e independently hydrogen or C ⁇ _6alkyl; R 2 ' i s C ⁇ _6alkyl, hydroxyC ⁇ _6alkyl, or C ⁇ _4alkanoyl;
  • R 3' is hydrogen or C ⁇ _6alkyl
  • R 3 4' is hydrogen or C ⁇ _6alkyl
  • R 3 ⁇ ' and R 7' are independently hydrogen or C ⁇ _6alkyl or together with the nitrogen to which they are attached,
  • R36' and R ' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 3 ', wherein R 4 3' i s Ci ⁇ alkyl, COR44' or CO2R 45 ', wherein R44' and R45' are independently hydrogen or C ⁇ _6alkyl;
  • R 8' is hydrogen or C ⁇ . ⁇ alkyl
  • R 9' is C ⁇ _6alkoxy, CO 2 H, CO 2 C ⁇ _ 6 alkyl or CONR 3 6'R37' ;
  • R 1' and R42' are independently hydrogen or Cj.galkyl;
  • P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
  • a' is 1, 2, 3 or 4;
  • b' is O, 1, 2 or 3;
  • c' is 1, 2 or 3;
  • d' is 0, 1, 2, 3, 4, 5, or 6;
  • e' is 1, 2, 3, 4, 5 or 6; and further wherein, when Ar is (i), (ii) or (iii), and
  • A is CONR 46 ', NHCO, - NHCH2, or CH 2 NH, wherein R 4 6' is hydrogen or C ⁇ alkyl, E is a group (a):
  • Ri and R 2 are independently hydrogen or Ci.galkyl; alternatively B(CRlR2) a is OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR1R 2 CR 1 (OCOCH 3 )CR 1 R 2 ;
  • R and R4 are independently hydrogen, C ⁇ _6alkyl, C3_7cycloalkyl, aralkyl, C5. ⁇ cycloalkenyl, a C5_7heterocyclic ring, 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, CONRIOR 1 1 , NRIOR 1 1 , hydroxy, OCOR12, NHCOCF3, NHSO 2 R 13 , NHCO 2 R 14 , or NHCOC 0 _ 6 alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH; R 5 is hydrogen, C ⁇ alkyl, aryl, CN, CONR 15 R 16 , CO 2 R 17 , trifluoromethyl,
  • R9 is hydrogen, C ⁇ _6alkyl, or phenylC _6alkyl
  • R 13 , R 14 , Rl 8 , and R 19 are independently C ⁇ alkyl
  • a is 1, 2, 3, or 4
  • b is 1 or 2
  • c and d are independently 0, 1 or 2
  • e is 2, 3 or 4
  • f is O, 1, 2 or 3
  • Ar is (i), (ii) or (iii)
  • A is CONR46', NHCO, or CH 2 NH
  • R 6' is hydrogen or Cj.galkyl
  • E is a group (b):
  • R 0 is hydrogen, C ⁇ _galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5.. 7heterocyclic ring;
  • J is oxygen, CR 3 6R37 ; or NR 38 ? or J is a group S(O)i,; R34 ; R35 ? 36 ? R37 ; an d R38 are independently hydrogen or Cx.galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is C0NR46', NHCO,
  • R 9 a nd R 0 are independently hydrogen or Cx.galkyl;
  • R41 is a group of formula (d):
  • R41 is a group of formula (e):
  • R 42 is hydrogen, C ⁇ alkyl, aryl, CN, CONR 48 R49 5 c ⁇ 2 R 50 , trifluoromethyl, NHCO 2 R 51 , hydroxy, Cj ⁇ alkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _6alkyl, OCF3, S(O) s R 52 , SO 2 NR 53 R54 5 or halogen;
  • R44, R45 ; R46 ? R 48 ? R 49 ; R50 5 R53 5 R54 R 55 ? and R 5 ⁇ are independently hydrogen or C ⁇ galkyl;
  • R4 is hydrogen, Cj.galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C ⁇ . 7heterocyclic ring;
  • R51 and R 52 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 O, l, or 2; t is 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONH, NHCO, or, CH 2 NH, alternatively, E is a group (f):
  • R ⁇ and R ⁇ 8 are independently hydrogen or Cx.galkyl; R ⁇ and R ⁇ 0 are independently hydrogen, Cx.galkyl, C3_7cycloalkyl, aralkyl,
  • C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR61R6 5 NR61R6 5 hydroxy, OCOR 63 , NHCOCF3, NHSO 2 R 6 , NHCO 2 R 65 , or NHCOC 0 -6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH; T is -(CR 6 6R67) V _ or - ⁇ (CR 66 R 67 ) w -; W is oxygen, S(O) x , NR 68 , or W is CR 69 CR 70 or CR 69 R 70 ; R61 ; R62 5 63 5 R66 J R67 R68 ; R69
  • R64 ⁇ d R65 aj-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; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46' S NHCO, or CH 2 NH, wherein R46' is hydrogen or C j .galkyl, alternatively, E is a group (g):
  • R 1 is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a basic nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R 1 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 ⁇ _6alkyl and optionally substituted on nitrogen with hydrogen, Cj.galkyl or C3_7cycloalkyl, Cs- cycloalkenyl, or a C5_7heterocyclic ring; R 71 is substituted with one or more of R 71 ", wherein R 71 " is hydrogen, CR la R 2 "NR3"R4" ; CR l R 2 “OR3", COR 5 ", CONR 6 "R 7 “, CO 2 R 8 ", cyano, NR 3 "R4", n itro, hydroxy, C ⁇
  • R 72 is hydrogen, Ci.galkyl, aryl, CN, CONR 74 R 7 5, CO 2 R °, trifluoromethyl, NHCO R 77 , hydroxy, C ⁇ _6alkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _6alkyl, OCF3, S(O) z R 78 , SO 2 NR 79 R 80 , or halogen;
  • R 74 , R75 3 R76 ; R79 ? R80 J R81 ? and R 82 are independently hydrogen or C ⁇ _ galkyl;
  • R 77 and R 78 are independently Cx.galkyl; y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is C0NR46' 5 NHCO, ox CH 2 NH, wherein R46 ' is hydrogen or C ⁇ .galkyl ; alternatively, E is a group (h):
  • R and R 8 4 are independently hydrogen or C ⁇ _6alkyl;
  • R 85 and R ⁇ are independently hydrogen, C ⁇ _6alkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR 88 R 89 , NR 90 R 91 , hydroxy, OCOR 92 , NHCOCF3, NHSO 2 R 93 , NHCO 2 R 9 , or NHCOC 0 -6alkyl wherein the alkyl of NHCOCo_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 , R95, ⁇ d R 96 are independently hydrogen or C ⁇ _ galkyl;
  • R 3 and R 9 4 are independently C ⁇ _6alkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH 2 NH, wherein R46'i s hydrogen or Ci.galkyl, alternatively, E is a group (i):
  • R 97 and R 98 are independently hydrogen, C ⁇ galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR ⁇ R 1 * ⁇ NR ⁇ R 1 * ⁇ hydroxy, OCOR 106 , NHCOCF3, NHSO 2 R 107 , NHCO 2 R 108 , or NHCOC 0 -6alkyl wherein the alkyl of NHCOCo- ⁇ ai yl is optionally substituted by OH;
  • R 99 and R 1 ⁇ are independently hydrogen or Cl-6alkyl;
  • R 1 ⁇ 1 is hydrogen or C ⁇ _6alkyl or
  • R ⁇ 1 and R30' together form a group -AD- where AD is (CR 10 ⁇ 110 )ai or AD is (CR 109 R 110 ) a j-AE and AE is oxygen, sulfur or CRiO ⁇ CR ⁇ O;
  • AC is oxygen, CR 1 1 ⁇ R 1 12 or NR 1 13 or AC is a group S(O)ak;
  • R 106 R 109, R l 10, R l 11, R l 12, and R 11 are independently hydrogen or C ⁇ _galkyl;
  • R 107 and R 108 are independently Cl-6alkyl; 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 O, 1, 2, or 3; and ak is 0, 1 or 2, provided that when R 2 " is hydrogen and E is a group (a), (f) (h) or (i), then one or both of R 3 or R 4 ; R 5 or R 60 ; R 85 or R 86 ; or R 97 or R 98 is C5_ 7cycloalkenyl, or a C5_7heterocyclic ring; or when R 2 " is hydrogen and E is a group (b) or (c), then R 0 and R4 7 are C5_7cycloalkenyl, or a C5_7heterocyclic ring; or when R 2 " is hydrogen and E is group (g), then either R 71 " is not hydrogen and/or R 7 is substituted on nitrogen with C5
  • Ar is (i),(ii), or (iii).
  • Ar is (i) or (ii).
  • the terminal phenyl group in (i) and (ii) can be attached to the phenyl group bearing group A in any position.
  • the terminal phenyl ring is attached to the phenyl bearing group A in a position meta or para to group A.
  • R 1 ' and R 2 ' are each independently one or more of hydrogen, C ⁇ _ ⁇ kyl, C2-6alkenyl, C _6alkynyl, C3_7cycloalkyl, C3_6cycloalkenyl, aryl,
  • R ' and R4' are each independently one or more of hydrogen, C ⁇ _ galkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxy Cj.galkyl, C ⁇ _6alkylOC ⁇ _6alkyl, CONR 29 'R30' 5 CO2R 31 ', cyano, aryl, trifluoromethyl, NR 29 'R 30 ', nitro, hydroxy, C ⁇ _ 5alkoxy, acyloxy, or halogen.
  • R 2 ' is also R 2 " wherein R 2 " is hydrogen, (CH 2 ) a CN, (CH 2 ) a CO H, COCR 15 'R 16 OR 18 ', Oaryl, Oaralkyl, O(CH 2 ) a CO 2 R 18 ', and Saryl.
  • R 2 " is hydrogen, (CH 2 ) a CN, (CH 2 )a ⁇ O 2 H, COCR ⁇ 'R ⁇ R 18 ', and O(CH ) a CO 2 R 18 ' attached to the 3 '- or 4 -position.
  • R 5 ' is one or more of hydrogen, C ⁇ _galkyl, Cx.galkoxy or halogen.
  • R ⁇ ' is one or more of hydrogen, Cj.galkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyC ⁇ _6alkyl, hydroxyC3_6alkenyl, hydroxyC 3 .
  • R 7 ' and R 8 ' are each independently hydrogen or C ⁇ _galkyl, or together with the nitrogen to which they are attached, R 7 ' and R 8 ' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
  • R 9 ' is hydrogen, Cj.galkyl or C ⁇ _4alkoxy alkyl.
  • R 10 ' is C ⁇ alkyl.
  • R 1 1' is C ⁇ . ⁇ alkyl or phenyl.
  • R 12 ' and R 13 ' are independently hydrogen or C ⁇ _6alkyl, or together with the nitrogen to which they are attached, R 12 ' and R 13 ' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
  • Rl4' i s C ⁇ alkyl optionally substituted by Ci.galkoxy.
  • R 15 ' and R 1 ⁇ ' are independently hydrogen or Ci.galkyl.
  • R 1 ' is hydrogen or C ⁇ _6alkyl.
  • R ' is hydrogen or Cx.galkyl.
  • R 19 ' and R ⁇ ' are independently hydrogen or C ⁇ _6alkyl.
  • R 1 ' is hydrogen or Cx.galkyl.
  • R 22 ' is hydrogen or Ci ⁇ galkyl optionally substituted with one or two substituents selected from C ⁇ alkyl, Ci.galkoxy, hydroxy, or NR 7 'R 8 '.
  • R 23 ' and R 2 4' are independently hydrogen or C ⁇ _6alkyl.
  • R 25 ' and R 2 ⁇ ' are independently hydrogen or C ⁇ _6alkyl, or together with the nitrogen to which they are attached, R 25 ' and R 2 ⁇ ' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
  • R 27 is hydrogen or C ⁇ _galkyl.
  • R 28 ' is C ⁇ alkyl.
  • R 29 ', R 0' and R 1 ' are independently hydrogen or C ⁇ _6alkyl.
  • R 2' is Cx.galkyl, hydroxyC ⁇ _6alkyl, or Ci ⁇ alkanoyl.
  • R 3' is hydrogen or Ci.galkyl.
  • R 4' is hydrogen or Ci.galkyl.
  • R 5 ' is hydrogen or C ⁇ _6alkyl.
  • R 6' and R.3 7 ' are independently hydrogen or C ⁇ _galkyl or together with the nitrogen to which they are attached, R 6' and R 7 ' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 3', wherein R 3' i s C ⁇ _6alkyl, COR 4' 0 r CO 2 R 5', wherein R4 ' and R45' are independently hydrogen or Cx.galkyl.
  • R 8 ' is hydrogen or Cx.galkyl.
  • R39' is or CONR36'R3T.
  • R 1 ' and R4 2 ' are independently hydrogen or C ⁇ _6alkyl.
  • P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl.
  • Saturated and partially saturated rings are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams.
  • the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom.
  • Suitable substituents for these rings include one or more of R4'.
  • P is 1,2,4- oxadiazol-3-yl and R4' is 5-methyl.
  • a' is 1, 2, 3 or 4.
  • b' is 0, 1, 2 or 3.
  • c' is 1, 2 or 3.
  • d' is 0, 1, 2, 3, 4, 5, or 6.
  • e' is 1, 2, 3, 4, 5 or 6.
  • substituent E is selected from the following groups:
  • Ar is (i), (ii) or (iii), and A is CONR 4 6', NHCO, -NHCH 2 , or
  • R46' i is a group (a):
  • B is preferably CR 7 R 8 , or oxygen.
  • R and R 2 are suitably independently hydrogen or C ⁇ galkyl.
  • R and R 2 are hydrogen.
  • B(CR 1 R 2 ) a is OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 .
  • B(CR 1 R 2 ) a is
  • OCR 1 R 2 CR 1 (OH)CR 1 R 2 or OCR 1 R 2 CR 1 (OCOCH 3 )CR 1 R 2 , R 1 and R 2 are hydrogen.
  • R and R are suitably independently hydrogen, Cx.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR ⁇ R 1, NR ⁇ R 1 1, hydroxy, OCOR 12 NHCOCF3, NHSO 2 R 3 , NHCO 2 R 14 , or NHCOCQ. galkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH.
  • R 3 and R4 are both C ⁇ _galkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur.
  • B-(CR 1 R 2 ) a -NR 3 R 4 is ortho to R 5 , meta to A and para to R 6 , and R 5 is para to A.
  • R 5 is suitably hydrogen, C ⁇ alkyl, aryl, CN, CONR 15 R 16 , CO 2 R 17 , trifluoromethyl, NHCO R 18 , hydroxy, C ⁇ alkoxy, benzyloxy, OCH CO 2 C ⁇ _6alkyl, OCF3, S(O) d R 19 , SO 2 NR 20 R 21 , or halogen.
  • R 5 is preferably C ⁇ galkoxy, SC ⁇ _ galkyl or halogen.
  • R 6 is hydrogen.
  • R 7 , R 8 , R 10 , Rl 1, R 12 , R 15 , R 16 , R 17 > R 20 , R 21 , R 22 , and R 2 3 are suitably independently hydrogen or Cj.galkyl.
  • R 9 is suitably hydrogen, Ci.galkyl, or phenylCj.galkyl.
  • R 1 , Rl Ri ⁇ , ⁇ d R19 are suitably independently Cx.galkyl.
  • a is suitably 1, 2, 3, or 4.
  • b is suitably 1 or 2.
  • b is 1.
  • c and d are suitably independently 0, 1, or 2.
  • e is suitably 2, 3, or 4.
  • f is suitably 0, 1, 2, or 3.
  • Ar is (i), (ii) or (iii), and A is CONR 46 ', NHCO, or CH 2 NH, wherein R46' is hydrogen or C ⁇ _6alkyl, E suitably is a group (b):
  • R24, R25, R26 ; R27 ? R28 ; R29 ; R31 5 and R 2 are suitably independently hydrogen or Ci . galkyl.
  • R 2 4 R25 ? R26 3 R27 ; R28 5 R29 ⁇ R31 ? and R 3 2 are preferably hydrogen.
  • R30 is suitably hydrogen, C ⁇ _galkyl, C3_7cycloalkyl, C5_7cycloalkenyl or a
  • R30 is Cj.galkyl, C3_7cycloalkyl, C5_ 7cycloalkenyl, or a C5_7heterocyclic ring.
  • R33 is suitably hydrogen, C ⁇ _6alkyl, trifluoromethyl, hydroxy or halogen, or R33 3nd R 46 ' together form a group -K- where K is (CR 3 4R35) 1 or K is (CR 4R35)J .
  • R 3 3 is hydrogen.
  • J is suitably oxygen, CR36R37 ; 0 r NR , or J is a group 8(0) ⁇ .
  • J is oxygen.
  • J is para to A.
  • R3 , R35 ; R36 5 37 5 R38 ⁇ Q suitably independently hydrogen or C ⁇ _galkyl.
  • g is suitably 1, 2, or 3.
  • h is suitably 1, 2, or 3.
  • h is 1.
  • i is suitably 2, 3, or 4.
  • j is suitably 0, 1, 2, or 3.
  • k is suitably 0, 1 or 2.
  • R44 3nd R45 are independently hydrogen or Cx.galkyl, or suitably, Q is NR46 wherein R46 i s hydrogen or alkyl; suitably, R 9 and R40 are independently hydrogen or Ci.galkyl; suitably, R 42 is hydrogen, C ⁇ _6alkyl, aryl, CN, CONR 48 R 49 , CO 2 R 5 0, trifluoromethyl, NHCO 2 R 5 , hydroxy, Cx.galkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _6alkyl, OCF 3 , S(O) s R 52 , SO 2 NR 53 R54 5 or halogen, wherein R 48 , R4 9 , R50 5 R53 ?
  • 7cycloalkenyl, or a C5_7heterocyclic ring 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.
  • R 57 and R 58 are independently hydrogen or C ⁇ _ ⁇ alkyl; suitably R 59 and R ⁇ 0 are independently hydrogen, Ci.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring 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 Ci.galkyl, aryl, CONR 61 R 62 , NR 61 R 62 , hydroxy, OCOR 63 , NHCOCF3, NHSO 2 R 64 , NHCO 2 R65 0 r NHCOC 0 _6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH, and wherein R ⁇ 1 , R6 ?
  • R ⁇ are independently hydrogen or C ⁇ _6alkyl, and R ⁇ 4 and R ⁇ 5 are independently C ⁇ . ⁇ alkyl;
  • T is -(CR 66 R 67 ) V - or -O(CR 66 R 67 ) w -, wherein R 66 and R 67 are independently hydrogen or Ci.galkyl, wherein v is 2 or 3, and w is 1, 2 or 3;
  • Ar is (i), (ii) or (iii), and A is CONR 4 6', NHCO, or CH 2 NH, wherein R46' i s hydrogen or C ⁇ _6alkyl, E suitably is a group (g):
  • R 7 is an optionally substituted 5- to 7-membered saturated or partially saturated heterocyclic ring containing a basic nitrogen atom and optionally a further one or two heteroatoms selected from nitrogen, oxygen or sulfur, or R 7 is an optionally substituted 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur, which ring systems may be optionally substituted with one or more of Cx.galkyl, and substituted on nitrogen with hydrogen, Cj.galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring.
  • R 71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and is substituted on nitrogen with Cx.galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring.
  • R 71 is substituted with one or more of R 7 !
  • R 7 * is hydrogen, CR la R 2 "NR3”R4", CR 1 R2" ⁇ R “, COR 5 ", CONR 6 “R 7 “, CO 2 R 8 “, cyano, NR 3 “R4", nitro, hydroxy, C ⁇ alkoxy, SR 9 “, SORlO", SO 2 R 10 ", SO 2 NR 6 “R 7 “ or SO3H wherein R “ and R2a are independently hydrogen or C ⁇ _galkyl, provided that R 1 " is not a substituent on the basic nitrogen of R 7 .
  • R 3 " and R4" are independently hydrogen or Ci.galkyl, or taken 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 one oxygen or one sulfur atom.
  • R 4 " is COR 11 ", CONR 12 “R 13 “, CO 2 R 14 “, SO 2 R 15 “, SO2NR 12 “R 13 “, or SO 2 OR 16 " wherein R 1 1” is hydrogen, C ⁇ _6alkyl, aryl, or trifluoromethyl; R 12 and R 13 ' are independently hydrogen or Cj.galkyl, or taken 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 one oxygen or one sulfur atom; Rl4" is Cx. ⁇ alkyl or aryl; R 15 " is Cx.galkyl, aryl, or trifluoromethyl; and R 1 " ' is aryl; R 5 " is hydrogen, C ⁇ _6alkyl, aryl, or trifluoromethyl; R6” and R 7 ' are independently hydrogen or C ⁇ _6 lkyl, or taken together with the nitrogen to which they are attached form a 5- to 6-
  • R 1 is preferably located meta to A, ortho to R 72 and para to R 73 , and R 72 is located para to A.
  • R 72 is hydrogen, C ⁇ galkyl, aryl, CN, CONR 74 R 75 , CO 2 R 7 6, trifluoromethyl, NHCO 2 R 77 , hydroxy, Ci.galkoxy, benzyloxy, OCH 2 CO 2 C ⁇ _6alkyl, OCF , 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 Cjlgalkyl, and z is 0, 1, or 2.
  • R 72 is preferably C ⁇ _galkoxy, SC ⁇ _6alkyl or halogen.
  • R 73 is hydrogen.
  • y is an integer from 1-2.
  • y is 1.
  • Ar is (i), (ii) or (iii), and A is CONR 4 6', NHCO, or CH 2 NH, wherein R46' is hydrogen or C ⁇ _6alkyl
  • E suitably is a group (h): (CRS3R84) ac NR ⁇ SR 86
  • R 3 and R 8 4 are independently hydrogen or C ⁇ _6alkyl.
  • R 85 and R 8 ⁇ are independently hydrogen, C ⁇ galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR 8 R 89 , NR 90 R 91 , hydroxy, OCOR 92 NHCOCF3, NHSO 2 R 93 , NHCO 2 R 94 , orNHCOC 0 - galkyl wherein the alkyl of the NHCOCo- ⁇ alkyl is optionally substituted by OH, and wherein R 88 , R 89 , R 9 0, R91 and R 92 are independently hydrogen or
  • 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.
  • R 6' i hydrogen or C ⁇ _6alkyl
  • E suitably is a group (i):
  • R 97 and R 98 are independently hydrogen, Cj.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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 Ci.galkyl, aryl, CONR - ⁇ R 1 " 3 , NR 104 R 105 , hydroxy, OCOR 10 6, NHCOCF3, NHSO 2 R 107 , NHCO ⁇ O 8 , or
  • NHCOCo-6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH, and wherein R 102 , R 103 , R!04 ? R105 and R Q 6 are independently hydrogen or C ⁇ _ galkyl, and R 1 ⁇ and R ⁇ 8 are independently Cl-6alkyl.
  • R 99 and R 1 ⁇ are independently hydrogen or Cx.galkyl; suitably, AC is oxygen, CR 1 ! iR 112 or NR 113 wherein R 11 1, R 112 and R 113 are independently hydrogen or C ⁇ _5alkyl or AC is a group S(O)ak wherein ak is 0, 1 or 2; suitably, ag is an integer from 1-3, ah is an integer from 1-4, and af is 0-4.
  • A is CONR 4 6', NHCO, or CH 2 NH, wherein R 4 6' i s hydrogen. More preferably, A is CONR46' 0 r NHCO, wherein R46' i s hydrogen. Most preferably, A is CONR46', wherein R46' is hydrogen.
  • E is group (a), (b), or (g). More preferably, when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A. More preferably, when Ar is (i), (ii) or (iii), E is group (g). Most preferably, when Ar is (i) or (ii), E is group (g). More preferably, R 2 " is hydrogen, or (CH ⁇ a'CN. (CH 2 ) a CO 2 H,
  • R " is hydrogen, cyanomethyl, or cyanoethyl attached to the 3 -position.
  • A is attached to group (a) meta to B- (CR 1 R 2 ) a -NR 3 R and para to (R 5 )b, wherein B is oxygen or CR 7 R 8 , R 1 and R 2 ⁇ e hydrogen, R 5 is methoxy, methylthio or iodo, R 3 and R4 are independently C3_6alkyl, or R 3 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 C ⁇ _6alkyl and acetamido or hydroxyl, R ⁇ is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH 2 , and b is 1.
  • A is attached to group (a) meta to B- (CR 1 R2) a -NR 3 R4 and para to (R 5 ) D , wherein B is oxygen or CH 2 , R and R ⁇ are hydrogen, R 5 is methoxy, R 3 and R4 are independently isopropyl or tert-butyl, or R 3 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), R6 is hydrogen, a is 2 when B is oxygen, and b is 1.
  • E is group (b)
  • A is attached to group (b) para to J
  • J is oxygen
  • R 33 is hydrogen
  • R 30 is C3_6alkyl
  • g is 2 and h is 1.
  • E is group (b)
  • A is attached to group (b) para to J
  • J is oxygen
  • R 33 is hydrogen
  • R31 an R32 are hydrogen
  • R 0 is isopropyl
  • g is 2 and h is 1.
  • R 71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_6alkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring, R 72 is methoxy, methylthio or iodo, y is 1, R 7 is hydrogen, and R 71 " is hydrogen or cyano, attached to the benzylic carbon of R 71 .
  • E is group (g)
  • A is attached to group (g) meta to R 7 and para to R 72 wherein R 71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclo ⁇ ent-3-enyl, R 71 ' is hydrogen or 4- cyano, R 72 is methoxy, y is 1, and R 73 is hydrogen.
  • a preferred subgenus of compounds of formula (I) is wherein A is C0NR46', NHCO, or CH NH, wherein R 4 6' i s hydrogen; Ar is (i), (ii), or (iii); and E is group (a), (b), or (g).
  • a more preferred subgenus of compounds of formula (I) is wherein A is CONR46' or NHCO, wherein R46' ⁇ S hydrogen; Ar is (i) or (ii), and the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (a), (b), or (g); and R 2 " is hydrogen, or (CH 2 ) a €N, (CH 2 ) a CO 2 H, COCR ⁇ 'R ⁇ 'OR 18 ', and O(CH 2 )a ! CO 2 R ⁇ 8 ' attached to the 3 -position.
  • A is attached to group (a) meta to B-(CR 1 R 2 ) a -NR 3 R 4 and para to (R 5 )b, wherein B is oxygen or CR 7 R 8 , R 1 and R 2 are hydrogen, R 5 is methoxy, methylthio or iodo, R 3 and R4 are independently C3_6alkyl, or R 3 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 C ⁇ _galkyl and acetamido or hydroxyl, is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH 2 , and b is 1.
  • R 71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_6alkyl, C3_7cycloalkyl, or C5_ 7cycloalkenyl
  • R 72 is methoxy, methylthio or iodo
  • y is 1
  • R 73 is hydrogen
  • R 7 " is attached to the benzylic carbon of R 7 , and is hydrogen or cyano.
  • A is CONR46', wherein R46' is hydrogen; Ar is (i), (ii), or (iii); E is group (a), (b), or (g), wherein when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; and wherein when E is group (a), A is attached to group (a) meta to B-(CR 1 R 2 ) a -NR 3 R4 and para to (R 5 )b, wherein B is oxygen or CH , R 1 and R 2 are hydrogen, R 5 is methoxy, R3 and R 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-te
  • R28 ; R29, R31 ⁇ R32 are hydrogen, R 0 is isopropyl, g is 2 and h is 1; and wherein when E is group (g), A is attached to group (g) meta to R 71 and para to R 72 wherein R 71 is piperidin-4-yl, 1,2,3,6- tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclopent-3-enyl, R 7 " is hydrogen or 4-cyano, R 72 is methoxy, y is 1, and R 73 is hydrogen.
  • a particularly preferred subgenus of compounds of formula (I) is wherein A is CONR46', wherein R 4 6' i s hydrogen; Ar is (i) or (ii), wherein the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (g); R 2 " is hydrogen, cyanomethyl, or cyanoethyl attached to the 3 -position; wherein A is attached to group (g) meta to R 71 and para to R 72 , R 71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4- yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclopent-3-enyl, R 71 " is hydrogen or 4-cyano, R 72 is
  • acyloxy is used herein at all occurrences to mean a moiety -O-C(O)-R, wherein R is hydrogen or C ⁇ _6alkyl as defined below.
  • C ⁇ _4alkanoyl is used herein at all occurrences to mean a -C(O)C ⁇ _ 4alkyl group wherein the alkyl portion is as defined below.
  • alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 6 carbon atoms, unless the length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl, and the like.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, ' bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
  • Cj.galkoxyCx.galkoxy is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
  • C ⁇ _4alkoxyalkyl is used herein at all occurrences to mean a C ⁇ _ 4alkoxy group as defined above bonded to an alkyl group as defined below, including, but not limited to, -CH 2 -CH 2 -O-CH -CH 2 -CH3 and the like.
  • Cx.galkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkynyl is used herein at all occurrences to mean a straight or branched chain radical of 2 to 8 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
  • aralkyl is used herein at all occurrences to mean an aryl moiety as defined above, which is connected to an alkyl moiety as defined below, including, but not limited to, benzyl or phenethyl, and the like.
  • aryl is used herein at all occurrences to mean a 6-14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to, phenyl, naphthalenyl, biphenyl, phenanthryl, anthracenyl, and the like.
  • 6,6 or 6,5 bicyclic ring is used herein at all occurrences to mean a 6,6 or
  • 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen, or sulfur, which ring system may be optionally substituted with C ⁇ _6alkyl.
  • ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings.
  • cycloalkenyl is used herein at all occurrences to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one double bond between two of the carbon atoms in the ring, including but not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkyl and “cyclic alkyl” are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo- fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4- tetrahydronaphthalenyl, and the like.
  • halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • heteroaryl is used herein at all occurrences to mean a 5-14- membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, which ring or ring systems contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, indolyl, benzofuranyl, thianaphthenyl, quinolyl, isoquinolyl, pyrrolyl, furanyl, thienyl, pyridyl, and the like.
  • hydroxyC ⁇ _6alkoxy 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.
  • hydroxyCi.galkyl and hydroxy alkyl 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 C ⁇ _galkyl.
  • examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine, pyrrolidine, piperidine, morpholine, imidazolidine, pyrazolidine, hexahydroazepine, tropane, isoquinuclidine, granatane, and the like.
  • heterocyclic ring When the heterocyclic ring is fused to a phenyl group, as when E is the group (h), the term "heterocyclic ring", together with the phenyl ring to which it is fused, forms a ring which includes, but is not limited to, dihydro-1,4- benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by C ⁇ _ ⁇ ky 1 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 Rb moiety, wherein R a and Rb are, independently, hydrogen or O to Cg alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, pyridine, and the like. It will be recognized that the saturated or unsaturated 5-, 6- or 7-membered ring may optionally have one or more additional heteroatoms in the ring.
  • optionally substituted is used herein at all occurrences to mean an optionally substituted 5- to 7-membered heterocyclic ring wherein the optional substituents are one or more of C ⁇ _galkyl.
  • oxo is used herein at all occurrences to mean a double bonded oxygen atom attached to a chemical moiety as a substituent.
  • 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.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated forms 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 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.
  • atopic disorders for example, atopic dermatitis and allergies
  • rheumatoid arthritis for example, atopic dermatitis and allergies
  • sarcoidosis or idi
  • 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 HTV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound as depicted in formula (I).
  • treating is meant either prophylactic or therapeutic therapy.
  • Such formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well- known variables.
  • the formula (I) compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, inflammatory bowel disease, and HIV infection, in an amount sufficient to decrease symptoms associated with these disease states.
  • the route of administration may be oral or parenteral.
  • parenteral in another aspect, 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.
  • 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.
  • the compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
  • compounds of formula (I) wherein A is NR46' are synthesized from an appropriately substituted benzoic acid, for example 1-1, and an appropriately substituted aniline 1-2 by treatment with a suitable coupling reagent, for example benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and a suitable base, for example diisopropylethylamine, in a suitable solvent, for example acetonitrile, to afford the title compound 1-3.
  • a suitable coupling reagent for example benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • a suitable base for example diisopropyleth
  • R 72 is, for example, C ⁇ _galkoxy
  • R 71 is piperidinyl
  • R 71 " is attached to the piperidinyl ring at the 4-position and is, for example, COR 5 ", CONR 6 "R 7 ", CO 2 R 8 ", cyano, SO 2 R 10 ", or SO 2 NR 6 "R 7 "
  • COR 5 ", CONR 6 "R 7 ", CO 2 R 8 ", cyano, SO 2 R 10 ", or SO 2 NR 6 "R 7 " can be prepared following the general procedures of Cammack and Reeves, J. Heterocyclic Chem., 1986, 23, 73-5; Iorio, et. al., Farmaco, Ed. Sci., 1977, 32, 212-19; Buchi, et. al., Helv. Chim.
  • 3-5 may be obtained from 3-4 by reductive amination using an appropriately substituted aldehyde or ketone, an appropriate reducing agent, for example sodium cyanoborohydride, in an appropriate solvent, for example methanol containing acetic acid.
  • an appropriate reducing agent for example sodium cyanoborohydride
  • Anilines wherein R 71 " is NR3"R4" or SR 9 " can be prepared following the general procedures of Chen, et. al., Bioorg. Med. Chem. Lett., 1997, 7, 555-560, Ong, et. al., J. Med.
  • Nitric acid (70%, 3.1 mL) was added portionwise to a solution of the compound of Preparation 5(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 min, combined with an identical concurrently run reaction, and poured into water (600 mL).
  • the pH of the resultant mixture was adjusted to >9 by the addition of aqueous sodium carbonate followed by 10% sodium hydroxide.
  • Preparation 6 Preparation of N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl)]phenyl]-4-(4 ,4.5,5- tetramethyl- 1.3 ,2-dioxaborolan-2-yl)benzamide
  • a mixture of the compound of Preparation 5(e) (2.48 g, 10 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoic acid (2.48 g, 10 mmol), and l-hydroxy-7-azabenzotriazole (1.39 g, 10 mmol) dissolved in acetonitrile (75 mL) was treated with l-(dimethylaminopropyl)-3- ethylcarbodimide hydrochloride (2.31 g, 12 mmol) and stirred at RT for 16 h.
  • 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 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

This invention relates to substituted benzanilides 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 and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, by the use of substituted benzanilides 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

SUBSTITUTED BENZANILIDES AS MODULATORS OF THE CCR5 RECEPTOR
FIELD OF THE INVENTION This invention relates to substituted benzanilides which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature
Medicine 1996, 2, 1174-8). 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 (M.J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial ucosa of asthmatics (C.J. Corrigan and A.B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 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. R ANTES, 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, TJ. 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 LL-1 or TNF*. Although RANTES mRNA is not usually detected in normal tissues (J.M. Pattison, P J. Nelson, and A.M. Krensky, Clin. Immunother. 4: 1-1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. 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. Ala , 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 that are important in the maintenance of a chronic inflammatory reaction.
Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders. 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 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.
Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted benzanilides 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 novel compounds of formula (I) and their use as CCR5 modulators for the 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, all in mammals, preferably humans. The preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein.
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 ATDS. 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 benzanilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt 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 HJV infection.
Preferred compounds for use as CCR5 modulators are those compounds of Formula (I) as noted herein. A preferred group of compounds for use herein are those compounds of the
Formula (I) or a pharmaceutically acceptable salt or solvate thereof:
Ar-A-E Formula (I) wherein Ar is a group selected from (i), (ii) or (iii);
Figure imgf000006_0001
wherein: the basic nitrogen in moiety E may be optionally quaternized with Ci.βalkyl or is optionally present as the N-oxide;
R1' and R ' are each independently one or more of hydrogen, Cι_6alkyl, C2_6alkenyl. C2- galkynyl, C3_7cycloalkyl, C3.6cycloalkenyl, aryl, (CH2)aNR7R8', (CH2)a'NR7'COR9', (CH2)a'NR7'CO2R10', (CH2)a'NR7'SO2Rl r, (CH )a'CONR12'Rl3', hydroxyCι_6alkyl, Cχ_ 4alkoxyalkyl (optionally substituted by a C^alko y or hydroxy group), (CH2)a'CO2Ci. alkyl, (CH2)b C(O)Rl4', CR15 =NOR16', CNR15'=NORl6', COR17', CONR^'R13',
CONRl2'(CH2)cOC1_4alkyl, CONRl2'(CH2)a'C02R18', CONHNR^^O CONR12'SO2 21', C02R22', cyano, trifluoromethyl, NR7R8', NR7'COR9', NR23'cO(CH2)a'NR2 'R 4'; NR23'C0NR23'R24'? NR7'CO2R10', NR7'SO2R11', N=CNR23'NR23'R24', nitro, hydroxy, Cι_ 6alkoxy, hydroxyCι_6alkoxy, Cι_6alkoxyCι_6ϊdko y, OC(O)NR25'R26'3 SR27'J SOR28', S02R28' Sθ2NR25'R 'or halogen;
R ' and R^' are each independently one or more of hydrogen, Cι_6alkyl, C^. jcycloalkyl, C3_gcycloalkenyl, hydroxyCi-galkyl,
Figure imgf000006_0002
CONR29'R30', CO2R31', cyano, aryl, trifluoromethyl, NR29'R30') nitro? hydroxy, Cι_ galkoxy, acyloxy, or halogen; when Ar is (i) or (ii) the phenyl ring substituted with R ' may be substituted with R2", wherein R2" is hydrogen, (CH2)aCN, (CH2)aCO2H, CR^ =CR16'C02R18', COCR15'R16'OR18'5 Oaryl, Oaralkyl, O(CH2)a'CO2R18', d Saryl;
R5' is one or more of hydrogen, C^alkyl, Cι_galkoxy or halogen;
Rδ'is one or more of hydrogen, Ci.galkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyCi .galkyl, hydroxyC3_6alkenyl, hydroxyC3_6alkynyl, (CH2)dOR.32', (CH2)d!COR33', (CH2)d'CR34 =NOR35', CONR36'R37', CO2R38', hydroxy, O(CH2)e'R39', NR 6'R37', SR40', SO2NR41'R42' or halogen; or, R^' and R^' form a fused benzo ring optionally substituted with Cχ_g • alkyl, Cx.galkoxy or halogen; R7' and R8' are independently hydrogen or Cj.galkyl, or together with the nitrogen to which they are attached, R7' and R8' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R^'is hydrogen, Cx.galkyl or Cχ_4alkoxyalkyl; RlO'is Cι_6alkyl;
Ri 1' is Cχ_6alkyl or phenyl;
Rl ' and Rχ ' are independently hydrogen or Cχ_6alkyl, or together with the nitrogen to which they are attached, Rl2 and Rχ form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
Rl4'is Cχ_4alkyl, optionally substituted by Cχ_galkoxy;
Rl5' and R1^' are independently hydrogen or Cχ_6alkyl;
Rl7' is hydrogen or Cχ_6alkyl;
Rl8 is hydrogen or Cχ_βalkyl; Rl9' and R20' are independently hydrogen or Cχ_6alkyl;
R^l'is hydrogen or Cχ_6alkyl;
R22 is hydrogen or Cχ_5alkyl optionally substituted with one or two substituents selected from Ci.galkyl, Cx.galkoxy, hydroxy, or NR7 R8';
R23' and R24' are independently hydrogen or Cχ_6alkyl; R25' and R26' are independently hydrogen or Cx.galkyl, or together with the nitrogen to which they are attached, R^5' and R26' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R2 ' is hydrogen or C^.^alkyl; R28'is Cι_6alkyl;
R29', R30' an(j R31' aj-e independently hydrogen or Cχ_6alkyl; R 2' is Cι_6alkyl, hydroxyCι _6alkyl, or Cι_4alkanoyl;
R 3' is hydrogen or Cχ_6alkyl;
R34' is hydrogen or Cχ_6alkyl;
R35 is hydrogen or Cχ_galkyl; R3^' and R 7' are independently hydrogen or Cχ_6alkyl or together with the nitrogen to which they are attached, R36' and R ' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 3', wherein R43' is Ci^alkyl, COR44' or CO2R45', wherein R44' and R45' are independently hydrogen or Cχ_6alkyl;
R 8' is hydrogen or C^.^alkyl;
R 9' is Cι_6alkoxy, CO2H, CO2Cι_6alkyl or CONR36'R37';
R40' is Ci.6alkyl;
R 1' and R42' are independently hydrogen or Cj.galkyl; P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; a' is 1, 2, 3 or 4; b'is O, 1, 2 or 3; c' is 1, 2 or 3; d' is 0, 1, 2, 3, 4, 5, or 6; and e' is 1, 2, 3, 4, 5 or 6; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, - NHCH2, or CH2NH, wherein R46' is hydrogen or C^alkyl, E is a group (a):
Figure imgf000008_0001
R6 (a); wherein:
B is oxygen, Ci C, S(O)c, CR =CR8, or CR7R8, or B is NR9; Ri and R2 are independently hydrogen or Ci.galkyl; alternatively B(CRlR2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R and R4 are independently hydrogen, Cχ_6alkyl, C3_7cycloalkyl, aralkyl, C5. ^cycloalkenyl, a C5_7heterocyclic ring, 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, CONRIOR1 1, NRIOR1 1, hydroxy, OCOR12, NHCOCF3, NHSO2R13, NHCO2R14, or NHCOC0_6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH; R5 is hydrogen, C^alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl,
NHCO2R18, hydroxy, C^alkoxy, benzyloxy, OCH2CO2C _6aιkyl, OCF3, S(O)dR19, SO2NR20R21 or halogen;
R6 is hydrogen, Chalky!, aryl, trifluoromethyl, hydroxy, Cj.galkoxy or halogen, or R^ taken together with R 0' forms a group D where D is (CR22R23)e or D is (CR22R23)f-G where G is oxygen, sulfur or CR22=CR23, CR22=N, =CR22O, =CR22S, or =CR22-NR23;
R7, R8, RlO, Rll, Rl , Rl5, R16 R17, R20, R21, R22 and R23 ^e independently hydrogen or Ci.galkyl;
R9 is hydrogen, Cχ_6alkyl, or phenylC _6alkyl; R13, R14, Rl8, and R19 are independently C^alkyl; a is 1, 2, 3, or 4; b is 1 or 2; c and d are independently 0, 1 or 2; e is 2, 3 or 4; f is O, 1, 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R 6' is hydrogen or Cj.galkyl, alternatively, E is a group (b):
Figure imgf000009_0001
R24, R25, R26; R27S R28 ? R29, R311 and R32 ^e independently hydrogen or
Cι_6alkyl;
R 0 is hydrogen, Cχ_galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5.. 7heterocyclic ring;
R 3 is hydrogen, Cχ.galkyl, trifluoromethyl, hydroxy or halogen, or R 3 and R30' together form a group -K- where K is (CR34R35)i or K is (CR34R35)J _M ^d M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N;
J is oxygen, CR36R37; or NR38 ? or J is a group S(O)i,; R34; R35? 36? R37; and R38 are independently hydrogen or Cx.galkyl; g is 1, 2 or 3; h is 1, 2 or 3; i is 2, 3, or 4; j is 0, 1, 2, or 3; k is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is C0NR46', NHCO,
NHCH2, or CH2NH, wherein R 6'is hydrogen or Cj.galkyl, alternatively, E is a group (c):
Figure imgf000010_0001
wherein:
Q is oxygen, S(O)n, CR4 =CR45, CR 4R45? or Q is NR46; R 9 and R 0 are independently hydrogen or Cx.galkyl; R41 is a group of formula (d):
Figure imgf000010_0002
or R41 is a group of formula (e):
Figure imgf000010_0003
R42 is hydrogen, C^alkyl, aryl, CN, CONR48R495 cθ2R50, trifluoromethyl, NHCO2R51, hydroxy, Cj^alkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)sR52, SO2NR53R545 or halogen;
R43 is hydrogen or R43 together with R 0' forms a group R where R is CR55=CR56; CR55=CR56CR55R56, or (CR55R56)t;
R44, R45; R46? R48? R49; R505 R535 R54 R55? and R5^ are independently hydrogen or C^galkyl;
R4 is hydrogen, Cj.galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a Cζ. 7heterocyclic ring; R51 and R52 are independently Cχ_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 O, l, or 2; t is 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONH, NHCO, or, CH2NH, alternatively, E is a group (f):
Figure imgf000011_0001
R^ and R^8 are independently hydrogen or Cx.galkyl; R^ and R^0 are independently hydrogen, Cx.galkyl, C3_7cycloalkyl, aralkyl,
C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR61R6 5 NR61R6 5 hydroxy, OCOR63, NHCOCF3, NHSO2R6 , NHCO2R65, or NHCOC0-6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH; T is -(CR66R67)V_ or -θ(CR66R67)w-; W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70; R61; R625 635 R66J R67 R68; R69? and R70 are independently hydrogen or C1_6alkyl;
R64 ^d R65 aj-e independently Cχ_6alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46'S NHCO, or CH2NH, wherein R46' is hydrogen or Cj.galkyl, alternatively, E is a group (g):
Figure imgf000012_0001
R 1 is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a basic nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R 1 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, Cj.galkyl or C3_7cycloalkyl, Cs- cycloalkenyl, or a C5_7heterocyclic ring; R71 is substituted with one or more of R71", wherein R71" is hydrogen, CRlaR2"NR3"R4"; CRl R2"OR3", COR5", CONR6"R7", CO2R8", cyano, NR3"R4", nitro, hydroxy, C^galkoxy, SR9", SOR10", SO2R10", SO2 NR6"R7" or SO3H, wherein Rla and R2" are independently hydrogen or Ci .βalkyl; R ' and R ' are independently hydrogen or Cx.galkyl, or taken 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 one oxygen or one sulfur atom; alternatively R4" is COR11", CONR12"R13", CO2R14", SO^15", SC^NR12'^", or SO2OR16", wherein R11" is hydrogen, Ci_galkyl, aryl, or trifluoromethyl; R 2" and R1 " are independently hydrogen or Cχ_6alkyl, or taken 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 one oxygen or one sulfur atom; R1 " is Cj.galkyl or aryl; R15" is C _ galkyl, aryl, or trifluoromethyl; and R " is aryl; R?" is Cj.galkyl, aryl, or trifluoromethyl; R" and R7" are independently hydrogen or Cx.galkyl, or taken 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 one oxygen or one sulfur atom; R8 is hydrogen or Cj.galkyl; R9" is hydrogen, Cχ_galkyl, aryl, or trifluoromethyl; and R1^ is Cχ_6alkyl, aryl, or trifluoromethyl;
R72 is hydrogen, Ci.galkyl, aryl, CN, CONR74R75, CO2R °, trifluoromethyl, NHCO R77, hydroxy, Cι_6alkoxy, benzyloxy, OCH2CO2Cι _6alkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R is hydrogen, Ci.galkyl, hydroxy, Cχ_6alkoxy or halogen, or R 3 and R 0' taken together from a group -X- where X is (CR81R82)aa or X is (CR81R82)aD-Y and Y is oxygen, sulfur or CR81=CR82;
R74, R753 R76; R79? R80J R81? and R82 are independently hydrogen or Cχ_ galkyl;
R77 and R78 are independently Cx.galkyl; y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is C0NR46'5 NHCO, ox CH2NH, wherein R46 ' is hydrogen or C \ .galkyl ; alternatively, E is a group (h):
Figure imgf000013_0001
R87 (h);
R and R84 are independently hydrogen or Cχ_6alkyl; R85 and R ^ are independently hydrogen, Cχ_6alkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOCF3, NHSO2R93, NHCO2R9 , or NHCOC0-6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH;
R87 is hydrogen or Cχ_6alkyl, Cj.galkoxy, or halogen, or R87 together with R 0' 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, ^d R96 are independently hydrogen or Cχ_ galkyl;
R 3 and R94 are independently Cχ_6alkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R46'is hydrogen or Ci.galkyl, alternatively, E is a group (i):
Figure imgf000014_0001
R97 and R98 are independently hydrogen, C^galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR^R1*^ NR^R1*^ hydroxy, OCOR106, NHCOCF3, NHSO2 R107, NHCO2R108, or NHCOC0-6alkyl wherein the alkyl of NHCOCo-όai yl is optionally substituted by OH;
R99 and R1^ are independently hydrogen or Cl-6alkyl; R1^1 is hydrogen or Cχ_6alkyl or R ^1 and R30' together form a group -AD- where AD is (CR10^110)ai or AD is (CR109R110)aj-AE and AE is oxygen, sulfur or CRiO^CRϋO;
AC is oxygen, CR1 1 ^R1 12 or NR1 13 or AC is a group S(O)ak;
R102, R103, R1045 R105; R106 R109, Rl 10, Rl 11, Rl 12, and R11 are independently hydrogen or Cχ_galkyl;
R107 and R108 are independently Cl-6alkyl; 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 O, 1, 2, or 3; and ak is 0, 1 or 2, provided that when R2" is hydrogen and E is a group (a), (f) (h) or (i), then one or both of R3 or R4; R5 or R60; R85 or R86; or R97 or R98 is C5_ 7cycloalkenyl, or a C5_7heterocyclic ring; or when R2" is hydrogen and E is a group (b) or (c), then R 0 and R47 are C5_7cycloalkenyl, or a C5_7heterocyclic ring; or when R2" is hydrogen and E is group (g), then either R71" is not hydrogen and/or R7 is substituted on nitrogen with C5_7cycloalkenyl or a C5_7heterocyclic ring.
For compounds of formula (I) various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quaternized with Cχ_ βalkyl or is optionally present as the N-oxide.
Suitably, Ar is (i),(ii), or (iii). Preferably, Ar is (i) or (ii). Suitably, when Ar is (i) or (ii), the terminal phenyl group in (i) and (ii) can be attached to the phenyl group bearing group A in any position. Preferably, the terminal phenyl ring is attached to the phenyl bearing group A in a position meta or para to group A. Suitably, R1' and R2' are each independently one or more of hydrogen, Cχ_ ό^kyl, C2-6alkenyl, C _6alkynyl, C3_7cycloalkyl, C3_6cycloalkenyl, aryl,
(CH2)aNR 'R8', (CH2)a>NR 'COR9', (CH2)a'NR7'CO2R10', (CH2)a'NR7'SO2R11', (CH2)aCONR12'R13', hydroxyCχ_6alkyl, Ci_4alko y alkyl (optionally substituted by a Cι_4alkoxy or hydroxy group), (CH2)a O2Ci.6alkyl, (CH2) OC(O)R14', CR15
Figure imgf000015_0001
4alkyl, CONR12'(CH2)aCO2R18', CONHNR19'R20', CONR12'SO2R21', CO2R22', cyano, trifluoromethyl, NR7'R8', NR7'COR9', NR23'CO(CH2)a'NR23'R24', NR23'C0NR23'R24', NR 'CO2R10', NR7'SO2R11', N=CNR23'NR23'R24', nitro, hydroxy, Cχ_6alkoxy, hydroxyCi.galkoxy, Cχ_6alkoxyCχ_6alkoxy, OC(O)NR25'R26', SR27', SOR28', SO2R28', SO2NR25'R26' or halogen. Suitably, R ' and R4' are each independently one or more of hydrogen, Cχ_ galkyl, C3_7cycloalkyl, C3_6cycloalkenyl, hydroxy Cj.galkyl, Cχ_6alkylOCχ_6alkyl, CONR29'R30'5 CO2R31', cyano, aryl, trifluoromethyl, NR29'R30', nitro, hydroxy, Cχ_ 5alkoxy, acyloxy, or halogen.
Suitably, R2'is also R2" wherein R2" is hydrogen, (CH2)aCN, (CH2)aCO H,
Figure imgf000015_0002
COCR15'R16OR18', Oaryl, Oaralkyl, O(CH2)aCO2R18', and Saryl. Preferably, R2" is hydrogen, (CH2)aCN, (CH2)a< O2H, COCR^'R^ΌR18', and O(CH )aCO2R18' attached to the 3 '- or 4 -position.
Suitably, R5' is one or more of hydrogen, Cι_galkyl, Cx.galkoxy or halogen. Suitably, R^' is one or more of hydrogen, Cj.galkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyCχ_6alkyl, hydroxyC3_6alkenyl, hydroxyC3.6alkynyl, (CH2)d R32', (CH2)d'COR33', (CH2)dCR34=NOR35', CONR36'R3 ', CO2R38', hydroxy, O(CH2)e>R39', NR36'R37'5 SR40'5 SO2NR41'R42' or halogen; or, R5' and R^' form a fused benzo ring optionally substituted with Cχ_6 alkyl, C^alkoxy or halogen. Suitably, R7' and R8' are each independently hydrogen or Cχ_galkyl, or together with the nitrogen to which they are attached, R7' and R8' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom. Suitably, R9' is hydrogen, Cj.galkyl or Cχ_4alkoxy alkyl.
Suitably, R10' is C^alkyl. Suitably, R11' is C^.^alkyl or phenyl.
Suitably, R12' and R13' are independently hydrogen or Cχ_6alkyl, or together with the nitrogen to which they are attached, R12' and R13' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
Suitably, Rl4' is C^alkyl, optionally substituted by Ci.galkoxy.
Suitably, R15' and R1^' are independently hydrogen or Ci.galkyl.
Suitably, R1 'is hydrogen or Cχ_6alkyl.
Suitably, R 'is hydrogen or Cx.galkyl. Suitably, R19' and R ^' are independently hydrogen or Cχ_6alkyl.
Suitably, R 1' is hydrogen or Cx.galkyl.
Suitably, R22' is hydrogen or Ci^galkyl optionally substituted with one or two substituents selected from C^alkyl, Ci.galkoxy, hydroxy, or NR7'R8'.
Suitably, R23' and R24' are independently hydrogen or Cχ_6alkyl. Suitably, R25' and R2^' are independently hydrogen or Cχ_6alkyl, or together with the nitrogen to which they are attached, R25' and R2^' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom.
Suitably, R27 is hydrogen or Cχ_galkyl. Suitably, R28' is C^alkyl.
Suitably, R29', R 0' and R 1' are independently hydrogen or Cχ_6alkyl.
Suitably, R 2' is Cx.galkyl, hydroxyCχ_6alkyl, or Ci^alkanoyl.
Suitably, R 3' is hydrogen or Ci.galkyl.
Suitably, R 4' is hydrogen or Ci.galkyl. Suitably, R 5' is hydrogen or Cχ_6alkyl.
Suitably, R 6' and R.37' are independently hydrogen or Cχ_galkyl or together with the nitrogen to which they are attached, R 6' and R 7' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 3', wherein R 3' is Cι_6alkyl, COR 4' 0r CO2R 5', wherein R4 ' and R45' are independently hydrogen or Cx.galkyl.
Suitably, R 8' is hydrogen or Cx.galkyl.
Suitably, R39' is
Figure imgf000016_0001
or CONR36'R3T.
Suitably, R40' is Ci^al yl. Suitably, R 1 ' and R42' are independently hydrogen or Cχ_6alkyl. Suitably, P is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl. Saturated and partially saturated rings are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams. Suitably, the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom. Suitable substituents for these rings include one or more of R4'. Preferably, P is 1,2,4- oxadiazol-3-yl and R4' is 5-methyl.
Suitably, a' is 1, 2, 3 or 4.
Suitably, b' is 0, 1, 2 or 3.
Suitably, c' is 1, 2 or 3.
Suitably, d'is 0, 1, 2, 3, 4, 5, or 6. and
Suitably, e' is 1, 2, 3, 4, 5 or 6.
Suitably, when Ar is (i), (ii), or (iii), substituent E is selected from the following groups:
Figure imgf000017_0001
Figure imgf000018_0001
Suitably, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, -NHCH2, or
CH2NH, wherein R46' i is a group (a):
Figure imgf000018_0002
R6 (a).
B is suitably oxygen, Cg C, S(O)c, CR7=CR8> or CR7R8, or B is NR9. B is preferably CR7R8, or oxygen.
R and R2 are suitably independently hydrogen or C^galkyl. Preferably, R and R2 are hydrogen. Alternatively, B(CR1R2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2. Preferably, when B(CR1R2)a is
OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2, R1 and R2 are hydrogen.
R and R are suitably independently hydrogen, Cx.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR^R 1, NR^R11, hydroxy, OCOR12 NHCOCF3, NHSO2 R 3, NHCO2R14, or NHCOCQ. galkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH. Preferably R3 and R4 are both Cχ_galkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur. Preferably, B-(CR1R2)a-NR3R4 is ortho to R5, meta to A and para to R6, and R5 is para to A. R5 is suitably hydrogen, C^alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO R18, hydroxy, C^alkoxy, benzyloxy, OCH CO2Cχ_6alkyl, OCF3, S(O)dR19, SO2NR20R21, or halogen. R5 is preferably C^galkoxy, SCχ_ galkyl or halogen. R6 is suitably hydrogen, Cx.galkyl, aryl, trifluoromethyl, hydroxy, Cx.galkoxy, or halogen, or R6 taken together with R46' forms a group D where D is (CR 2R23)e or D is (CR22R23)f_G where G is oxygen, sulfur, or CR22=CR23, CR 2=N, =CR22O, =CR22S, or =CR22-NR23. Preferably, R6 is hydrogen. R7, R8, R10, Rl 1, R12, R15, R16, R17> R20, R21, R22, and R23 are suitably independently hydrogen or Cj.galkyl.
R9 is suitably hydrogen, Ci.galkyl, or phenylCj.galkyl.
R1 , Rl Riδ, ^d R19 are suitably independently Cx.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, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen or Cχ_6alkyl, E suitably is a group (b):
Figure imgf000019_0001
R24, R25, R26; R27? R28; R29; R315 and R 2 are suitably independently hydrogen or Ci.galkyl. R24 R25? R263 R27; R285 R29^ R31? and R32 are preferably hydrogen. R30 is suitably hydrogen, Cχ_galkyl, C3_7cycloalkyl, C5_7cycloalkenyl or a
C5_7heterocyclic ring. Preferably, R30 is Cj.galkyl, C3_7cycloalkyl, C5_ 7cycloalkenyl, or a C5_7heterocyclic ring.
R33 is suitably hydrogen, Cχ_6alkyl, trifluoromethyl, hydroxy or halogen, or R33 3nd R46' together form a group -K- where K is (CR34R35)1 or K is (CR 4R35)J . M and M is oxygen, sulfur, CR34=CR 5, CR34=N, or N=N. Preferably, R33 is hydrogen.
J is suitably oxygen, CR36R37; 0r NR , or J is a group 8(0)^. Preferably, J is oxygen. Preferably, J is para to A.
R3 , R35; R365 375 R38 ^Q suitably independently hydrogen or Cχ_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, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, -NHCH2, or CH2NH, wherein R46' is group (c):
Figure imgf000020_0001
Suitably, Q is oxygen, S(O)n, CR44=CR45, C=C , or CR44R45; wherein n is 0,
1 or 2, and R44 3nd R45 are independently hydrogen or Cx.galkyl, or suitably, Q is NR46 wherein R46 is hydrogen or alkyl; suitably, R 9 and R40 are independently hydrogen or Ci.galkyl; suitably, R42 is hydrogen, Cι_6alkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO2R5 , hydroxy, Cx.galkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)sR52, SO2NR53R545 or halogen, wherein R48, R49, R505 R53? and R^4 are hydrogen or Cχ_galkyl, and R51 and R52 are Cχ_6alkyl; suitably, R43 is hydrogen or R43 together with R 6' forms a group R where R is CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t wherein R55 and R56 are independently hydrogen or Cχ_6alkyl and t is 2 or 3; suitably, R 1 is selected from a group of formula (d) or (e); suitably R47 is hydrogen, C^galkyl, 03.7 cycloalkyl, C5_
7cycloalkenyl, or a C5_7heterocyclic ring; 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, when Ar is (i), (ii) or (iii), and A is CONH, NHCO, or CH2NH, E suitably is a group (f):
Figure imgf000020_0002
R57 and R58 are independently hydrogen or Cχ_βalkyl; suitably R59 and R^0 are independently hydrogen, Ci.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring 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 Ci.galkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOCF3, NHSO2R64, NHCO2R65 0r NHCOC0_6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH, and wherein R^1, R6 ? and R^ are independently hydrogen or Cχ_6alkyl, and R^4 and R^5 are independently C^.^alkyl; suitably, T is -(CR66R67)V- or -O(CR66R67)w-, wherein R66 and R67 are independently hydrogen or Ci.galkyl, 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 R^8 [S hydrogen or Cι_6alkyl, or W is CR69=CR 0, C=C, or CR6 R70, wherein R69 and R70 are independently hydrogen or Cχ_galkyl; and suitably, u is an integer from 1-4.
Alternatively, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen or Cχ_6alkyl, E suitably is a group (g):
Figure imgf000021_0001
Suitably, R7 is an optionally substituted 5- to 7-membered saturated or partially saturated heterocyclic ring containing a basic nitrogen atom and optionally a further one or two heteroatoms selected from nitrogen, oxygen or sulfur, or R7 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 Cx.galkyl, and substituted on nitrogen with hydrogen, Cj.galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring. 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 is substituted on nitrogen with Cx.galkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring. Suitably, R71 is substituted with one or more of R7 ! " wherein R7 * is hydrogen, CRlaR2"NR3"R4", CR1 R2"θR ", COR5", CONR6"R7", CO2R8", cyano, NR3"R4", nitro, hydroxy, C^alkoxy, SR9", SORlO", SO2R10", SO2 NR6"R7" or SO3H wherein R " and R2a are independently hydrogen or Cχ_galkyl, provided that R 1" is not a substituent on the basic nitrogen of R7 . Suitably, R3" and R4" are independently hydrogen or Ci.galkyl, or taken 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 one oxygen or one sulfur atom.
Alternatively, R4" is COR11", CONR12"R13", CO2R14", SO2R15", SO2NR12"R13", or SO2OR16" wherein R11" is hydrogen, Cχ_6alkyl, aryl, or trifluoromethyl; R12 and R13' are independently hydrogen or Cj.galkyl, or taken 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 one oxygen or one sulfur atom; Rl4" is Cx.βalkyl or aryl; R15" is Cx.galkyl, aryl, or trifluoromethyl; and R1" ' is aryl; R5" is hydrogen, Cχ_6alkyl, aryl, or trifluoromethyl; R6" and R7' are independently hydrogen or Cι_6 lkyl, or taken 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 one oxygen or one sulfur atom; R8" is hydrogen or Cj.galkyl; R9" is hydrogen, Ci^ lkyl, aryl, or trifluoromethyl; and R1^ is Cj.galkyl, aryl, or trifluoromethyl. Preferably, R71" is hydrogen or cyano.
R 1 is preferably located meta to A, ortho to R72 and para to R73, and R72 is located para to A. Suitably, R72 is hydrogen, C^galkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, Ci.galkoxy, benzyloxy, OCH2CO2Cχ_6alkyl, OCF , S(O)zR78, SO2NR79R80, or halogen wherein R74, R75, R76, R79 and R80 are independently hydrogen or C^.^alkyl, R77 and R78 are Cjlgalkyl, and z is 0, 1, or 2. R72 is preferably Cχ_galkoxy, SCχ_6alkyl or halogen. R73 is hydrogen, Cχ_6alkyl, hydroxy, C^.^alkoxy or halogen, or R73 and R46' taken together from a group -X- where X is (CR 1R 2)aa, wherein aa is 2, 3 or 4, and R81 and R82 are independently hydrogen or Cχ_6alkyl, or X is (CR 1R 2)a^-Y, wherein ab is 0, 1, 2 or 3, and Y is oxygen, sulfur or CR 1=CR82 wherein R81 and R82 aj-g independently hydrogen or Cj.galkyl. Preferably, R73 is hydrogen. Suitably, y is an integer from 1-2. Preferably, y is 1.
Alternatively, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen or Cχ_6alkyl, E suitably is a group (h): (CRS3R84)ac NRβSR86
Figure imgf000022_0001
R87 (h).
Suitably, R87 is hydrogen, Cj.galkyl, Cj.galkoxy or halogen, or R87 together with R46' form a group -AA-, wherein AA is (CR 5R8 )ad, wherein ad is 1, 2 or 3, and R95 and R88 are independently hydrogen or Ci^alkyl, or AA is (CR95CR96)ae-AB, wherein ae is 0, 1 or 2, and AB is oxygen, sulfur, CR95=CR96, CR =N, CR95NR96 or N=N, wherein R95 and R9^ are independently hydrogen or Cχ_6alkyl. Suitably, R 3 and R84 are independently hydrogen or Cχ_6alkyl. Suitably, R85 and R8^ are independently hydrogen, C^galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR8 R89, NR90R91, hydroxy, OCOR92 NHCOCF3, NHSO2R93, NHCO2R94, orNHCOC0- galkyl wherein the alkyl of the NHCOCo-δalkyl is optionally substituted by OH, and wherein R88, R89, R90, R91 and R92 are independently hydrogen or C _galkyl, and R93 and R94 are independently Ci.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, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or
CH2NH, wherein R 6' is hydrogen or Cχ_6alkyl, E suitably is a group (i):
Figure imgf000023_0001
Suitably, R1^1 is hydrogen or Cχ_6alkyl or R1^1 and R46' together form a group -AD- wherein AD is (CR1^9R 0)ai wherein ai is 2, 3 or 4 or AD is (CR1^9R11^)aj-AE wherein aj is 0, 1, 2 or 3 and AE is oxygen, sulfur or CR109=CR110 , and R109 and R110 are independently hydrogen or Ci.galkyl. Suitably, R97 and R98 are independently hydrogen, Cj.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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 Ci.galkyl, aryl, CONR -^R1"3, NR104R105, hydroxy, OCOR106, NHCOCF3, NHSO2 R107, NHCO^O8, or
NHCOCo-6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH, and wherein R102, R103, R!04? R105 and R Q6 are independently hydrogen or Cχ_ galkyl, and R1^ and R ^8 are independently Cl-6alkyl.
Suitably, R99 and R1^ are independently hydrogen or Cx.galkyl; suitably, AC is oxygen, CR1 ! iR112 or NR113 wherein R111, R112 and R113 are independently hydrogen or Cχ_5alkyl 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.
Preferably, A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen. More preferably, A is CONR46' 0r NHCO, wherein R46' is hydrogen. Most preferably, A is CONR46', wherein R46' is hydrogen.
Preferably, when Ar is (i), (ii), or (iii), E is group (a), (b), or (g). More preferably, when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A. More preferably, when Ar is (i), (ii) or (iii), E is group (g). Most preferably, when Ar is (i) or (ii), E is group (g). More preferably, R2" is hydrogen, or (CH^a'CN. (CH2)aCO2H,
COCR15'R16'OR18', and O(CH2)aCO2R18' attached to the 3'-position.
Most preferably, R " is hydrogen, cyanomethyl, or cyanoethyl attached to the 3 -position.
More preferably, when E is group (a), A is attached to group (a) meta to B- (CR1R2)a-NR3R and para to (R5)b, wherein B is oxygen or CR7R8, R1 and R 2 ^e hydrogen, R5 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 Cχ_6alkyl and acetamido or hydroxyl, R^ is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, and b is 1.
Most preferably, when E is group (a), A is attached to group (a) meta to B- (CR1R2)a-NR3R4 and para to (R5)D, wherein B is oxygen or CH2, R and R ^ are hydrogen, R5 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), R6 is hydrogen, a is 2 when B is oxygen, and b is 1.
More preferably, when E is group (b), A is attached to group (b) para to J, J is oxygen, R33 is hydrogen, R24 R25? R26> R275 R28? R29; R31 ^d R32 ^Q hydrogen, R30 is C3_6alkyl, g is 2 and h is 1.
Most preferably, when E is group (b), A is attached to group (b) para to J, J is oxygen, R33 is hydrogen, R24 R25? R26? R27; R285 R29; R31 an R32 are hydrogen, R 0 is isopropyl, g is 2 and h is 1.
More preferably, when E is group (g), A is attached to group (g) meta to R71 and para to R72, R71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_6alkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring, R72 is methoxy, methylthio or iodo, y is 1, R7 is hydrogen, and R71" is hydrogen or cyano, attached to the benzylic carbon of R71. Most preferably, when E is group (g), A is attached to group (g) meta to R7 and para to R72 wherein R71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cycloρent-3-enyl, R71 ' is hydrogen or 4- cyano, R72 is methoxy, y is 1, and R73 is hydrogen.
A preferred subgenus of compounds of formula (I) is wherein A is C0NR46', NHCO, or CH NH, wherein R46' is hydrogen; Ar is (i), (ii), or (iii); and E is group (a), (b), or (g).
A more preferred subgenus of compounds of formula (I) is wherein A is CONR46' or NHCO, wherein R46' ΪS hydrogen; Ar is (i) or (ii), and the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (a), (b), or (g); and R2" is hydrogen, or (CH2)a€N, (CH2)aCO2H, COCR^'R^'OR18', and O(CH2)a!CO2R^8' attached to the 3 -position. When E is group (a), A is attached to group (a) meta to B-(CR1R2)a-NR3R4 and para to (R5)b, wherein B is oxygen or CR7R8, R1 and R 2 are hydrogen, R5 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 Cι_galkyl and acetamido or hydroxyl, is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, and b is 1. When E is group (b), A is attached to group (b) para to J, J is oxygen, R33 is hydrogen, R24, R25, R26; R275 R28? R29 R31 ^d R32 are hydrogen, R30 is Cs.galkyl, g is 2 and h is 1. When E is group (g), A is attached to group (g) meta to R71 and para to R72, R71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_6alkyl, C3_7cycloalkyl, or C5_ 7cycloalkenyl, R72 is methoxy, methylthio or iodo, y is 1, R73 is hydrogen, and R7 " is attached to the benzylic carbon of R7 , and is hydrogen or cyano.
Another preferred subgenus of compounds of formula (I) is wherein A is CONR46', wherein R46' is hydrogen; Ar is (i), (ii), or (iii); E is group (a), (b), or (g), wherein when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; and wherein when E is group (a), A is attached to group (a) meta to B-(CR1R2)a-NR3R4 and para to (R5)b, wherein B is oxygen or CH , R1 and R 2 are hydrogen, R5 is methoxy, R3 and R 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; and wherein when E is group (b), A is attached to group (b) para to J, J is oxygen, R33 js hydrogen, R2 , R25, R 6 R27? R28; R29, R31 ^ R32 are hydrogen, R 0 is isopropyl, g is 2 and h is 1; and wherein when E is group (g), A is attached to group (g) meta to R71 and para to R72 wherein R71 is piperidin-4-yl, 1,2,3,6- tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclopent-3-enyl, R7 " is hydrogen or 4-cyano, R72 is methoxy, y is 1, and R73 is hydrogen.
A particularly preferred subgenus of compounds of formula (I) is wherein A is CONR46', wherein R46' is hydrogen; Ar is (i) or (ii), wherein the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (g); R2" is hydrogen, cyanomethyl, or cyanoethyl attached to the 3 -position; wherein A is attached to group (g) meta to R71 and para to R72, R71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4- yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclopent-3-enyl, R71" is hydrogen or 4-cyano, R72 is methoxy, y is 1, and R73 is hydrogen.
The term "acyloxy" is used herein at all occurrences to mean a moiety -O-C(O)-R, wherein R is hydrogen or Cχ_6alkyl as defined below.
The term " Cχ_4alkanoyl " is used herein at all occurrences to mean a -C(O)Cι_ 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 "Cj.galkoxyCx.galkoxy" is used herein at all occurrences to mean an alkoxy group as defined above, substituted with an alkoxy group as defined above.
The term "Cχ_4alkoxyalkyl" is used herein at all occurrences to mean a Cχ_ 4alkoxy group as defined above bonded to an alkyl group as defined below, including, but not limited to, -CH2-CH2-O-CH -CH2-CH3 and the like.
The term "Cx.galkyl" is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
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 limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1- propylene, 2-propylene, and the like.
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 Cχ_6alkyl. 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 "hydroxyCχ_6alkoxy" 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 "hydroxyCi.galkyl" and "hydroxy alkyl" are used herein interchangeably to mean an hydroxyl group bonded to a Cχ_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 Cχ_galkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine, pyrrolidine, piperidine, morpholine, imidazolidine, pyrazolidine, hexahydroazepine, tropane, isoquinuclidine, granatane, and the like. 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 Cχ_ ό^ky1 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 O 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 Cχ_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-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(ethoxyacetyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'- (hydroxyacetyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (methoxyacetyl)- 1 , 1 '-biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(2-methoxy-2- oxoethoxy)- 1 , 1 -biphenyl-4-carboxamide;
N- [3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl]- 1,1 - biphenyl-4-carboxamide; 3'-(2-Cyanoethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 -biphenyl-4-carboxamide;
3 -(2-Cyanomethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- l,r-biρhenyl-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3 - (cy anomethyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- 1 , 1 -biphenyl-4-carboxamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(cy anomethyl)- 1 , 1 -biphenyl-4-carboxamide;
3'-(2-Cyanoethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
3 -(2-Cyanomethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- l, -biphenyl-4-carboxamide; N-[3-[l-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-methoxyphenyl]-l , 1 '- biphenyl-4-carboxamide;
3 '-(2-Carboxyethyl)-N-[3-[ 1 -( 1 -methylethyl)-4-ρiρeridinyl]-4-methoxyρhenyl]- 1 , 1 -biphenyl-4-carboxamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(carboxyethyl)- 1 , 1 '-biphenyl-4-carboxamide;
3 -Chloro-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - ethoxy carbonyl- l,r-biphenyl-4-carboxamide;
N-[3-[4-Cyano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - sulfamoyl- 1 , 1 -biphenyl-4-carboxamide;
3 -(2-Cyanoethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide; N- [3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl] -3 -ureido-
1 , 1 -biphenyl-4-carboxamide;
3 '-(Cyanomethyl)-N-[3-[4-cy ano- 1 -( 1 -methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l, -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'- isopropoxy- 1 , 1 '-biphenyl-4-carboxamide;
3 -Cy ano-N- [3 - [4-cyano- 1 -( 1 -methylethy l)-4-piperidiny 1] -4-methoxyphenyl] - 1 , 1 '-biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5'- dimethyl- 1 , 1 '-biphenyl-4-carboxamide; 3 -Acetamido-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l, -biphenyl-4-carboxamide;
3 -Acetyl-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
3 -(2-Carboxyethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piρeridinyl]-4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(lH- tetrazol-5-yl)- 1 , 1 -biphenyl-4-carboxamide;
N- [3-[4-Cyano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 '-(5- methyl- 1 ,2,4-oxadiazol-3-yl)- 1 , 1 -biphenyl-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 -
(methanesulfonamido)- 1 , 1 -biphenyl-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - dichloro- 1 , 1 -biρhenyl-4-carboxamide ;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - bis(methoxycarbonyl)- 1 , 1 -bipheny 1-4-carboxamide; and 3 -Carboxamido-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide.
Among the more preferred compounds of the invention is the following compound: N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(ethoxyacetyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (hydroxy acetyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'- (methoxy acetyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(2-ethoxy-2- oxoethoxy)- 1 , 1 -biphenyl-4-carboxamide;
N- [3 -[4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl] -1,1 - biphenyl-4-carboxamide; 3 '-(2-Cy anoethyl)-N-[4-methoxy-3- [2-(2,2,6,6-tetramethyl- 1 - piperidinyl)ethoxy]phenyl]- 1 , 1 -biphenyl-4-carboxamide;
3'-(2-Cyanomethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- 1,1 -bipheny 1-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3 - (cy anomethyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- 1 , 1 -biρhenyl-4-carboxamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(cy anomethyl)- 1 , 1 -bipheny 1-4-carboxamide ;
3'-(2-Cyanoethyl)-N-[3-[l-(l-methylethyl)-4-ρiρeridinyl]-4-methoxyphenyl]- 1 , 1 '-bipheny 1-4-carboxamide;
3 -(2-Cyanomethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1,1 -biphenyl-4-carboxamide; N-[3-[l-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-methoxyphenyl]-l, - biphenyl-4-carboχamide;
3'-(2-Carboxyethyl)-N-[3-[l-(l-methylethyl)-4-ρiρeridinyl]-4-methoxyρhenyl]- 1 , 1 '-biphenyl-4-carboxamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(carboxyethyl)- 1 , 1 -bipheny 1-4-carboxamide;
3'-Chloro-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl] — 3'- ethoxycarbonyl- 1 , l'-bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'- sulf amoyl- 1 , r-biphenyl-4-carboxamide;
3'-(2-Cyanoethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl] -1,1 '-bipheny 1-4-carboxamide; N- [3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl] -3 '-ureido-
1 , 1 '-biphenyl-4-carboxamide ;
3'-(Cy anomethyl)-N- [3 - [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N-[3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'- isopropoxy- 1 , 1 '-biphenyl-4-carboxamide;
3'-Cyano-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N- [3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl] -3 ' ,5 '- dimethyl- 1 , 1 '-biphenyl-4-carboxamide; 3'-Acetamido-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
3'-Acetyl-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
3'-(2-Carboxyethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 '-bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(lH- tetrazol-5-yl)- 1 , 1 '-bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)- 1 , 1 '-bipheny 1-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-
(methanesulfonamido)- 1 , 1 '-biphenyl-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - dichloro- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyρhenyl]-3',5 - bis(methoxycarbonyl)- 1 , 1 -biphenyl-4-carboxamide; and 3 -Carboxamido-N- [3- [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4- methoxyphenyl]-l , 1 -biphenyl-4-carboxamide.
Among the most preferred compounds of the invention is the following compound: 3 -(2-Cyanomethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N- [3 - [ 1 -(tetrahy dro-2H-pyran-4-yl)-4-piperidinyl]-4-methoxyphenyl] -1,1 - biphenyl-4-carboxamide ;
3 '-(2-Cyanoethyl)-N-[3-[ 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1,1 -bipheny 1-4-carboxamide;
3 -(2-Cyanomethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
3 -Chloro-N- [3 - [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 '-bipheny 1-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl] — 3'- ethoxycarbonyl- 1 , 1 '-biphenyl-4-carboxamide;
3'-(2-Cyanoethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxy phenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-ureido- 1,1 '-bipheny 1-4-carboxamide;
3'-(Cyanomethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N- [3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl]-3 '- isopropoxy- 1 , 1 '-bipheny 1-4-carboxamide; 3'-Cyano-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-
1 , 1 '-bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5'- dimethyl- 1 , 1 '-bipheny 1-4-carboxamide;
3 ' - Acetamido-N- [3 - [4-cyano- 1 -( 1 -methy lethy 1) -4-piperidiny 1] -4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide; 3'-Acetyl-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-ρiperidinyl]-4-methoxyphenyl]-3'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)- 1 , 1 -biphenyl-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 -
(methanesulfonamido)- 1 , 1 -biphenyl-4-carboxamide; and
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - bis(methoxycarbonyl)- 1 , 1 -biphenyl-4-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 HTV 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) wherein A is NR46' are synthesized from an appropriately substituted benzoic acid, for example 1-1, and an appropriately substituted aniline 1-2 by treatment with a suitable coupling reagent, for example benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and a suitable base, for example diisopropylethylamine, in a suitable solvent, for example acetonitrile, to afford the title compound 1-3. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - VI (published by Wiley- Interscience). Alternatively, compounds of formula (I) may be obtained as shown in Scheme 2 by treatment of a suitably substituted aniline 1-2 with a suitably substituted boronobenzoic acid, for example 2-1, with a suitable coupling reagent, for example 1- (dimethylaminopropyl)-3-ethylcarbodimide hydrochloride and 1- hydroxy-7- azabenzotriazole, in a suitable solvent, for example acetonitrile, to give 2-2. Treatment of 2-2 with a suitably substituted aryl bromide, aryl iodide or aryl triflate, in the presence of a suitable catalyst, for example [l,l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II), and a suitable base, for example 2M sodium carbonate, in a suitable solvent, for example dimethylformamide, at a suitable temperature, for example 80°C, for a suitable time, for example overnight, affords compounds of formula (I) 1-3. Scheme 1
Figure imgf000038_0001
1-1 1-2 1-3
Scheme 2
Figure imgf000039_0001
2-1 1 -2
Figure imgf000039_0002
2-2
Specifically, compounds of formula (I) wherein Ar is represented by group (i) or (ii), A is CONH and E is represented by group (a), were prepared according to the methods of international application publication number
WO 95/26328, published 5 October 1995 and international application publication number WO 95/15954, published 15 June 1995.
Compounds of formula (I) wherein Ar is represented by group (ii), A is CONH and E is represented by group (f), were prepared according to the methods of international application publication number WO 95/17401, published 29 June 1995. Compounds of formula (I) wherein Ar is represented by group (i), A is CONH and E is represented by group (g), were prepared according the methods of international application publication number WO 96/31508 published 10 October 1996.
Anilines used in the preparation of compounds of formula (I) wherein E is represented by group (g), R72 is, for example, Cχ_galkoxy, R71 is piperidinyl, and R71" is attached to the piperidinyl ring at the 4-position and is, for example, COR5", CONR6"R7", CO2R8", cyano, SO2R10", or SO2 NR6"R7" can be prepared following the general procedures of Cammack and Reeves, J. Heterocyclic Chem., 1986, 23, 73-5; Iorio, et. al., Farmaco, Ed. Sci., 1977, 32, 212-19; Buchi, et. al., Helv. Chim. Acta, 1952, 35, 1527-1536; and DE 735866, and the general procedure shown in Scheme 3. Alternatively, 3-5 may be obtained from 3-4 by reductive amination using an appropriately substituted aldehyde or ketone, an appropriate reducing agent, for example sodium cyanoborohydride, in an appropriate solvent, for example methanol containing acetic acid. Anilines wherein R71" is NR3"R4" or SR9" can be prepared following the general procedures of Chen, et. al., Bioorg. Med. Chem. Lett., 1997, 7, 555-560, Ong, et. al., J. Med. Chem., 1981, 24, 74-79, Kornblum et al., Tetrahedron, 1989, 45, 1311- 1322, and Kornblum et al., J. Org. Chem., 1988, 53, 1475-1481, and as shown in Scheme 4 using 4-1 (WO 98/27081). Anilines wherein R71" is CRlaR2"NR3"R4" or CRlaR2"θR " can be prepared following the general procedures of Ong, et. al., J. Med. Chem., 1983, 26, 981-986 and Iorio, et. al., Farmaco, Ed. Sci., 1977, 32, 212-19; by reduction of 3-5 or 3-6 wherein R71" is COR5", CONR6"R7", CO2R8", or cyano, with a suitable reducing agent, for example lithium aluminum hydride, in a suitable solvent, for example ether, or, wherein R71" is cyano, by catalytic hydrogenation.
Scheme 3
Figure imgf000041_0001
3-4 3-5
Figure imgf000041_0002
3-6
(a) CH3N(CH2CH2C1)2, NaH, DMF, 50-90°C; (b) HNO3, Ac2O; (c) C1C02CHC1CH3, DLEA, 1,2-dichloroethane; MeOH, •; (d) iPrl, K2CO3, acetone; 70°C, 24 h; (e) H2, Pd/C, ethanol.
Scheme 4
Figure imgf000042_0001
4-1 4-2
(a) NaCN, HOAc, H2SO4; (b) HSR9", H2SO4, H2O.
Compounds of formula (I) wherein Ar is represented by group (i), A is CONH and E is represented by group (c), were prepared according the methods of international application publication number WO 95/30675, published 16 November 1995.
Compounds of formula (I) wherein Ar is represented by group (i), A is CONH and E is represented by group (b), were prepared according the methods of international application publication number WO 96/11934, published 25 April 1996. Compounds of formula (I) wherein Ar is represented by group (i) or (ii) and A is represented by CONR46' and E is represented by group (a), where R ' and R^ are represented by group D, where D is (CR22R23)e, where e is 2, 3 or 4 and R22 and R23 are independently hydrogen or Cχ_6alkyl or D is (CR22R23)f-G where f is 0, 1, 2 or 3 and G is oxygen, sulfur or CR22=CR23, were prepared according the methods of international application publication number WO 96/06079, published 29 February 1996 and international application publication number WO 95/17398, published 29 June 1995.
Compounds of formula (I) wherein Ar is represented by group (i) or (ii), and A is represented by CONR46' and E is represented by group (h), were prepared according the methods of international application publication number WO 97/07120, published 27 February 1997.
Compounds of formula (I) wherein Ar is represented by group (i) and A is represented by CONR46' and E is represented by group (b), where R46' and R33 are represented by the group K, where K is (CR34R35)-; where i is 2, 3, or 4 and R34 and R3 are independently hydrogen or Ci.galkyl or K is (CR3 R35 .]y[ where j is 0, 1, 2, or 3 and L is oxygen, sulfur or CR 4=CR 5, were prepared according the methods of international application publication number WO 96/19477, published 27 June 1996. Compounds of formula (I) wherein Ar is represented by group (i) and A is represented by CONR46' and E is represented by group (i), were prepared according the methods of international application publication number WO 97/19070, published 29 May 1997. Specifically, compounds of formula (I) wherein Ar is represented by group (i),
(ii) or (iii), A is CONR46', NHCO or CH2NH, and E is represented by group (a), were 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, international application publication number WO 96/06079, published 29 February 1996, GB 2276161 published 21 September 1994, and GB 2276165 published 21 September 1994.
Compounds of formula (I) wherein Ar is (i) or (ii), and A is CONR46' or NHCO, and E is represented by group (b), were prepared according to the methods of international application publication number WO 96/11934, published 25 April 1996, and WO 96/19477, published 27 June 1996. Other applications cover 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 97/35861, published 2 October 1997; WO 97/35862, published 2 October 1997. Compounds of formula (I) wherein Ar is (i), (ii) or (iii), A is CONR46', NHCO or CH NH, and E is (c), were prepared according the methods of international application publication number WO 95/30675, published 16 November 1995, and GB 2276165, published 21 September 1994.
Compounds of formula (I) wherein Ar is (i) or (ii), A is CONR46', and E is a group (g), were prepared according the methods of international application publication number WO 96/31508, published 10 October 1996.
Compounds of formula (I) when Ar is (i) or (ii), A is CONR46', 3nd E is group (h), were prepared according the methods of international application publication number WO 95/32967, published 7 December 1995 and WO 97/07120, published 27 February 1997.
Compounds of formula (I) Ar is (i) or (ii), and A is CONR46' or CH2NH, and E is group (i), were prepared according the methods of international application publication number WO 97/19070, published 29 May 1997.
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 3 '-(2-Ethoxy-2-oxoethoxy)- 1 , 1 -biphenyl-4-carboxylic acid a) tributyl(ethoxymethyl)stannane
Following the general procedure of Kaufman, Synlett 1997, (12), 1377-1378, a solution of butyllithium in hexane (2.5M, 3 mL, 7.5 mmol) was added dropwise to a stirred solution of diisopropylamine (1.15 mL, 8.2 mL) in anhydrous tetrahydrofuran (15 mL) at 0°C, stirred for 5 min, and treated with tributyltin hydride (2 mL, 7.4 mmol) added over 3 min. The resulting yellow-green solution was stirred for 15 min, cooled to -78°C, and treated with chloromethyl ethyl ether (o.5 mL, 7.5 mmol). The mixture was stirred for 10 min, warmed to RT, stirred for 2 h, quenched with water, and extracted with ether. The combined organic phase was washed with brine and with water, dried (MgSO4), and concentrated in vacuo. The residue was purified by chromatography (silica gel, hexane followed by dichloromethane) to give the title compound (1.28 g). b) 2-ethoxy- 1 -(3-iodophenyl)ethanone Following the general procedure of Labadie, et. al., J. Org. Chem. 1983, 48,
4634-42, a solution of 3-iodobenzoyl chloride (0.53 g, 2 mmol) and benzylchlorobis(triphenylphosphine)palladium (15 mg) in chloroform (1 mL) was treated with a solution of the compound of Preparation 1(a) (0.7 g, 2 mmol) in chloroform (4 mL). The resulting yellow solution was placed in a sealed vial, heated to 65°C, and shaken for 16 h. The mixture was cooled, poured into ether (30 mL), and the resulting mixture was extracted with water and then with aqueous potassium fluoride with vigorous shaking. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (silica gel, 4:1 hexane/ethyl acetate) to give the title compound (50 mg).
c) 3'-(2-ethoxy-2-oxoethoxy)-l,l -biphenyl-4-carboxylic acid A mixture of the compound of Preparation 1(b) (70 mg, 0.24 mmol), 4- boronobenzoic acid (40 mg, 0.24mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.012 mmol), and sodium carbonate (68 mg, 0.64 mmol) dissolved in water (3 mL) and dimethylformamide (3 mL) was heated to reflux for 16 h. The mixture was concentrated in vacuo and the residue was partitioned between ether and 5% sodium carbonate. The aqueous phase was acidified with 3M hydrochloric acid and the resulting precipitate was isolated by filtration, washed with water, and dried to give the title compound.
Preparation 2 Preparation of 3 '-(2-Methoxy-2-oxoethoxy)- 1.1 '-biphenyl-4-carboxylic acid Following the procedure of Preparation 1(a)- 1(c), except substituting chloromethyl methyl ether for chloromethyl ethyl ether, gave the title compound.
Preparation 3 Preparation of 3'-(2-Ethoxy-2-oxoethoxy)-l, -biphenyl-4-carboxylic acid
A mixture of methyl (3-bromophenoxy)acetate (1.29 g, 5 mmol), prepared from 3-bromophenol, methyl bromoacetate, and potassium carbonate in acetone, 4- boronobenzoic acid (1.25 g, 7.5 mmol), triethylamine (2.1 mL, 15 mmol), palladium acetate (33.5 mg), and tri-o-tolylphosphine (95 mg) in dry dimethylformamide (20 mL) was heated to 100°C for 3.5 h, cooled, and concentrated in vacuo. The residue was taken up in water, extracted with ethyl acetate and then with dichloromethane. The combined dichloromethane extract was concentrated in vacuo to give the title compound.
Preparation 4 Preparation of 3- [4-Cy ano- 1 -( 1 -methylethyl)-4-piρeridinyl)-4-methoxy-benzenamine a) 4-[2-(methoxy)phenyl]-l-methyl-4-piperidinecarbonitrile Following the general procedure of Ong, et. al., J. Heterocycl. Chem. 1981, 18,
815-20 and of Patane, et. al., Bioorg. Med. Chem. Lett. 2000, 10, 1621-1624, a solution of (2-methoxyphenyl)acetonitrile (7.4 g, 50 mmol) in anhydrous dimethylformamide (120 mL) was added over 5 min to sodium hydride (4.8 g, 200 mmol) with good stirring. The mixture was stirred for 1 h and treated with a solution of N-methylbis(2- chloroethyl)amine (7.19 g, 50 mmol) in dimethylformamide (100 mL) at a rate such that the internal temperature remained below 50°C. The resulting mixture was gradually heated to 90°C and stirred at 90°C for 16 h. The mixture was carefully quenched with ice water and extracted with ether three times. The combined organic phase was extracted with 2N hydrochloric acid and the acidic aqueous extract was carefully basified with 10% aqueous sodium hydroxide. The resulting mixture was extracted with ether, dried (MgSO4), and concentrated in vacuo to give the title compound (9.65 g, 84%). MS(ES) m/e 231.2 [M+H]+. b) 4-[2-methoxy-5-(nitro)phenyl]-l-methyl-4-piperidinecarbonitrile 70% Nitric acid (4.9 mL, 76 mmol) was added dropwise to a solution of the compound of Preparation 4(a) (8.7 g, 38 mmol) stirred in acetic anhydride (50 mL) at 0°C and the mixture was stirred for 1 h. The reaction was carefully quenched with ice water, and the resulting mixture was basified with 10% aqueous sodium hydroxide, and extracted with dichloromethane three times. The combined organic phase was dried (MgSO4) and concentrated in vacuo to give a mixture of the title compound, accompanied by a small amount of 4-[2-methoxy-3-(nitro)phenyl]-l-methyl-4- piperidinecarbonitrile, as a yellow oil that solidified on standing (9.2 g). c) 4-[2-methoxy-5-(nitro)phenyl]-4-piperidinecarbonitrile A solution of the compound of Preparation 4(b) (9.2 g, 33 mmol) and diisopropylethylamine (6.5 g, 50 mmol) in 1,2-dichloroethane (250 mL) was treated with 1-chloroethyl chloroformate (6.5 g, 43 mmol) at RT, stirred for 1 h, heated to reflux for 20 min, cooled, and concentrated in vacuo. The residue was dissolved in methanol, heated to reflux for 2 h, and the mixture was concentrated in vacuo. The residue was partitioned between 5% sodium bicarbonate and dichoromethane, the aqueous phase was extracted with dichloromethane, and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as a tan solid (7.88 g). d) 4-[2-methoxy-5-(nitro)phenylj- 1 -( 1 -methylethyl)-4-piperidinecarbonitrile The compound of Preparation 4(c) (7.9 g, 30 mmol) was dissolved in acetonitrile (150 mL) and acetone (50 mL) and treated with potassium carbonate (16.7 g, 120 mmol) followed by isopropyl iodide (15.3 g, 90 mmol). The resulting mixture was heated to 70°C for 24 h, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water three times, dried (MgSO4), concentrated in vacuo, and the resulting tan oil was purified by flash chromatography (silica gel, 3:1 hexane/ethyl acetate followed by 1:1 hexane/ethyl acetate) to give the title compound as a yellow oil that solidified on standing (2.35 g). MS(ES) m/e 304.2 [M+H]+. e) 3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxybenzenamine A mixture of the compound of Preparation 4(d) (2.1 g, 7 mmol) in and 10% palladium-on-carbon (1 g) in ethanol (70 mL) was shaken in a hydrogen atmosphere (50 psi) for 2 h. The resulting mixture was filtered through Celite®, and the filtrate was concentrated in vacuo to give the title compound as a tan oil (2 g). MS(ES) m/e 274.2 [M+H]+.
Preparation 5 Preparation of 4-Methoxy-3 -Tl- l -methylethyl)-4-piperidinyl)benzenamine a) 4-(2-methoxyphenyl)- 1 -(trifluoroacetyl)piperidine Trifluoroacetic anhydride (8.1 g, 39 mmol) was added portionwise over 10 min 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 5(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 min, combined with an identical concurrently run reaction, and poured into water (600 mL). The pH of the resultant mixture was adjusted to >9 by the addition of aqueous sodium carbonate followed by 10% sodium hydroxide. 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 5(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 (MgSO4), 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 -methylethyl)piρeridine 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 5(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 5(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 6 Preparation of N-[4-methoxy-3-[l-(l-methylethyl)-4-piperidinyl)]phenyl]-4-(4 ,4.5,5- tetramethyl- 1.3 ,2-dioxaborolan-2-yl)benzamide A mixture of the compound of Preparation 5(e) (2.48 g, 10 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoic acid (2.48 g, 10 mmol), and l-hydroxy-7-azabenzotriazole (1.39 g, 10 mmol) dissolved in acetonitrile (75 mL) was treated with l-(dimethylaminopropyl)-3- ethylcarbodimide hydrochloride (2.31 g, 12 mmol) and stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and aqueous 5% sodium carbonate. The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound. MS(ES) m/e 478.4 [M+H]+.
Preparation 7-9 Following the procedure of Preparation 6, except substituting 3-[2-[bis(l- methylethyl)amino]ethoxy]-4-methoxyaniline (WO 9515954), 4-methoxy-3-[2- (2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]benzenamine,
(WO 9901127), or 3-[3-[j is(l-methylethyl)amino]propoxy]-4-methoxy-]benzenamine (WO 9901127) for the compound of Preparation 5(e), gave the following compounds: N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide: MS(ES) m e 496.4 [M+H]+;
N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l-piperidinyl)ethoxy]phenyl]-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide: MS(ES) m/e 536.4 [M+H]+; and N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide: MS(ES) m/e 510.6 [M+H]+.
Preparation 10 Preparation of N-r3-(4-Piperidinyl)-4-methoxyphenyll- 1 , 1 -biphenyl-4-carboxamide a) 3-[l-(trifluoroacetyl)-4-piperidinyl]-4-methoxyaniline
Following the general procedure of Preparation 5(h), except substituting the compound of Preparation 5(e) for the compound of Preparation 5(g), gave the title compound. b) 3-(4-piperidinyl)-4-methoxyaniline Following the general procedure of Preparation 5(f), except substituting the compound of Preparation 10(a) for the compound of Preparation 5(e), gave the title compound. c) 3-[l-(tert-butoxycarbonyl)-4-piperidinyl]-4-methoxyaniline
The compound of Preparation 10(b) (1.7 g, 8.5 mmol) was treated with di-tert- butyl dicarbonate (1.9 g, 8.6 mmol) in dichloromethane, stirred for 2 h, and concentrated in vacuo to give the title compound which was used without further purification. MS(ES) m/e 307.2 [M+H]+. d) N-[3-[l-(tert-butoxycarbonyl)-4-piperidinyl]-4-methoxyphenyl]-l, - biρhenyl-4-carboxamide The compound of Preparation 10(c) (0.21 g, 0.7 mmol) was added to a mixture of 1,1 -bipheny 1-4-carboxylic acid (0.14 g, 0.7 mmol), benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.31 g, 0.7 mmol) and triethylamine (0.14 g, 1.4 mmol) in dichloromethane (4 mL), and stirred at RT for 16 h. The resulting mixture was diluted with water and extracted with dichloromethane. The organic extracts were combined and dried (MgSO4), concentrated in vacuo, and the residue was purified by chromatography (silica gel, 3:1 hexane/ethyl acetate) to afford the title compound MS(ES) m/e 487.4 [M+H]+. e) N-[3-(4-piperidinyl)-4-methoxyphenyl]-l, -biphenyl-4-carboxamide The compound of Preparation 10(d) (285 mg) dissolved in dichloromethane was treated with trifluoroacetic acid and stirred at RT. The resulting mixture was concentrated in vacuo to give the title compound, which was used without purification.
Preparation 11 Preparation of N- r4-methoxy-3-[4-cyano- 1 -( 1 -methylethyl)-4-piρeridinyl)1phenyl1-4- (4 ,4,5,5-tetramethyl- 1 ,3.2-dioxaborolan-2-yl)benzamide Following the procedure of Preparation 6, except substituting the compound of Preparation 4(e) for the compound of Preparation 5(e), gave the title compound: MS(ES) m e 503.2 [M+H]+.
Example 1 Preparation of N-r3-[2-rBis(l-methylethyl)amino1ethoxy1-4-methoxyphenyll-3'- (ethoxyacetyl)- 1 , 1 -biphenyl-4-carboxamide A solution of the compound of Preparation 1(c) (48 mg, 0.17 mmol), 3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyaniline (WO 9515954) (45 mg, 0.17 mmol), and benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (75 mg, 0.17 mmol) in acetonitrile (5 mL) was treated with triethylamine (40 mg, 0.4 mmol) and the mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A:0.1% trifluoroacetic acid in acetonitrile B.O.I % aqueous trifluoroacetic acid, A: 10 to 90% during 10 min, UV detection at 254 nm) to give the title compound. MS(ES) m/e 533.1 [M+H]+.
Example 2 Preparation of N-[3-[2-rBis(l-methylethyl)aminolethoxy1-4-methoxyphenyl1-3 - (hydroxy acetyl)- 1 , 1 -bipheny 1-4-carboxamide Following the general procedure of
Katritzky, A. R. and Sengupta, S, Tetrahedron Lett. 1987, 28, 1847-50, 2.5M butyllithium in hexane (2 mL, 5 mmol) was added at to a solution of 1- trimethylsilylmethanol (0.5 g, 2.5 mmol) in tetrahydrofuran (25 mL) at -78°C and the mixture was warmed to RT for 5 min after which a stream of dry carbon dioxide was bubbled through the solution for 10 min. The volatile components of the mixture were removed in vacuo, the vessel was purged with argon, and the residue was dissolved in tetrahydrofuran (25 mL). The solution was cooled to -78°C, treated slowly with 1.3M sec-butyllitbium in cyclohexane (4.2 mL, 5.5 mmol), maintained at -25°C for 2 h, cooled to -78°C and treated with a solution of N-[3-[2-[bis(l- methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-ethoxycarbonyl-l,r-biphenyl-4- carboxamide (WO 0040239) (0.38 g, 0.7 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at RT for 30 min, quenched with saturated aqueous ammonium chloride, and extracted with ether. The combined organic phase was dried (MgSO4), taken up in dimethyl sulfoxide, and the mixture was concentrated in vacuo. The upper oily layer was removed and the residue was 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 min, UV detection at 254 nm) to give the title compound. MS(ES) m/e 505.1 [M+H]+.
Example 3 N-[3-[2-rBis(l-methylethyl)amino1ethoxyl-4-methoxyphenyl1-3'-(methoxyacetyl)-l,r- biphenyl-4-carboxamide Following the procedure of Example 1, except substituting the compound of
Preparation 2 for the compound of Preparation 1(c), gave the title compound. MS(ES) m/e 519.1 [M+H]+;
Example 4 Preparation of N-r3-r2-rBis(l-methylethyl)amino1ethoxy1-4-methoxyphenyll-3'-(2- ethoxy-2-oxoethoxy)- 1 , 1 '-biphenyl-4-carboxamide
A solution of the compound of Preparation 3 (240 mg, 0.8 mmol), triethylamine (0.8 mL), and 3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyaniline (WO 9515954) (213 mg, 0.8 mmol) was treated with benzotriazol-1- yloxytris(dimethylamino)phosρhonium hexafluorophosphate (400 mg) and stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0.25% methanol/dichloromethane). Fractions containing the title compound were pooled, concentrated in vacuo, the residue was triturated with ether, and the resulting white solid that was dried to afford the title compound (60 mg). MS(ES) m/e 549.0 [M+H]+. Example 5 Preparation of N-[3-[4-Cyano-l-(l-methylethylV4-piperidinyl1-4-methoxyphenyl1-l, - biphenyl-4-carboxamide
The compound of Preparation 4(e) (41 mg, 0.15 mmol) and [1,1 -bipheny l]-4-carbonyl chloride (32.5 mg, 0.15 mmol) were dissolved in dichloromethane (1.5 mL), diisopropylethylamine (39 mg, 0.30 mmol) was added, and the resulting mixture was stirred at RT of 16 h. The mixture was concentrated in vacuo and the residue was 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 min, UV detection at 254 nm) to give the title compound. MS(ES) m/e 454.2 [M+H]+.
Example 6 Preparation of 3 '-(2-Carboxyethyl)-N- 3- [ 1 -( 1 -methylethyl)-4-piperidinyll -4- methoxyphenyl] -1,1 -biphenyl-4-carboxamide
A mixture of a solution of the compound of Preparation 6 in dimethylformamide (0.188M, 0.8 mL, 0.15 mmol), a solution of 3- bromobenzenepropanoic acid in dimethylformamide (1M, 0.3 mL. 0.3 mmol), a solution of [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) in dimethylformamide (0.0245M, 0.2 mL), and aqueous 2M sodium carbonate (0.3 mL, 0.6 mmol) was heated to 80°C for 16 h, concentrated in vacuo, and the residue was 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 min, UV detection at 254 nm) to give the title compound. MS(ES) m e 501.2 [M+H]+
Examples 7-8 Following the procedure of Example 6, except substituting 3-(3- bromophenyl)propionitrile or 3-bromophenylacetonitrile for 3-(3- bromophenyl)propanoic acid, gave the following compounds:
3'-(2-cyanoethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- l,r-biphenyl-4-carboxamide: MS(ES) m/e 482.3 [M+H]+; and
3 '-(2-cy anomethyl)-N- [3 - [ 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxypheny 1] - l,r-biphenyl-4-carboxamide: MS(ES) m/e 468.3 [M+H]+.
Example 9 Preparation of N-[3-[2-[Bis(l-methylethyl)amino1ethoxy1-4-methoxyρhenyl1-3'- (carboxyethyl)- 1 , 1 '-biphenyl-4-carboxamide
Following the procedure of Example 6, except substituting the compound of Preparation 7 for the compound of Preparation 6, gave the title compound: MS(ES) m/e 519.2 [M+H]+.
Examples 10-11 Following the procedures of Examples 7-8, except substituting the compound of Preparation 7 for the compound of Preparation 6, gave the following compounds: N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- l,r-biphenyl-4-carboxarnide: MS(ES) m/e 500.1[M+H]+; and
N-[3-[2-[bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(cyanomethyl)- l,l'-biphenyl-4-carboxamide: MS(ES) m/e 486.3 [M+H]+.
Examples 12-13
Following the procedures of Examples 7-8, except substituting the compound of Preparation 8 for the compound of Preparation 6, gave the following compounds:
3'-(2-cyanoethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1,1 -bipheny 1-4-carboxamide: MS(ES) m/e 540.4 [M+H]+; and
3'-(2-cyanomethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]-l, -biphenyl-4-carboxamide: MS(ES) m/e 526.4 [M+H]+.
Examples 14-15 Following the procedures of Examples 7-8, except substituting the compound of
Preparation 9 for the compound of Preparation 6, gave the following compounds:
N- [3 - [3 - [bis( 1 -methylethy l)amino]propoxy] -4-methoxypheny 1] -3 '-(cy anoethyl)- l,l'-biphenyl-4-carboxamide: MS(ES) m/e 514.4 [M+H]+; and
N-[3-[3-[bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3 - (cyanomethyl)-l,l'-biρhenyl-4-carboxamide: MS(ES) m e 500.2 [M+H]+.
Example 16 Preparation of N-r3-ri-(tetrahvdro-2H-pyran-4-yl)-4-piperidinyn-4-methoxyphenyl1- 1.1 '-biphenyl-4-carboxamide A solution of the compound of Preparation 10(e) (46 mg, 0.1-2 mmol) and tetrahydro-4H-pyran-4-one (59 mg, 0.6 mmol) in methanol (1 mL) was treated with acetic acid (72 mg, 1.2 mmol), and sodium cyanoborohydride (30 mg, 0.48 mmol). The resulting mixture was heated to reflux for 16 h, cooled, filtered and concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide and purified by HPLC to give the title compound: MS(ES) m/e 471.4 [M+H]+
Example 17 Preparation of 3 -chloro-N- [3 - r4-cy ano- 1 -( 1 -methylethyl)-4-piperidinyll -4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide The compound of Preparation 11
(76 mg, 0.15 mmol) in dimethylformamide (0.8 mL) and 3-chlorobromobenzene (57 mg, 0.3 mmol) in dimethylformamide (0.3 mL) were mixed with [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4 mg, 0.005 mmol) followed by 2M sodium carbonate (0.3 mL, 0.6 mmol). The mixture was heated to 80°C for 16 h, filtered and 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 min, UV detection at 254 nm) to give the title compound: MS(ES) m/e 488.2 [M+H]+.
Example 18 Preparation of 3'-(2-carboxyethyl)-N-[3-r4-cvano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-! , 1 -bipheny 1-4-carboxamide
Following the general procedure of Example 6, except substituting the compound of Preparation 11 for the compound of Preparation 6 gave the title compound: MS(ES) m/e 526.2 [M+H]+.
Examples 19-33
Following the general procedure of Example 18, except substituting ethyl 3-bromobenzoate, 3-bromobenzenesulfonamde, 3-(3-bromophenyl)propionitrile, 3-bromophenylurea, (3-bromophenyl)acetonitrile, l-bromo-3-isopropoxybenzene, 3- bromobenzonitrile, l-bromo-3,5-dimethylbenzene, N-(3-bromophenyl)acetamide, l-(3- bromophenyl)ethanone, 5-(3-bromophenyl)-lH-tetrazole, 3-(3-bromophenyl)-5-methyl- oxa[l,2,4]oxadiazole, N-(3-bromophenyl)methanesulfonamide, l-bromo-3,5- dichlorobenzene, and dimethyl 5-bromo-isophthalate for 3-bromobenzenepropanoic acid, gave the following compounds:
N- [3 -[4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl]-3 - ethoxycarbonyl-l,r-biρhenyl-4-carboxamide: MS(ES) m/e 526.2 [M+H]+; N-[3-[4-cyano-l-(l-methylethyl)-4-ρiperidinyl]-4-methoxyphenyl]-3 - sulfamoyl-l,l'-biphenyl-4-carboxamide: MS(ES) m/e 533.2 [M+H]+;
3'-(2-cyanoethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l, -biphenyl-4-carboxamide: MS(ES) m/e 507.2 [M+H]+; N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-ureido- l,l'-biphenyl-4-carboxamide: MS(ES) m/e 512.4 [M+H]+;
3'-(cyanomethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l,l'-biphenyl-4-carboxamide: MS(ES) m/e 493.2 [M+H]+; N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - isopropoxy-l, -biphenyl-4-carboxamide: MS(ES) m/e 512.4 [M+H]+;
3 '-cy ano-N- [3- [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyρhenyl] - l,l'-biphenyl-4-carboxamide: MS(ES) m/e 479.2 [M+H]+;
N- [3- [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl] -3 ',5 '- dimethyl-l,r-biρhenyl-4-carboxamide: MS(ES) m/e 482.4 [M+H]+; 3 -acetamido-N- [3 -[4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4- methoxyphenylH , 1 '-biphenyl-4-carboxamide: MS(ES) m/e 511.4 [M+H]+;
3'-acetyl-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- l,l'-biphenyl-4-carboxamide: MS(ES) m/e 496.4 [M+H]+;
N-[3-[4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 '-( 1H- tetrazol-5-yl)-l,l'-biphenyl-4-carboxamide: MS(ES) m/e 522.2 [M+H]+;
N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(5- methyl-l,2,4-oxadiazol-3-yl)-l, -biphenyl-4-carboxamide: MS(ES) m/e 536.2 [M+H]+;
N- [3 - [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 '- (methanesulfonamido)-l,l'-biphenyl-4-carboxamide: MS(ES) m/e 547.2 [M+H]+; N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - dichloro-l,l'-biphenyl-4-carboxamide: MS(ES) m/e 522.2 [M+H]+; and
N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - bis(methoxycarbonyl)-l, -biphenyl-4-carboxamide: MS(ES) m/e 570.2 [M+H]+.
Example 34 Preparation of 3 -carboxamido-N- r3- r4-cy ano- 1 -( 1 -methylethyl)-4-piperidinyl] -4- methoxyphenyll- 1 , 1 -biphenyl-4-carboxamide Following the general procedure of
Example 18, except substituting 3-bromobenzenecarboxamide for 3- bromobenzenepropanoic acid, gave the title compound: MS(ES) m/e 497.4 [M+H]+. 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 NaCI, 4.6 mM KC1, 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 prewarmed 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 Ca2+ was determined for each concentration of antagonist and the IC50 defined as the concentration of test compound that inhibits 50% of the maximal 33 nM RANTES response, obtained from the concentration-response curves (5-7 concentrations of antagonists).
The compounds of this invention show CCR5 receptor modulator activity having IC50 values in the range of 0.0001 to 100 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 compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Ar— A-E Formula (I) wherein Ar is a group selected from (i), (ii) or (iii);
Figure imgf000058_0001
wherein: the basic nitrogen in moiety E may be optionally quaternized with C^galkyl or is optionally present as the N-oxide;
R1' and R2' are each independently one or more of hydrogen, C .galkyl, C2_6al enyl, C2- 6alkynyl, C3_7cycloalkyl, C3.6cycloalkenyl, aryl, (CH2)aNR7'R8', (CH2)a'NR7'COR9', (CH2)a'NR7'CO2R10', (CH2)a'NR7'S02R1 1', (CH2)a'CONR12,Rl3', hydroxyCi.galkyl, Cι_ 4alkoxyalkyl (optionally substituted by a C _4alkoxy or hydroxy group), (CH2)a'Cθ2Cχ_galk l, (CH2)b'OC(0)R14', CR15 =NOR16', CNR^NORiS', COR17', CONR12'R13', C0NR12'(CH2)c C1.4alkyl, CONR12'(CH2)a'CO2R18', CONHNR19'R20', CONR12'sO2R21', C02R22', cyano, trifluoromethyl, NR7'R8', NR7'COR9', NR?3'cO(CH2)a'NR23'R24'; NR23'CONR23'R24'; NR7'CO2R1()', NR7'SO2Rn', N=CNR23'NR23'R24', nitro, hydroxy, Cχ_ 6alkoxy, hydroxy Ci^alkoxy, Cι_6alkoxyC1_6alkoxy, OC(0)NR 5'R26'5 SR27', SOR2^', SO2R28' S02NR25'R 65 or halogen;
R3' and R4' are each independently one or more of hydrogen, Ci .galkyl, C3. 7cycloalkyl, C3_6cycloalkenyl, hydroxyCι_galkyl, Cχ_6alkylOCχ_6alkyl, CONR2 'R30'5 CO2R31', cyano, aryl, trifluoromethyl, NR29'R30'5 nitro, hydroxy, Cχ_ βalkoxy, acyloxy, or halogen;
R2'is also R2" wherein R2" is hydrogen, (CH2)a !CN, (CH2)aCθ2H, CR15 =CR16'CO2R18', COCR15'R16'OR18', Oaryl, Oaralkyl, 0(CH2)a€O2R18', and Saryl;
R5' is one or more of hydrogen, Cx.galkyl, Cx.galkoxy or halogen; R6' is one or more of hydrogen, Cχ_6alkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyCχ.6alkyl, hydroxyC3_6alkenyl, hydroxyC3_6alkynyl, (CH2)d R32', (CH2)dCOR 3', (CH2)d=CR34'=NOR35', CONR36'R37', CO2R38', hydroxy, O(CH2)e'R39', NR36'R37', SR40', SO2NR41'R42' or halogen; or, R5' and R^' form a fused benzo ring optionally substituted with Cχ_6 alkyl, Cx.galkoxy or halogen;
R7 and R8' are independently hydrogen or Ci.galkyl, or together with the nitrogen to which they are attached, R7' and R8' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R9'is hydrogen, Cχ_galkyl or Cχ_4alkoxy alkyl;
RiO' is Cx.galkyl;
R1 !' is Cχ_6alkyl or phenyl;
R12' and Rl3 are independently hydrogen or Cχ_6alkyl, or together with the nitrogen to which they are attached, R12' and R13' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R^'is Cχ_4alkyl, optionally substituted by Cχ_galkoxy;
R15' and R1^' are independently hydrogen or Cχ.6alkyl; R17' is hydrogen or Ci^galkyl;
R1 ' is hydrogen or Cχ_galkyl;
R19' and R2^' are independently hydrogen or Cx.galkyl;
R21' is hydrogen or Cχ_6alkyl;
R22' is hydrogen or Ci.galkyl optionally substituted with one or two substituents selected from Cx.galkyl, Cj.galkoxy, hydroxy, or NR R ;
R2 ' and R 4' are independently hydrogen or Cj.galkyl;
R25' and R ^' are independently hydrogen or Cj.galkyl, or together with the nitrogen to which they are attached, R25' and R2^' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R27' is hydrogen or C^.^alkyl;
R28'is C1_6alkyl;
R29'5 R30' and R31' 3re independently hydrogen or Cj.galkyl;
R 2' is Cj.galkyl, hydroxyCχ_6alkyl, or Cχ_4alkanoyl; R33' is hydrogen or C^.^alkyl;
R34' is hydrogen or Cχ_galkyl; R35' is hydrogen or Cχ_6alkyl;
R36' and R37' are independently hydrogen or C^.^alkyl or together with the nitrogen to which they are attached, R3^' and R37' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR 3', wherein R43' is Ci.galkyl, COR44' or CO2R45', wherein R44' and R45' are independently hydrogen or Ci.galkyl;
R38' is hydrogen or Ci.galkyl;
R39'is Cj^alkoxy, CO2H, CO2Cι_6alkyl or CONR36'R37'; R40'is Cι_6al yl;
R41' and R42' are independently hydrogen or Cχ_6alkyl;
P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; a' is 1, 2, 3 or 4; b'is O, 1, 2 or 3; c'is 1, 2 or 3; d'is O, 1, 2, 3, 4, 5, or 6; and e'is 1, 2, 3, 4, 5 or 6; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR4^', NHCO, - NHCH2, or CH2NH, wherein R46' is hydrogen or C^alkyl, E is a group (a):
Figure imgf000060_0001
wherein: B is oxygen, i C, S(O)c, CR7=CR8, or CR7R8, or B is NR9;
R1 and R2 are independently hydrogen or Cx.galkyl; alternatively B(CR1R2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, Cχ_galkyl, C3_7cycloalkyl, aralkyl, C5. 7cycloalkenyl, a C5_7heterocyclic ring, 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
Figure imgf000060_0002
hydroxy, OCOR^, NHCOCF3, NHSO2R13, NHCO2R14, or NHCOC0-6alkyl wherein the alkyl of NHCOCrj-ό^kyl is optionally substituted by OH;
R5 is hydrogen, Cι_6alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, Cj^alkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)dR19, SO2NR2θR21 or halogen; is hydrogen, Cχ_6alkyl, aryl, trifluoromethyl, hydroxy, C galkoxy or halogen, or R6 taken together with R ^' forms a group D where D is (CR R23)6 Gr D is (CR2 R23)f_G where G is oxygen, sulfur or CR22=CR23, CR2 =N, =CR22O, =CR 2S, or =CR22-NR23; R7, R8, R10, R11, R12, R15, Rl6, R17, R20? R21, R225 ^d R23 are independently hydrogen or Cχ_galkyl;
R9 is hydrogen, Cχ_6alkyl, or phenylC _6alkyl;
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; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR4^', NHCO, or CH2NH, wherein R46' is hydrogen or Cχ.galkyl, alternatively, E is a group (b):
Figure imgf000061_0001
R24, R255 R26; R275 R28? R29? R31? and R32 are independently hydrogen or
Cι_6alkyl; R3^ is hydrogen, Cj.galkyl, or C3_7cycloalkyl, C5_7cycloalkenyl, or a Cζ_
7heterocyclic ring;
R33 is hydrogen, Ci.galkyl, trifluoromethyl, hydroxy or halogen, or R3 and
R 0' together form a group -K- where K is (CR34R35)i or K is (CR 4R35)j -M and M is oxygen, sulfur, CR 4=CR35, CR34=N, or N=N; J is oxygen, CR36R37, or NR38, or J is a group S(O)k;
R34, R35, R ^, R 7; and R 8 are independently hydrogen or Cχ_6alkyl; 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; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO,
NHCH2, or CH2NH, wherein R46' is hydrogen or C^alkyl, alternatively, E is a group (c):
Figure imgf000062_0001
wherein:
Q is oxygen, S(O)n, CR44=CR45, CR44R45, or Q is NR46; R39 and R4^ are independently hydrogen or Cχ_6alkyl; R41 is a group of formula (d):
Figure imgf000062_0002
or R41 is a group of formula (e):
Figure imgf000062_0003
R42 is hydrogen, C^gal yl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO2R51, hydroxy, Ci^alkoxy, benzyloxy, pCH2CO2Cχ_6alkyl, OCF3, S(O)sR52, SO2NR53R54, or halogen;
R43 is hydrogen or R4 together with R30' forms a group R where R is CR55=CR56, CR55=CR56CR55R56, or (CR55R56)t;
R44, R45, R46, R48, R49, R50, R535 R54? R55; and R56 are independently hydrogen or C .galkyl;
R47 is hydrogen, Cχ_6alkyl, or C3_7 cycloalkyl, 03.7 cycloalkyl, C5_ 7cycloalkenyl, or a C5_7heterocyclic ring; R51 and R52 are independently C \ _6 lkyl ; l is O, 1, 2, or 3; m is 1 or 2; n is O, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; r is 0,1, 2, or 3; s is O, 1, or 2; t is 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONH, NHCO, or CH2NH, alternatively, E is a group (f):
Figure imgf000063_0001
R57 and R58 are independently hydrogen or Cχ_6alkyl;
R59 and RP® are independently hydrogen, Cx.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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 Cx.galkyl, aryl, CONR61R62J NR^RO2, hydroxy, OCOR63, NHCOCF3, NHSO2R64, NHCO2R65, or NHCOC0-6alkyl wherein the alkyl of NHCOCo_6alkyl is optionally substituted by OH; T is -(CR66R67)V- or -O(CR66R67)w-;
W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70;
R61; R62? R635 R665 R67 R685 R69? and R70 are independently hydrogen or Cι_6alkyl;
R^ and R^5 are independently Cχ_6alkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR4^', NHCO, or CH2NH, wherein R46' is hydrogen or Ci.galkyl, alternatively, E is a group (g):
Figure imgf000064_0001
R71 is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a basic nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R71 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 .galkyl and optionally substituted on nitrogen with hydrogen, C^galkyl or C3_7cycloalkyl, C3_7cycloalkyl, C5_7cycloalkenyl, or a C5.. 7heterocyclic ring;
R7 ! is substituted with one or more of R7 ^ " , provided that R71 " is not present on the basic nitrogen of R71, wherein R71" is hydrogen, CRlaR2"NR3"R4", CRlaR2"θR3", COR5", CONR6"R7", CO2R8", cyano, NR3"R4", nitro, hydroxy, Ci^alkoxy, SR9", SOR10", SO2R10", S0 NR6"R7" or SO3H, wherein:
R a and R2" are independently hydrogen or Cχ_galkyl;
R3 ' and R4" are independently hydrogen or Cj.galkyl, or taken 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 one oxygen or one sulfur atom; alternatively R4" is CORll ", CONR12"Rl3", C02R14", S02R15", S02NR12"R13", or S02OR16", wherein RU" is hydrogen, Cχ_galkyl, aryl, or trifluoromethyl; R12" and R 3" are independently hydrogen or Cj_ galkyl, or taken 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 one oxygen or one sulfur atom; R14" is hydrogen or Cj^alkyl; R 5" is hydrogen, C|.galkyl, aryl, or trifluoromethyl; and R1^" is hydrogen or aryl;
R5" is Ci.galkyl, aryl, or trifluoromethyl;
R6" and R7" are independently hydrogen or Cj.galkyl, or taken 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 one oxygen or one sulfur atom;
R8" is hydrogen or Ci.galkyl;
R9 ' is hydrogen,
Figure imgf000064_0002
aryl, or trifluoromethyl; and
R1^ is Ci.galkyl, aryl, or trifluoromethyl;
R72 is hydrogen, C^alkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, Ci^alkoxy, benzyloxy, OCH2CO2Ci_6al yl, OCF3, S(0)zR78, S02NR79R °, or halogen; R73 is hydrogen, Cχ_6alkyl, hydroxy, Cχ_6aikoxy 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 CR81=CR82;
R74, R75, R76, R79, R 0, R81, and R82 are independently hydrogen or Cχ_ ffϋk ,
R77 and R78 are independently Ci.galkyl; y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is 0, 1, 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR4^', NHCO, or CH2NH, wherein R4^' is hydrogen or Cj.galkyl; alternatively, E is a group (h):
Figure imgf000065_0001
R87 (h); R83 and R84 are independently hydrogen or Cχ_galkyl;
R85 and R8" are independently hydrogen, Ci.galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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 i _6alkyl, aryl, CONR88R89, NR90R91 , hydroxy, OCOR92, NHCOCF3, NHSO2R93, NHCO2R94, or NHCOC0-6alkyl wherein the alkyl of NHCOCθ-6alkyl is optionally substituted by OH;
R87 is hydrogen or Cχ_6alkyl, C .galkoxy, or halogen, or R87 together with R 0' 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;
R885 R895 R90? R915 R92; R95? ^d R96 are independently hydrogen or Cχ_ 6alkyl; R93 and R94 are independently Ci.galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR4^', NHCO, or
CH2NH, wherein R4^' is hydrogen or Cι_6alkyl, alternatively, E is a group (i):
Figure imgf000066_0001
R97 and R98 are independently hydrogen,
Figure imgf000066_0002
C3_7cycloalkyl, aralkyl,
C5_7cycloalkenyl, a C5_7heterocyclic ring, 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 Ci^al yl, aryl, CONR^RiOS, NR10 R105, hydroxy, OCOR106, NHCOCF3, NHSO2 R107, NHCO2R108, or NHCOC0-6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH; R99 and R1^ are independently hydrogen or Cl-6alkyl; R1^1 is hydrogen or Cχ_galkyl or R1^1 and R30' together form a group ΣAD- where AD is (CR109R1 10)ai or AD is (CR10^110)aj-AE and AE is oxygen, sulfur or CR109=CR110;
AC is oxygen, CR11 iR112 or NR113 or AC is a group S(O)ak;
R102 R103, R104; R105 , R106, R109 R110, Rl 11 , Rl 12, ^ Rl 13 ^ independently hydrogen or C^alkyl;
R107 and R108 are independently Cl-6alkyl; 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, provided that when R2 is hydrogen and E is a group (a), (f) (h) or (i), then one or both of R3 or R4; R59 or R60; R85 or R86; or R97 or R98 is C5_ 7cycloalkenyl, or a C5_7heterocyclic ring; or when R2 is hydrogen and E is a group (b) or (c), then R30 and R47 are C5_7cycloalkenyl, or a C5_7heterocyclic ring; or when R2" is hydrogen and E is group (g), then either R71 ' is not hydrogen and/or R71 is substituted on nitrogen with C5_7cycloalkenyl or a C5_7heterocyclic ring.
2. The compound of formula (I) according to claim 1, wherein A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen; Ar is (i), (ii), or (iii); and E is group (a), (b), or (g).
3. The compound of formula (I) according to claim 1, wherein A is CONR46' or NHCO, wherein R46' is hydrogen; Ar is (i) or (ii), and the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (a), (b), or (g); and R2" is hydrogen, or (CH2)aCN, (CH2)aCO2H, COCR15'R16OR18', and O(CH2)a'CO2R18' attached to the 3 -position.
4. The compound according to claim 3, wherein when E is group (a), A is attached to group (a) meta to B-(CR1R2)a-NR3R4 and para to (R5)b, wherein B is oxygen or CR7R8, R1 and R are hydrogen, R5 is methoxy, methylthio or iodo, R3 and R4 are independently C3_galkyl, 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 Cχ_galkyl and acetamido or hydroxyl, R6 is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, and b is 1.
5. The compound according to claim 3, wherein when E is group (b), A 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_galkyl, g is 2 and h is 1.
6. The compound according to claim 3, wherein when E is group (g), A is attached to group (g) meta to R71 and para to R72, R71 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_galkyl or C3_7cycloalkyl, C5_7cycloalkenyl, or a C5_7heterocyclic ring; R72 is methoxy, methylthio or iodo, y is 1, R 3 is hydrogen, and R71 is hydrogen or cyano.
7. The compound of formula (I) according to claim 1, wherein A is CONR46', wherein R46' is hydrogen; Ar is (i), (ii), or (iii); E is group (a), (b), or (g), wherein when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; and wherein when E is group (a), A is attached to group (a) meta to B-(CR1R2)a-NR3R4 and para to (R5)b, wherein B is oxygen or CH2, R1 and R 2 are hydrogen, R5 is methoxy, R 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), R6 is hydrogen, a is 2 when B is oxygen, and b is 1 ; and wherein when E is group (b), A is attached to group (b) para to J, J is oxygen, R33 is hydrogen, R24, R2 ^ R26? R27? R28? R2 , R31 and R32 are hydrogen, R 0 is isopropyl, g is 2 and h is 1; and wherein when E is group (g), A is attached to group (g) meta to R71 and para to R72 wherein R71 is piperidin- 4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclopent-3- enyl, R71" is hydrogen or 4-cyano, R72 is methoxy, y is 1, and R73 is hydrogen.
8. The compound of formula (I) according to claim 1, wherein A is CONR46', wherein R46' is hydrogen; Ar is (i) or (ii), wherein the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (g); R2 is hydrogen, cyanomethyl, or cyanoethyl attached to the 3 -position; wherein A is attached to group (g) meta to R71 and para to R72, R71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, 3-pentyl, cyclopropyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, or cyclopent-3-enyl, R71" is hydrogen or 4-cyano, R7 is methoxy, y is 1, and R73 is hydrogen.
9. The compound of formula (I) according to claim 1, selected from: N- [3 - [2- [B is ( 1 -methy lethy 1) amino] ethoxy ] -4-methoxypheny 1] -3 '-
(ethoxyacetyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'- (hydroxy acetyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (methoxy acetyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(2-methoxy-2- oxoethoxy)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-l,r- biphenyl-4-carboxamide;
3'-(2-Cyanoethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 -bipheny 1-4-carboxamide;
3 '-(2-Cyanomethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl- 1 - piperidinyl)ethoxy]phenyl]-l, -biphenyl-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3 - (cyanomethyl)-l, -biphenyl-4-carboxamide; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -(cyanoethyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2- [Bis( 1 -methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 '- (cyanomethyl)- 1 , 1 '-biphenyl-4-carboxamide; 3 -(2-Cyanoethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-
1 , 1 -biphenyl-4-carboxamide;
3 -(2-Cyanomethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[ 1 -(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-methoxyphenyl]- 1,1 - biphenyl-4-carboxamide;
3 -(2-Carboxyethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- l, -biphenyl-4-carboxamide; and
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (carboxyethyl)- 1 , 1 '-bipheny 1-4-carboxamide; 3 -Chloro-N- [3-[4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl]-4-methoxyphenyl]-
1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - ethoxycarbonyl- 1 , 1 -biphenyl-4-carboxamide;
N- [3 - [4-Cy ano- 1 -( 1 -methylethyl)-4-piperidinyl] -4-methoxyphenyl]-3 - sulf amoyl- 1 , 1 -biphenyl-4-carboxamide;
3'-(2-Cyanoethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-ρiperidinyl]-4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide;
N- [3 - [4-Cy ano- 1 -( 1 -methylethy l)-4-piperidinyl] -4-methoxyphenyl] -3 -ureido- 1 , 1 -biphenyl-4-carboxamide; 3'-(Cyanomethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxy phenyl]- 1 , 1 -biphenyl-4-carboxamide;
N- [3 - [4-Cy ano- 1 -( 1 -methylethy l)-4-piperidinyl] -4-methoxyphenyl]-3 '- isopropoxy- 1 , 1 '-biphenyl-4-carboxamide;
3'-Cyano-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- l,l'-biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - dimethyl- 1 , 1 -biphenyl-4-carboxamide;
3'-Acetamido-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l,r-biphenyl-4-carboxamide; 3 -Acetyl-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-
1 , 1 -biphenyl-4-carboxamide; 3 -(2-Carboxyethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(lH- tetrazol-5-yl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piρeridinyl]-4-methoxyphenyl]-3'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - (methanesulfonamido)-l, -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-ρiρeridinyl]-4-methoxyρhenyl]-3',5 - dichloro- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - bis(methoxycarbonyl)- 1 , 1 -bipheny 1-4-carboxamide; and
3'-Carboxamido-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]- 1 , 1 '-biphenyl-4-carboxamide.
10. A method of treating a CCR5-mediated disease in mammals, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Ar— A-E Formula (I) wherein Ar is a group selected from (i), (ii) or (iii);
Figure imgf000070_0001
wherein: the basic nitrogen in moiety E may be optionally quaternized with Cj.g lkyl or is optionally present as the N-oxide;
R1' and R2' are each independently one or more of hydrogen, Cx.galkyl, C2_galkenyl, C2_ 6alkynyl, C3.7cycloalkyl, C3.6cycloalkenyl, aryl, (CH2)aNR7'R8', (CH2)a'NR7'COR9', (CH2)a'NR7'CO2R10', (CH^NR^SO^11', (CH^CONR12^', hydroxyCx.galkyl, Cχ_ 4alkoxyalkyl (optionally substituted by a Cχ_4alkoxy or hydroxy group), (CH2)a'CO2Cχ_6alkyl, (CH2)bOC(O)R14', CR15 =NOR16', CNR15'=NOR16', COR17', CONR12^', CONR12'(CH2)cOCι_4alkyl, CONR12'(CH2)a'CO2R18', CONHNR19'R20', CONR12'SO2R21 ', CO2R22', cyano, trifluoromethyl, NR7'R8', NR7'COR9', NR23'cO(CH2)a'NR23'R24'? NR23'CONR23'R24'5 NR7'CO2R10', NR7'SO2Rn', N=CNR23'NR23'R24') nitro, hydroxy, Cχ_ ζalkoxy, hydroxyCx.galkoxy, Ci^alkoxyCi^alkoxy, OC(O)NR25'R26'5 SR27'5 SOR28', SO2R2^ SO2NR25'R26' or halogen;
R3' and R4' are each independently one or more of hydrogen, Cχ_galkyl, C _ 7cycloalkyl, C3_6cycloalkenyl, hydroxyCx.galkyl, Cχ_6alkylOCχ_6alkyl, CONR29'R30', CO2R31', cyano, aryl, trifluoromethyl, NR29'R30', nitro, hydroxy, Cχ_ βalkoxy, acyloxy, or halogen;
R2'is also R2" wherein R2" is hydrogen, (CH2)a€N, (CH2)aCO2H, CR15 =CR16'CO2R18', COCR15'R16'OR18', Oaryl, Oaralkyl, O(CH2)aCO2R18', and Saryl;
R5' is one or more of hydrogen, Cj.galkyl, Cχ_galkoxy or halogen;
R6'is one or more of hydrogen, C .galkyl, C3_7cycloalkyl (optionally substituted by a hydroxy or an oxo group), hydroxyCχ_6alkyl, hydroxyC3_6alkenyl, hydroxyC3.6alkynyl, (CH2)dOR32', (CH2)dCOR33', (CH2)d€R34'=NOR35', CONR36R37', CO2R38', hydroxy, O(CH2)eR39', NR36R37', SR40', SO2NR41'R42' or halogen; or, R5' and R6' form a fused benzo ring optionally substituted with Cχ_g alkyl, Cj.galkoxy or halogen;
R7' and R8' are independently hydrogen or C _galkyl, or together with the nitrogen to which they are attached, R7' and R8' form a 5- to 6-membered heterocyclic ring, which ring may optionally be substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R9' is hydrogen, Cχ_6alkyl or Cχ.4alkoxy alkyl;
RiO'is Cx.galkyl;
R1 !' is Cχ_galkyl or phenyl;
R12' and R13' are independently hydrogen or Cχ.galkyl, or together with the nitrogen to which they are attached, R12' and R13' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R14' is Cχ_4alkyl, optionally substituted by Cχ_galkoxy;
R15' and R16' are independently hydrogen or Ci.galkyl;
R17'is hydrogen or Cx.galkyl;
R18' is hydrogen or Cχ_6alkyl;
R19' and R20' are independently hydrogen or Cχ_galkyl;
R21' is hydrogen or Cχ_galkyl; R22' is hydrogen or Cι_6 lkyl optionally substituted with one or two substituents selected from Cχ_6alkyl, Cχ_galkoxy, hydroxy, or NR7'R8';
R23' and R24' are independently hydrogen or Ci.galkyl;
R25' and R26' are independently hydrogen or Cχ_galkyl, or together with the nitrogen to which they are attached, R25' and R26' form a 5- to 6-membered heterocyclic ring, which, when the ring is 6-membered, may optionally contain in the ring one oxygen or sulfur atom;
R27' is hydrogen or Cχ_6alkyl;
R28'is Cχ.6alkyl; R29', R ^' and R31' are independently hydrogen or Cx.galkyl;
R32'is Cχ_6alkyl, hydroxyCχ_6alkyl, or Cχ_4alkanoyl;
R33 ' is hydrogen or C \ .galkyl ;
R34' is hydrogen or Cj.galkyl;
R35' is hydrogen or Cj.galkyl; R36' and R37' are independently hydrogen or Cχ_galkyl or together with the nitrogen to which they are attached, R36' and R37' form a 5- to 6-membered heterocyclic ring, which ring may be optionally substituted by an oxo group and, which, when the ring is 6-membered, may optionally contain one oxygen or sulfur atom or an NH group or a group NR43', wherein R43' is Cι_6alkyl, COR44' or CO2R45', wherein R44' and R45' are independently hydrogen or C _galkyl;
R38'is hydrogen or Cj.galkyl;
R39'is Cι_6alkoxy, CO2H, CO2Cχ_6alkyl or CONR36'R37';
R40'is Cι_6alkyl;
R41 ' and R42' are independently hydrogen or Cχ_galkyl; P is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; a' is 1, 2, 3 or 4; b' is O, 1, 2 or 3; c' is 1, 2 or 3; d' is 0, 1, 2, 3, 4, 5, or 6; and e' is 1, 2, 3, 4, 5 or 6; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, - NHCH2, or CH2NH, wherein R46' is hydrogen or Ci.galkyl, E is a group (a):
Figure imgf000073_0001
wherein:
B is oxygen, Ci C, S(O)c, CR =CR8, or CR7R8, or B is NR9; R1 and R2 are independently hydrogen or Cx.galkyl; alternatively B(CR R2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, Cx.galkyl, C3_7cycloalkyl, aralkyl, C5. 7cycloalkenyl, a C5_7heterocyclic ring, 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^R1 ^ NR^R11, hydroxy, OCOR12, NHCOCF3, NHSO2R13, NHCO2R14, or NHCOC0-6alkyl wherein the alkyl of NHCOCQ-όalkyl is optionally substituted by OH;
R5 is hydrogen, C^galkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, Cι_6alkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)dR19, SO2NR20R21 or halogen;
R6 is hydrogen,
Figure imgf000073_0002
aryl, trifluoromethyl, hydroxy, Cχ_galkoxy or halogen, or R6 taken together with R3^' forms a group D where D is (CR2 R23)e or 73 is (CR22R23)f_G where G is oxygen, sulfur or CR22=CR23, CR22=N, =CR22o, =CR22S, or =CR22-NR23; R7, R8, R10, R11, R12, R15, R16, R17> R20, R21, R22, and R23 are independently hydrogen or Cχ_6alkyl;
R9 is hydrogen, Cχ.galkyl, or phenylCχ_6alkyl; 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; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen or Cι_6alkyl, alternatively, E is a group (b):
Figure imgf000074_0001
R245 R255 R265 R27, R28? R29; R31; and R32 are independently hydrogen or
Cι_6alkyl;
R 0 is hydrogen, Cj-galkyl, C3_7cycloalkyl C5_7cycloalkenyl, or a C5.. 7heterocyclic ring;
R33 is hydrogen, Cχ_6alkyl, trifluoromethyl, hydroxy or halogen, or R33 and R30' together form a group -K- where K is (CR34R3 ) or K is (CR34R35)j -M and M is oxygen, sulfur, CR34=CR35, CR34=N, or N=N;
J is oxygen, CR36R37, or NR38, or J is a group S(O)k;
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; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, - NHCH2, or CH2NH, wherein R46' is hydrogen or Cχ.galkyl, alternatively, E is a group (c):
Figure imgf000074_0002
wherein:
Q is oxygen, S(O)n, CR44=CR45, CR44R45, or Q is NR46; R39 and R ^ are independently hydrogen or Cχ_galkyl; R41 is a group of formula (d):
Figure imgf000074_0003
or R41 is a group of formula (e):
Figure imgf000075_0001
R42 is hydrogen, C^galkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO2R51, hydroxy, Ci^alkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)sR52, SO2NR53R54, or halogen;
R43 is hydrogen or R43 together with R3^' 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 Cχ_6alkyl; R47 is hydrogen, Cx.galkyl, 03.7 cycloalkyl C5_7cycloalkenyl, or a C5_
7heterocyclic ring;
R51 and R52 are independently Cχ_6alkyl; 1 is 0, 1, 2, or 3; m is 1 or 2; n is 0, 1, or 2 o, p, and q are independently integers having the value 1, 2, or 3; r is 0,1, 2, or 3; s is O, 1, or 2; t is 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONH, NHCO, or
CH2NH, alternatively, E is a group (f):
Figure imgf000075_0002
R57 and R58 are independently hydrogen or Cχ_6alkyl;
R59 and R6^ are independently hydrogen, Cχ_6alkyl, C3_7cycloalkyl, aralkyl, C5-7cycloalkenyl, a C5_7heterocyclic ring, 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 Ci.galkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOCF3, NHSO2R64, NHCO2R65, or NHCOC0_6alkyl wherein the alkyl of NHCOCo-6alkyl is optionally substituted by OH;
T is -(CR66R6 )V- or -O(CR66R67)w-;
W is oxygen, S(O)x, NR68, or W is CR69=CR70 or CR69R70;
R61, R62, R63, R66, R67 R68, R69? ^d R70 ^ independently hydrogen or Cι_6alkyl;
R64 and R65 are independently Cχ.galkyl; u is 1 to 4; v is 2 or 3; w is 1, 2, or 3; x is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R46' is hydrogen or Cj.galkyl, alternatively, E is a group (g):
Figure imgf000076_0001
R71 is a 5- to 7-membered saturated or partially saturated heterocyclic ring containing a basic nitrogen atom and optionally a further 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur or R71 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 Cx.galkyl and optionally substituted on nitrogen with hydrogen, Cχ_galkyl, C3_7cycloalkyl C5_7Cycloalkenyl, or a C5_7heterocyclic ring;
R71 is substituted with one or more of R71", wherein R71" is hydrogen, CR aR2"NR "R4", CRlaR2"OR3", COR5", C0NR6"R7", CO2R8", cyano, NR "R4", nitro, hydroxy, Cμgalkoxy, SR9", SOR10", SO2R10", SO2 NR6"R7" or SO3H, wherein:
Rla and R " are independently hydrogen or Cx.galkyl;
R3" and R4" are independently hydrogen or Cx.galkyl, or taken 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 one oxygen or one sulfur atom; alternatively R4" is COR11", CONR^'RiS", CO2R14", SO2R15", SO^R^-R ", or SO2OR16", wherein R11" is hydrogen, Cχ_galkyl, aryl, or trifluoromethyl; R12 and R 3" are independently hydrogen or Cχ_ galkyl, or taken 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 one oxygen or one sulfur atom; R 4" is hydrogen or Cχ_6alkyl; R15" is hydrogen, Cι_galkyl, aryl, or trifluoromethyl; and R16" is hydrogen or aryl;
R5" is Cj.galkyl, aryl, or trifluoromethyl;
R6" and R7" are independently hydrogen or Ci^galkyl, or taken 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 one oxygen or one sulfur atom;
R8" is hydrogen or C^.^alkyl;
R9" is hydrogen, Cχ_galkyl, aryl, or trifluoromethyl; and
RiO" is Cx.galkyl, aryl, or trifluoromethyl;
R72 is hydrogen, Ci.galkyl, aryl, CN, CONR7 R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, Ci.galkoxy, benzyloxy, OCH2CO2Cι_6alkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R73 is hydrogen, Cχ_galkyl, hydroxy, Cχ_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 CR81=CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or Cχ_ galkyl;
R77 and R78 are independently Cχ_galkyl; y is 1 or 2; z is O, 1, or 2; aa is 2, 3 or 4; ab is O, 1, 2 or 3; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or CH2NH, wherein R 6'is hydrogen or Cχ_6alkyl; alternatively, E is a group (h):
— τ Z - -(CR83R8 )ac NR85R86
R87 (h);
R83 and R84 are independently hydrogen or Cχ_galkyl;
R85 and R86 are independently hydrogen, Cχ_galkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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 Ci.ζalkyl, aryl, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOCF3, NHSO2R93, NHCO2R94, or NHCOC0_6alkyl wherein the alkyl of NHCOCo_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 or AA is (CR95=CR96)ae-AJ3 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_ galkyl;
R93 and R94 are independently Cj.galkyl; ac is 0 to 4; ad is 1, 2 or 3; ae is 0, 1 or 2; and further wherein, when Ar is (i), (ii) or (iii), and A is CONR46', NHCO, or
CH2NH, wherein R46' is hydrogen or Cχ_6alkyl, alternatively, E is a group (i):
Figure imgf000078_0001
R97 and R98 are independently hydrogen, C .βalkyl, C3_7cycloalkyl, aralkyl, C5_7cycloalkenyl, a C5_7heterocyclic ring, 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, CONR102R103, NR10 R105, hydroxy, OCORiO6, NHCOCF3, NHSO2 R^7, NHCO^O8, or NHCOC0_6 lkyl wherein the alkyl of NHCOCo-galkyl is optionally substituted by OH; R99 and R^O are independently hydrogen or Cl-6alkyl; R1^ is hydrogen or Cj.galkyl or R1^ and R3^' together form a group -AD- where AD is (CR^R110)ai or AD is (CR109R110)aj-AE and AE is oxygen, sulfur or CRiO^CRϋ ;
AC is oxygen, CR11 iR112 or NR1 13 or AC is a group S(O)ak;
Rl02, R1035 R104 R105, R106, R1095 Rl 10, R111, R112, md Rl 13 are independently hydrogen or Cχ_galkyl; R107 and R108 are independently Cl-6alkyl; 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 O, 1, 2, or 3; and ak is 0, 1 or 2, provided that when R2" is hydrogen and E is a group (a), (f) (h) or (i), then one or both of R3 or R4; R59 or R60; R85 or R86; or R97 or R98 is C5. 7cycloalkenyl, or a C5_7heterocyclic ring; or when R2" is hydrogen and E is a group (b) or (c), then R3^ and R47 are C5_7cycloalkenyl, or a C5_7heterocyclic ring; or when R2" is hydrogen and E is group (g), then either R7 " is not hydrogen and or R71 is substituted on nitrogen with C5_7cycloalkenyl or a C5_7heterocyclic ring.
11. The method of claim 10, wherein the compound of formula (I) is selected from:
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (ethoxy acetyl)- 1 , 1 -biphenyl-4-carboxamide ; N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 -
(hy droxy acetyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyρhenyl]-3'- (methoxyacetyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(2-methoxy-2- oxoethoxy)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano- 1-( l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 '- biphenyl-4-carboxamide;
3'-(2-Cyanoethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 -biphenyl-4-carboxamide; 3 -(2-Cyanomethyl)-N-[4-methoxy-3-[2-(2,2,6,6-tetramethyl-l- piperidinyl)ethoxy]phenyl]- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[3-[Bis(l-methylethyl)amino]propoxy]-4-methoxyphenyl]-3 - (cyanomethyl)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3'-(cyanoethyl)- 1 , 1 '-bipheny 1-4-carboxamide;
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (cyanomethyl)- 1 , 1 -biphenyl-4-carboxamide; 3'-(2-Cyanoethyl)-N-[3-[l-(l-methylethyl)-4-ρiρeridinyl]-4-methoxyphenyl]-
1 , 1 -bipheny 1-4-carboxamide; 3'-(2-Cyanomethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[l-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-methoxyphenyl]-l,l'- biphenyl-4-carboxamide; 3'-(2-Carboxyethyl)-N-[3-[l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-
1,1 -bipheny 1-4-carboxamide; and
N-[3-[2-[Bis(l-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3 - (carboxyethyl)- 1 , 1 -bipheny 1-4-carboxamide;
3 -Chloro-N- [3- [4-cyano- 1 -( 1 -methylethy l)-4-piperidinyl] -4-methoxyphenyl] - l, -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piρeridinyl]-4-methoxyphenyl]-3 - ethoxycarbonyl- 1 , 1 -bipheny 1-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - sulfamoyl- 1 , 1 -biphenyl-4-carboxamide; 3'-(2-Cyanoethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l, -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-ureido- 1 , 1 -bipheny 1-4-carboxamide;
3 '-(Cy anomethyl)-N- [3-[4-cy ano- 1 -( 1 -methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l, -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'- isopropoxy- 1 , 1 '-biphenyl-4-carboxamide;
3 '-Cy ano-N- [3 - [4-cyano- 1 -( 1 -methylethy l)-4-piperidinyl] -4-methoxyphenyl] - 1 , 1 -biphenyl-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-ρiρeridinyl]-4-methoxyρhenyl]-3',5'- dimethyl- 1 , 1 -bipheny 1-4-carboxamide;
3 '- Acetamido-N- [3 - [4-cyano- 1 -( 1 -methylethyl)-4-piperidinyl] -4- methoxyphenyl]- 1 , 1 -biphenyl-4-carboxamide;
3 '- Acetyl-N- [3- [4-cyano- 1 -( 1 -methylethy l)-4-piperidinyl] -4-methoxyphenyl] - 1,1 -biphenyl-4-carboxamide;
3 -(2-Carboxyethyl)-N-[3-[4-cyano-l-(l-methylethyl)-4-ρiperidinyl]-4- methoxyphenyl] -1,1 -biphenyl-4-carboxamide ;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(lH- tetrazol-5-yl)- 1 , 1 -bipheny 1-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)- 1 , 1 -biphenyl-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3 - (methanesulfonamido)- 1 , 1 -biphenyl-4-carboxamide;
N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - dichloro- 1 , 1 -bipheny 1-4-carboxamide; N-[3-[4-Cyano-l-(l-methylethyl)-4-piperidinyl]-4-methoxyphenyl]-3',5 - bis(methoxy carbonyl)- 1 , 1 -biphenyl-4-carboxamide; and
3'-Carboxamido-N-[3-[4-cyano-l-(l-methylethyl)-4-piperidinyl]-4- methoxyphenyl]-l, -biphenyl-4-carboxamide.
12. The method of claim 10, wherein the CCR5-mediated disease state is selected from COPD, asthma and atopic disorders, 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, or HIV infection.
13. The method according to claim 10, wherein the compound of formula (I) is as follows: A is CONR46' or NHCO, wherein R46' is hydrogen; Ar is (i) or (ii), and the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (a), (b), or (g); and R2" is hydrogen, or (CH2)aCN, (CH2)aCO2H, COCR15'R16OR18', and O(CH2)aCO2R18' attached to the 3 '-position.
14. The method according to claim 10, wherein the compound of formula (I) is as follows: when E is group (a), A is attached to group (a) meta to B-(CR1R2)a- NR R4 and para to (R5)b, wherein B is oxygen or CR7R8, R1 and R 2 are hydrogen, R5 is methoxy, methylthio or iodo, R3 and R4 are independently C3_galkyl, 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 Cχ_galkyl and acetamido or hydroxyl, R6 is hydrogen, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, and b is 1 ; or when E is group (b), A 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, R3^ is C3_6alkyl, g is 2 and h is 1; or when E is group (g), A is attached to group (g) meta to R71 and para to R72, R7 is an optionally substituted 5- or 6-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom and substituted on nitrogen with C3_galkyl or C3_7cycloalkyl, R72 is methoxy, methylthio or iodo, y is 1, R73 is hydrogen, and R71" is hydrogen or cyano.
15. The method according to claim 10, wherein the compound of formula (I) is as follows: A is CONR46', wherein R46' is hydrogen; Ar is (i), (ii), or (iii); E is group (a), (b), or (g), wherein when Ar is (i) or (ii), the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; and wherein when E is group (a), A is attached to group (a) meta to B-(CR1R )a-NR3R4 and para to (R5)b, wherein B is oxygen or CH2, R and R 2 3re hydrogen, R5 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 l-(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), R6 is hydrogen, a is 2 when B is oxygen, and b is 1; and wherein when E is group (b), A 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 l; and wherein when E is group (g), A is attached to group (g) meta to R71 and para to R72 wherein R7 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, cyclopropyl, or cyclopentyl, R71" is hydrogen or 4-cyano, R72 is methoxy, y is 1, and R73 is hydrogen.
16. The method according to claim 10, wherein the compound of formula (I) is as follows: A is CONR46', wherein R46' is hydrogen; Ar is (i) or (ii), wherein the terminal phenyl in (i) and (ii) is attached to the phenyl ring bearing group A in a position para to group A; E is group (g); R2 ' is hydrogen, cyanomethyl, or cyanoethyl attached to the 3 '-position; wherein A is attached to group (g) meta to R71 and para to R72, R71 is piperidin-4-yl, l,2,3,6-tetrahydropyridin-4-yl, or pyrrolidin-3-yl substituted on nitrogen with isopropyl, cyclopropyl, or cyclopentyl, R 1 is hydrogen or 4-cyano, R72 is methoxy, y is 1, and R73 is hydrogen.
PCT/US2003/023343 2002-07-31 2003-07-28 Substituted benzanilides as modulators of the ccr5 receptor WO2004011427A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003254177A AU2003254177A1 (en) 2002-07-31 2003-07-28 Substituted benzanilides as modulators of the ccr5 receptor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40008502P 2002-07-31 2002-07-31
US60/400,085 2002-07-31

Publications (2)

Publication Number Publication Date
WO2004011427A2 true WO2004011427A2 (en) 2004-02-05
WO2004011427A3 WO2004011427A3 (en) 2005-02-03

Family

ID=31188660

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/023343 WO2004011427A2 (en) 2002-07-31 2003-07-28 Substituted benzanilides as modulators of the ccr5 receptor

Country Status (2)

Country Link
AU (1) AU2003254177A1 (en)
WO (1) WO2004011427A2 (en)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7230022B2 (en) 2004-02-19 2007-06-12 Bristol-Myers Squibb Company Substituted fused bicyclic amines as modulators of chemokine receptor activity
WO2006034402A3 (en) * 2004-09-21 2007-08-09 Synta Pharmaceutical Corp Compounds for inflammation and immune-related uses
US7288563B2 (en) 2004-02-19 2007-10-30 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
WO2008002676A3 (en) * 2006-06-29 2008-05-02 Kinex Pharmaceuticals Llc Biaryl compositions and methods for modulating a kinase cascade
US7381738B2 (en) 2004-02-19 2008-06-03 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7479496B2 (en) 2004-02-19 2009-01-20 Bristol-Myers Squibb Company Substituted spiro azabicyclics as modulators of chemokine receptor activity
US7615651B2 (en) 2006-11-13 2009-11-10 Pfizer Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
US7820817B2 (en) 2004-05-28 2010-10-26 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7851470B2 (en) 2006-12-28 2010-12-14 Kinex Pharmaceuticals, Llc Composition and methods for modulating a kinase cascade
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7935697B2 (en) 2006-12-28 2011-05-03 Kinex Pharmaceuticals, Llc Compositions for modulating a kinase cascade and methods of use thereof
US7939529B2 (en) 2007-05-17 2011-05-10 Kinex Pharmaceuticals, Llc Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof
US7968574B2 (en) 2004-12-28 2011-06-28 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
US8003641B2 (en) 2004-12-28 2011-08-23 Kinex Pharmaceuticals, Llc Compositions and methods of treating cell proliferation disorders
US8124605B2 (en) 2007-07-06 2012-02-28 Kinex Pharmaceuticals, Llc Compositions and methods for modulating a kinase cascade
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8748423B2 (en) 2010-04-16 2014-06-10 Kinex Pharmaceuticals, Llc Compositions and methods for the prevention and treatment of cancer
US9676747B2 (en) 2011-12-21 2017-06-13 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9926273B2 (en) 2012-08-30 2018-03-27 Athenex, Inc. Composition and methods for modulating a kinase cascade
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10196357B2 (en) 2007-04-13 2019-02-05 Athenex, Inc. Biaryl compositions and methods for modulating a kinase cascade
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006085A2 (en) * 1998-07-28 2000-02-10 Smithkline Beecham Corporation Compounds and methods
US6147214A (en) * 1997-04-18 2000-11-14 Pfizer Inc Process and intermediates for the preparation of 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147214A (en) * 1997-04-18 2000-11-14 Pfizer Inc Process and intermediates for the preparation of 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide
WO2000006085A2 (en) * 1998-07-28 2000-02-10 Smithkline Beecham Corporation Compounds and methods

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7479496B2 (en) 2004-02-19 2009-01-20 Bristol-Myers Squibb Company Substituted spiro azabicyclics as modulators of chemokine receptor activity
US7288563B2 (en) 2004-02-19 2007-10-30 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7230022B2 (en) 2004-02-19 2007-06-12 Bristol-Myers Squibb Company Substituted fused bicyclic amines as modulators of chemokine receptor activity
US7381738B2 (en) 2004-02-19 2008-06-03 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7820817B2 (en) 2004-05-28 2010-10-26 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US8497295B2 (en) 2004-08-19 2013-07-30 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US7709518B2 (en) 2004-09-21 2010-05-04 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
WO2006034402A3 (en) * 2004-09-21 2007-08-09 Synta Pharmaceutical Corp Compounds for inflammation and immune-related uses
US8314134B2 (en) 2004-09-21 2012-11-20 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8524756B2 (en) 2004-09-21 2013-09-03 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8598169B2 (en) 2004-12-28 2013-12-03 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
US7968574B2 (en) 2004-12-28 2011-06-28 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
US8003641B2 (en) 2004-12-28 2011-08-23 Kinex Pharmaceuticals, Llc Compositions and methods of treating cell proliferation disorders
US8980890B2 (en) 2004-12-28 2015-03-17 Kinex Pharmaceuticals, Llc Compositions and methods of treating cell proliferation disorders
US9580387B2 (en) 2004-12-28 2017-02-28 Athenex, Inc. Biaryl compositions and methods for modulating a kinase cascade
US8236799B2 (en) 2004-12-28 2012-08-07 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
US9655903B2 (en) 2004-12-28 2017-05-23 Athenex, Inc. Compositions and methods of treating cell proliferation disorders
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8592486B2 (en) 2005-01-07 2013-11-26 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
WO2008002676A3 (en) * 2006-06-29 2008-05-02 Kinex Pharmaceuticals Llc Biaryl compositions and methods for modulating a kinase cascade
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7615651B2 (en) 2006-11-13 2009-11-10 Pfizer Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
US7851470B2 (en) 2006-12-28 2010-12-14 Kinex Pharmaceuticals, Llc Composition and methods for modulating a kinase cascade
US8293739B2 (en) 2006-12-28 2012-10-23 Kinex Pharmaceuticals, Llc Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof
US10323001B2 (en) 2006-12-28 2019-06-18 Athenex, Inc. Compositions for modulating a kinase cascade and methods of use thereof
US8309549B2 (en) 2006-12-28 2012-11-13 Kinex Pharmaceuticals, Llc Compositions for modulating a kinase cascade and methods of use thereof
US8901297B2 (en) 2006-12-28 2014-12-02 Kinex Pharmaceuticals, Llc Compositions for modulating a kinase cascade and methods of use thereof
US7935697B2 (en) 2006-12-28 2011-05-03 Kinex Pharmaceuticals, Llc Compositions for modulating a kinase cascade and methods of use thereof
US9556120B2 (en) 2006-12-28 2017-01-31 Athenex, Inc. Compositions for modulating a kinase cascade and methods of use thereof
US10196357B2 (en) 2007-04-13 2019-02-05 Athenex, Inc. Biaryl compositions and methods for modulating a kinase cascade
US7939529B2 (en) 2007-05-17 2011-05-10 Kinex Pharmaceuticals, Llc Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof
US8124605B2 (en) 2007-07-06 2012-02-28 Kinex Pharmaceuticals, Llc Compositions and methods for modulating a kinase cascade
US8748423B2 (en) 2010-04-16 2014-06-10 Kinex Pharmaceuticals, Llc Compositions and methods for the prevention and treatment of cancer
US9676747B2 (en) 2011-12-21 2017-06-13 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9751857B2 (en) 2011-12-21 2017-09-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10106505B2 (en) 2012-08-30 2018-10-23 Athenex, Inc. Composition and methods for modulating a kinase cascade
US9926273B2 (en) 2012-08-30 2018-03-27 Athenex, Inc. Composition and methods for modulating a kinase cascade
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10632112B2 (en) 2014-02-05 2020-04-28 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Also Published As

Publication number Publication date
WO2004011427A3 (en) 2005-02-03
AU2003254177A8 (en) 2004-02-16
AU2003254177A1 (en) 2004-02-16

Similar Documents

Publication Publication Date Title
WO2004011427A2 (en) Substituted benzanilides as modulators of the ccr5 receptor
US6399656B1 (en) Compounds and methods
WO2004010943A2 (en) Substituted benzanilides as modulators of the ccr5 receptor
EP1313477A1 (en) Compounds and methods
EP1100495A1 (en) Propenamides as ccr5 modulators
EP1100485A1 (en) Substituted anilide compounds and methods
US6476028B1 (en) Compounds and methods
WO2004010942A2 (en) Substituted heterocyclic compounds as modulators of the ccr5 receptor
JP4601429B2 (en) 4-Tetrazolyl-4-phenylpiperidine derivative for the treatment of pain
KR100667645B1 (en) Cyclic amine ccr3 antagonists
WO2000042852A1 (en) Compounds and methods
KR20020020223A (en) Pharmaceutical combinations for the treatment of stroke and traumatic brain injury
AU2002243136B2 (en) Benzimidazol derivatives modulate chemokine receptors
JP2013028538A (en) Novel amide derivative
JP2002534383A (en) Compounds and methods
JP2005525309A (en) The combination of MTP inhibitors or apoB secretion inhibitor and fibrate for use as a medicament
JPH09501405A (en) N-substituted 3-benzazepines or isoquinolines for antiarrhythmia
JP4276070B2 (en) Cyclic amine compound
US20040038982A1 (en) Compounds and methods
KR102591750B1 (en) indole derivatives
EP1343796A2 (en) Compounds and methods
MXPA01001023A (en) Substituted anilide compounds and methods
AU6967400A (en) Methods of administering APO B-secretion/MTP inhibitors
JP2005097196A (en) N-type calcium channel inhibitor
JP2009516664A (en) 4-Oxadiazolyl-piperidine compounds and their use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP