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US20070179297A1 - Chemical compounds - Google Patents

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Publication number
US20070179297A1
US20070179297A1 US11/732,411 US73241107A US2007179297A1 US 20070179297 A1 US20070179297 A1 US 20070179297A1 US 73241107 A US73241107 A US 73241107A US 2007179297 A1 US2007179297 A1 US 2007179297A1
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United States
Prior art keywords
alkyl
phenyl
optionally substituted
halogen
alkoxy
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US11/732,411
Inventor
Aaron Rigby
Hitesh Sanganee
Brian Springthorpe
Louise Lawrence
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AstraZeneca AB
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AstraZeneca AB
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Publication date
Priority claimed from GB0008626A external-priority patent/GB0008626D0/en
Priority claimed from GB0019111A external-priority patent/GB0019111D0/en
Priority claimed from SE0003664A external-priority patent/SE0003664D0/en
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to US11/732,411 priority Critical patent/US20070179297A1/en
Publication of US20070179297A1 publication Critical patent/US20070179297A1/en
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LAWRENCE, LOUISE, RIGBY, AARON, SANGANEE, HITESH, SPRINGTHORPE, BRIAN
Abandoned legal-status Critical Current

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • C—CHEMISTRY; METALLURGY
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    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a consideration in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif.
  • the chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C-C, or ⁇ ) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating peptide 2
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP-1 ⁇ and MIP-1 ⁇ ).
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • G protein-coupled receptors among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, H1, H2 and H3.
  • Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. H1 antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
  • the present invention provides a compound of formula (I): wherein:
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers).
  • the present invention covers all such isomers and mixtures thereof in all proportions.
  • Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate.
  • acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate.
  • Another example of an addition salt is sulphate.
  • the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
  • Alkenyl group are, for example, vinyl or allyl.
  • Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl, cyclopentyl, cyclohexyl, norbomyl or camphoryl.
  • the cycloalkyl ring is optionally fused to a benzene ring (for example forming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).
  • Cycloalkenyl is especially monocyclic and is, for example, cyclopentenyl or cyclohexenyl.
  • Aryl is preferably phenyl or naphthyl.
  • Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • Heterocyclyl is, for example, fliryl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benz
  • heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur.
  • Heterocyclyl is, for example, furyl, thienyl, 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, quinoxaline, dihydro-1-benzopyrylium (for example a coumarin or a chromone), piperidine, morpholine, pyrrole, indole, 2,3-dihydroindole, quinoline, thiazole, pyrazole, isoxazole, imidazole, pyridine, benzofuryl, benzimidazole, pyrimidine or dibenzothiophene.
  • heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, pyriridinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl
  • N-oxide of a compound of formula (I) is, for example, a 1-oxy-[1,4′]bipiperidinyl-1′-yl compound.
  • the present invention provides a compound of formula (I′): wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH 2 , CO, O, S, S(O), S(O) 2 or NR 37 ; provided that when m and p are both 1 then X is not CH 2 ; Y is NHR 2 or OH; T is CO, CS, SO 2 or CH 2 ; R 1 is hydrogen, C 1-6 alkyl, aryl or heterocyclyl; R 2 is hydrogen, C 1-6 alkyl, aryl(C 1-4 )alkyl or CO(C 1-6 alkyl); R 3 is C 1-6 alkyl ⁇ optionally substituted by halogen, CO 2 R 4 or phthalimide ⁇ , C 3-7 cycloalkyl ⁇ optionally substituted by C 1-4 alkyl or oxo ⁇ , C 3-7 cycloalkeny
  • the present invention provides a compound of formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH 2 , C(O), O, S, S(O), S(O) 2 or NR 37 ; provided that when m and p are both 1 then X is not CH 2 ; Y is NHR 2 or OH; T is C(O), C(S), S(O) 2 or CH 2 ; R 1 is hydrogen, C 1-6 alkyl, aryl or heterocyclyl; R 2 and R 47 are, independently, hydrogen, C 1-6 alkyl, aryl(C 1-4 )alkyl or CO(C 1-6 alkyl); R 3 is C 1-6 alkyl ⁇ optionally substituted by halogen, CO 2 R 4 or phthalimide ⁇ , C 3-7 cycloalkyl ⁇ optionally substituted by
  • variables m and p are such that m +p is 0, 1 or 2 (for example 1 or 2).
  • n is 0 or 1.
  • n, q and r are all 0.
  • s is 0.
  • s is 1.
  • q is 1.
  • n +r is equal to more than 1 (for example n +r is equal to 2, 3, 4 or 5).
  • t +m +p is not equal to 3 (for example t +m +p is equal to 2).
  • X is O.
  • R 1 is hydrogen, C 1-6 alkyl, optionally substituted (as above) aryl or optionally substituted (as above) monocyclic heterocyclyl.
  • R 1 is phenyl substituted with one or more of fluorine, chlorine, C 1-4 alkyl (especially methyl) or C 1-4 alkoxy (especially methoxy).
  • R 1 is not phenyl substituted by cycloalkyl.
  • R 1 is phenyl optionally substituted (for example with one, two or three) by halo (especially fluoro or chloro), C 1-4 alkyl (especially methyl) or C 1-4 alkoxy (especially methoxy).
  • R 1 is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
  • R 1 is one of the substituted phenyl groups exemplified in Method F below.
  • T is C(O), S(O) 2 or CH 2 . In a still further aspect T is C(O). In another aspect T is S(O) 2 or CH 2 .
  • R 3 is aryl or heterocyclyl either of which is optionally substituted as described above.
  • R 3 is unsubstituted phenyl, mono-substituted phenyl or mono-substituted heterocyclyl, the substituents being chosen from those described above.
  • R 3 is oxo substituted heterocyclyl, said heterocyclyl optionally further substituted with one or more substituents chosen from those described above.
  • R 3 is a bicyclic heterocyclyl optionally substituted as described above.
  • Bicyclic heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • Bicyclic heterocyclyl is, for example, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyri
  • R 3 is: C 1-6 alkyl ⁇ optionally substituted by CO 2 R 16 or phthalimide ⁇ , C 3-7 cycloalkyl ⁇ optionally substituted by oxo ⁇ , phenyl ⁇ optionally substituted by: halogen, OH, SH, C 1-6 alkyl (itself optionally substituted by naphthyloxy (itself optionally substituted by halo or alkenyl) or NR 17 C(O)OCH 2 (fluoren-9-yl)), C 1-6 alkoxy (itself optionally substituted by CO 2 R 18 , NR 19 R 20 or phenyl (itself optionally substituted by halogen or NO 2 )), C 1-6 alkylthio, C 1-4 haloalkyl, OCF 3 , nitro, C 3-7 cycloalkyl, NR 21 R 22 , NR 23 C(O)R 24 , CO 2 R 25 , C(O)NR 26 R 27 , S(O)
  • R 3 is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, amino, C 1-4 alkyl (itself optionally substituted by S(O) 2 (C 1-4 alkyl), S(O) 2 phenyl), C 1-4 alkoxy, S(O) k R 46 (wherein k is 0, 1 or 2 (preferably 2); and R 46 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-7 cycloalkyl(C 1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C 1-4 haloalkylthio, C(O)NH 2 , NHS(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl) or S(O) 2 N(C 1-4 alkyl) 2 .
  • variable R 3 can be benzo[1,2,3]thiadiazolyl, thiophenyl or phenyl; the phenyl and thiophenyl rings being optionally substituted by: halo, hydroxy, nitro, cyano, amino, C 1-4 alkyl (itself optionally substituted by S(O) 2 (C 1-4 alkyl), S(O) 2 phenyl), C 1-4 alkoxy, S(O) k R 46 (wherein k is 0, 1 or 2 (preferably 2); and R 46 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-7 cycloalkyl(C 1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C 1-4 haloalkylthio, C(O)NH 2 , NHS(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl) or S(O) 2 N
  • variable R 3 can be benzo[1,2,3]thiadiazolyl or phenyl (optionally substituted by: halo, hydroxy, nitro, cyano, amino, C 1-4 alkyl (itself optionally substituted by S(O) 2 phenyl), C 1-4 alkoxy, S(O) k R 46 (wherein k is 0, 1or 2; and R 46 is C 1-4 alkyl or phenyl) or C 1-4 haloalkylthio.
  • R 50 , R 51 and R 52 are, independently, hydrogen, halogen, (especially fluoro or chloro), C 1-4 alkyl (especially methyl) or C 1-4 alkoxy (especially methoxy).
  • R 3 is heterocyclyl (such as thienyl, isoxazolyl or indolyl, or a naphthyridinyl, an imidazopyridinyl or an isoquinolinyl) optionally substituted by oxo, halogen or C 1-6 alkyl.
  • the present invention provides a compound of formula (Ia)
  • R 35 and R 36 are, independently, hydrogen, halogen, (especially fluoro or chloro), C 1-4 alkyl (especially methyl) or C 1-4 alkoxy (especially methoxy).
  • R 35 and R 36 are both chlorine or both fluorine, especially 3,4 disposed on the phenyl ring to which they are attached.
  • the present invention provides a compound of formula (Ib): wherein T, n and R 3 are as defined above.
  • the present invention provides a compound of formula (Ic): wherein T, m, p and R 3 are as defined above.
  • the present invention provides a compound of formula (Id): wherein R 3 is as defined above.
  • the present invention provides a compound of formula (Ie): wherein R 1 , t, s and R 3 are as defined above.
  • the present invention provides a compound of formula (If): wherein R 1 , n, t, s and R 3 are as defined above.
  • the present invention provides a compound of formula (Ig): wherein R 1 , X and R 3 are as defined above.
  • a compound of formula (I), wherein s is 0, can be prepared by coupling a compound of formula (II): with a compound of formula (III): wherein L is a suitable leaving group, and the variables Y and T are optionally protected during the course of the reaction by standard protecting groups known in the art and deprotected in a separate step or during the reaction work-up.
  • L is a suitable leaving group
  • a compound of formula (I), wherein s is 1, R 47 is hydrogen and T is CO, can be prepared by reacting a compound of formula (II), wherein m and p are both 1, with an aromatic isocyanate of formula with an isocyanate O ⁇ C ⁇ N—(CH 2 ) n —(CH 2 ) r —R 3 .
  • a compound of formula (II) can be prepared by deprotecting a compound of formula (IV): for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane).
  • a suitable solvent such as dichloromethane
  • a source of hydrogen chloride such as dioxane
  • a compound of formula (IV), wherein X is O can be prepared by reacting a compound of formula (V): with a compound of formula (VI): in the presence of NaBH(OAc) 3 and acetic acid.
  • a compound of formula (IV), wherein X is CO or CH 2 can be prepared by oxidising or reducing a compound of formula (VII):
  • a compound of formula (VII) can be prepared by reacting a compound of formula (VIII): with a compound of formula (VI) in the presence of NaBH(OAc) 3 and acetic acid.
  • a compound of formula (VIII) can be prepared by reduction of a compound of formula (IX):
  • a compound of formula (I) wherein X is NR 37 can be prepared by reacting a compound of formula (X): with a compound of formula (XI): in the presence of NaBH(OAc) 3 and acetic acid.
  • a compound of formula (X) can be prepared by reacting NHR 1 R 37 with a compound of formula (XII): in the presence of NaBH(OAc) 3 and acetic acid and then deprotecting the piperidine nitrogen ⁇ for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane) ⁇ .
  • a compound of formula (I), wherein s, n, q and r are all 0 and T is CO can be prepared by reacting a compound of formula (XIII): with an acid: R 3 CO 2 H.
  • a compound of formula (XIII) can be prepared by deprotecting a compound of formula (XIV): wherein L* is BOC or a benzyl group.
  • a compound of formula (XIV) can be prepared by performing a fluoride displacement reaction on FR 1 in the presence of compound of formula (XV):
  • a compound of formula (XV) can be prepared by coupling a compound of formula (XVI) with a compound of formula (XVII):
  • a compound of formula (I) wherein s, n, q and r are all 0 and T is CO can be prepared by performing a fluoride displacement reaction on FR 1 in the presence of compound of formula (XVIII): provided that R 47 is not hydrogen.
  • a compound of formula (XVIII) can be prepared by reacting a compound of formula (XIX): with an appropriate mixed anhydride (such as an anhydride of formula R 3 C(O)OC(O)(C 1-6 alkyl), wherein alkyl is, for example, methyl, ethyl or iso -butyl).
  • an appropriate mixed anhydride such as an anhydride of formula R 3 C(O)OC(O)(C 1-6 alkyl
  • alkyl is, for example, methyl, ethyl or iso -butyl
  • a compound of formula (I) can be prepared by reductive ammination of a compound of formula (XX): with an amine of formula (XXI): under suitable conditions.
  • the present invention provides processes for the preparation of compounds of formula (I) (as defined above), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (le), (If) and (Ig).
  • the compounds of formula (I) are also H1 antagonists and may be used in the treatment of allergic disorders.
  • the compounds of formula (I) may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).
  • the present invention provides a compound of formula (I) (as defined anywhere herein), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, which is both a modulator of chemokine receptor (especially CCR3) activity and an H1 antagonist.
  • a compound of the formula (I) (as defined anywhere herein), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
  • a method for modulating chemokine receptor activity in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a method for antagonising H1 in a warm blooded animal, such as man, in need of such treatment comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the invention also provides a compound of the formula (I) (as defined anywhere herein), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.
  • the invention provides the use of a compound of formula (I) (as defined anywhere herein), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).
  • chemokine receptor activity especially CCR3 receptor activity
  • H1 warm blooded animal
  • the present invention provides the use of a compound of the formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH 2 , C(O), O, S, S(O), S(O) 2 or NR 37 ; Y is NHR 2 or OH; T is C(O), C(S), S(O) 2 or CH 2 ; R 1 is hydrogen, C 1-6 alkyl, aryl or heterocyclyl; R 2 and R 47 are, independently, hydrogen, C 1-6 alkyl, aryl(C 1-4 )alkyl or CO(C 1-6 alkyl); R 3 is C 1-6 alkyl ⁇ optionally substituted by halogen, CO 2 R 4 or phthalimide ⁇ , C 3-7 cycloalkyl ⁇ optionally substituted by C 1-4 alkyl or oxo ⁇ , C 3
  • the present invention provides the use of a compound of the formula (I′): wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH 2 , CO, O, S, S(O), S(O) 2 or NR 37 ; Y is NHR 2 or OH; T is CO, CS, SO 2 or CH 2 ; R 1 is hydrogen, C 1-6 alkyl, aryl or heterocyclyl; R 2 is hydrogen, C 1-6 alkyl, aryl(C 1-4 )alkyl or CO(C 1-6 alkyl); R 3 is C 1-6 alkyl ⁇ optionally substituted by halogen, CO 2 R 4 or phthalimide ⁇ , C 3-7 cycloalkyl ⁇ optionally substituted by C 1-4 alkyl or oxo ⁇ , C 3-7 cycloalkenyl ⁇ optionally substituted by C 1-6 alkyl or
  • the invention further provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
  • a compound of formula (I) (as defined anywhere above), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; or rhinitis ⁇ including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay
  • a compound of formula (I) (as defined anywhere above), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.
  • the invention also provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection).
  • a cold for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection.
  • the present invention also provides a the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
  • the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) or an H1 mediated disease state (such as an allergic disorder) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • a chemokine mediated disease state especially a CCR3 mediated disease state, especially asthma
  • an H1 mediated disease state such as an allergic disorder
  • a warm blooded animal such as man
  • the present invention also provides a method of treating a sign and/or symptom of a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • a sign and/or symptom of a cold for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection
  • a warm blooded animal such as man
  • a compound of the invention or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising H1, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • chemokine receptor for example CCR3 receptor
  • the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • a chemokine mediated disease state especially a CCR3 mediated disease state, especially asthma
  • a compound of the invention or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity
  • said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (I′), (Ia′′), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant, diluent or carrier a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
  • composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg ⁇ 1 to 100 mgkg ⁇ 1 of the compound, preferably in the range of 0.1 mgkg ⁇ 1 to 20 mgkg ⁇ 1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Compound X for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ -cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • This Example illustrates the preparation of 4-(3,4-dichlorophenoxy)piperidine.
  • Step a tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate (acetate salt of Compound 281 in Table 1).
  • Step a 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • Step b 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine
  • Step a The product of Step a was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (15 ml) was added. After 4 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the trifluoroacetate salt of the sub-titled product as a solid (1.15 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the sub-title compound as a solid (0.68 g).
  • Step c [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate
  • Step b The product of Step b (0.15 g) was dissolved in THF (4 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROPTM; 0.235 g), 3-methylsulphonylbenzoic acid (0.091 g) and N,N-di-iso-propylethylamine (0.238 ml) were added. After 18 hours at room temperature ethyl acetate and aqueous NaHCO 3 solution were added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na 2 SO 4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH 4 OAc aq (0.1%) to 95% MeCN//NH 4 OAc aq (0.1%)) gave the title compound (0.095 g).
  • PYBROPTM bromo-tris-pyrrolidino-phosphonium hexaflu
  • the compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.016 g).
  • Step a tert-Butyl 4-(3,4-difluorophenoxy)-1-piperidinecarboxylate
  • This compound was prepared according to the method of Example 1 Step a using 3,4-difluorophenol to afford the compound as an oil (5.4 g).
  • Step c 3-[4-(3,4-Difluoro-phenoxy)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step b The product of Step b (0.5 g) was dissolved in 1,2-dichloroethane (7 ml). tert-Butyl 3-oxo-1-pyrrolidinecarboxylate (0.43 g) was added followed by NaBH(OAc) 3 (0.7 g) and acetic acid (0.08 g). After 24 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO 4 and concentrated. Purification by silica chromatography (100% ethyl acetate) gave the sub-title product (0.79 g).
  • Step c The product of Step c was dissolved in dioxane (10 ml) and HCl (6N) (10 ml) was added and the reaction stirred for 3 hrs. Organic solvent was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na 2 SO 4 and concentrated to give the sub-title product as an oil (0.54 g).
  • Step e (4-Amino-3-methoxy-phenyl)- ⁇ 3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl ⁇ -methanone
  • This compound was prepared by the method of Example 2 Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.151 g).
  • Step a 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • This compound was prepared by the method of Example 2, Step a using 4-(3,4-difluorophenoxy)piperidine to give the sub-title compound as a solid (0.48 g).
  • Step b 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl
  • Step c (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone
  • This compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.133 g).
  • Step a 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • This compound was prepared by the method of Example 2, Step a using 3-oxo-piperidine-1-carboxylic acid tert-butyl ester to give the sub-title compound as a solid (0.946 g).
  • Step b 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl
  • Step c (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone
  • This compound was prepared by the same method as Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.070 g).
  • This compound was prepared by the method of Example 7 using product of Example 5, step b to give the title compound as a solid (0.095 g).
  • Step 1 Preparation of 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • Step 2 Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • Step 4 Preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone
  • Oxalyl chloride 55 ml, 0.63 mol was added dropwise over 10 minutes to a stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) in DCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for 2 hours at room temperature. The solution was then evaporated to give a solid that was redissolved in dichloromethane and again evaporated to give a yellow solid.
  • the solid acid chloride was dissolved in DCM (275 ml ) and was added over 10 minutes to a stirred solution of the product of Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) in dichloromethane (125 ml). The resultant solution was stirred at room temperature for 16 hours. The solution was then washed with water (500 ml), 1M aq NaOH (500 ml) and water (2 ⁇ 500 ml). The organic phase was dried (MgSO 4 ), filterered and the solvent removed to give a pale yellow foam. The foam was triturated with diethyl ether to give the title compound (12.96 g, 76%).
  • Oxalyl chloride (30 mls, 0.35 mol) was added dropwise over 10 minutes to a stirred suspension of 3-methanesulfonyl-benzoic acid (6 g, 0.03) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 4 hours at room temperature. The solution was then evaporated under high vacuum to give a solid which was redissolved in dichloromethane and again evaporated to give a yellow solid.
  • the hydrochloride salt (melting point 159° C.) was prepared by evaporation to dryness of a clear solution of Compound 281 of Table I and HCl in ethanol.
  • Oxalyl chloride (32 ml, 0.37 mol) was added dropwise over 10 minutes to a stirred suspension of 5-(methylsulfonyl)-2-thiophenecarboxylic acid (6.64 g, 0.032) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 2 hours at room temperature. The solution was then removed to give a solid which was redissolved in dichloromethane and the solvent again removed to give a yellow solid.
  • the solid acid chloride was dissolved in DCM (150 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (10 g, 0.03 mol) and triethylamine (9 ml, 0.065 mol) in dichloromethane (300 ml). The resultant solution was stirred at room temperature for 2 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2 ⁇ 100 ml) and water (300 ml). The organic phase was dried (MgSO 4 ), filterered and the solvent removed to give an orange foam.
  • the solid was dissolved in dichloromethane (200 ml) and purified by chromatography using ethyl acetate and then acetone as the eluant.
  • the purified material was precipitated from acetone by the addition of iso-hexane.
  • the crystals were filtered, washed with isohexane and then dried to give the title compound (11.5 g, 74%).
  • the product was eluted with DCM/MeOH mixtures and further purified by Reverse Phase preparative chromatography, MeOH/aqueous TFA gradient on a Symmetry column.
  • the free base was isolated by dissolving in EtOAc and washing with sodium bicarbonate solution, drying the organic layer with MgSO 4 and evaporation left the product as a white solid (0.047 g; M.pt. 83-84° C.).
  • the product was eluted with DCM/MeOH mixtures and further purified by SCX, eluting the product with 10% aq NH 3 in MeOH.
  • the nitro compound was dissolved in THF (10 ml) and hydrogenated over 10% Pd on C at 3 atmospheres in Peteric apparatus. The mixture was filtered and the filtrate evaporated, the residue was then purified by RPHPLC, using a Symmetry column and eluting with MeOH/aqueous TFA mixtures.
  • the product was isolated as the trifluoroacetate by evaporation of the appropriate HPLC fractions (0.046 g; m.pt. 84-85° C.).
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-1-oxy-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone.
  • Example 10 (0.100 g) in dichloromethane (5 ml) was treated with m-chloroperbenzoic acid (0.043 g) and the reaction stirred at room temperature for 0.5 hours. Saturated aqueous sodium hydrogencarbonate was added and the reaction mixture extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO 4 ) and evaporated to give a brown foam. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH 4 OAc aq (0.1%) to 95% MeCN//NH 4 OAc aq (0.1%)) gave the title compound as a white solid (0.021 g).
  • Step 1 4-(3,4-dichloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 4-(3,4-dichloro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester
  • step 2 The product of step 2 was deprotected following the procedure of Example 1 step b.
  • Step 4 4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • step 3 The product of step 3 was used in a reductive amination with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure of Example 2 step a.
  • step 4 The product of step 4 was deprotected following the procedure of Example 2 step b.
  • 1 H NMR (299.946 MHz, DMSO-D6) ⁇ 1.22-1.61 (7H, m), 1.77-1.83 (2H, m), 2.09-2.16 (1H, m), 2.25-2.45 (3H, m), 2.87-2.98 (4H, m), 3.35-3.43 (1H, m), 7.81 (1H, dd), 7.96 (1H, d), 8.05 (1H, d)
  • Step 6 [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone
  • step 5 The product of step 5 was coupled to 4-methanesulfonyl-benzoic acid following the procedure of Example 2 step c.
  • step 5 [4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 5 of Table V).
  • the product of step 5 was coupled to benzoic acid following the procedure of Example 2 step c.
  • Step b 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid
  • Step c [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone
  • Phenylisocyanate(0.078 ml) was added to a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see Example 2 step b) in dichloromethane (5 ml). The mixture was stirred at 23° C. for 16 hours. The resulting precipitate was filtered, washed with dichloromethane (2 ⁇ 5 ml) then crystallised from acetonitrile to afford the title compound as a solid (0.2 g; melting point 215-216° C.).
  • Hydrogen peroxide 100 ⁇ l, 30% was added to a cooled (0° C.) solution of Compound 312 of Table IV (0.13 g) in trifluoroacetic acid(1 ml). The mixture was allowed to reach ambient temperature and stirred for a further 1 hour. The solution was quenched with water(5 ml), basified to pH11 with 2M sodium hydroxide solution and extracted with ethyl acetate. The organic solution was separated, washed with water (2 ⁇ 5 ml), dried (MgSO 4 ), filtered and the filtrate evaporated to leave a gum.
  • the gum was dissolved in acetonitrile and purified by RPHPLC (Nova Pak column) eluting with acetonitrile/0.1% ammonium acetate aq (1:1). The required fractions were evaporated and then lyophilised to give the title compund as a colourless powder (0.03 g).
  • NMR data 3 (I) ⁇ (D 2 O) 1.97-1.69(2H, m), 2.21-2.08(2H, m), 2.51-2.23(4H, m), 3.07-2.96(1H, m), 3.31-3.17(2H, m), 3.45-3.32(2H, m), 3.56-3.45(1H, m), 3.75-3.56(2H, m), 4.88-4.70(3H, m), 7.07-7.02(1H, m), 7.36-7.30(1H, m), 7.46-7.37(1H, m), 7.55(2H, d), 7.74-7.72(1H, m) 8 (I) ⁇ (CDCl 3 ) 1.67-1.41(2H, m), 1.86-1.76(3H, m), 2.04-1.
  • CDI (9 g) added to a solution of 3-methoxy-4-nitrobenzoic acid (10 g) stirring in THF (200 ml) at RT. After 1 hour, 4-piperidone hydrochloride (6.9 g) and triethylamine (7.8 ml) were added and the mixture stirred overnight. The mixture was diluted with ethyl acetate, washed with 2N HCl (100 ml) then saturated NaHCO 3 solution (200 ml) then saturated brine (200 ml).
  • CDI (4.5 g) added to a solution of the benzo[1,2,3]thiadiazole-5-carboxylic acid (5 g) stirring in THF (100 ml) at RT. After 1 hour 4-piperidone hydrochloride (3.7 g) and triethylamine (4.3 ml) were added and the mixture stirred overnight. The resulting mixture was diluted with ethyl acetate, washed with 2M HCl (100 ml), saturated NaHCO 3 solution (200 ml ) and then with saturated brine (200 ml).
  • 3-(2-tert-Butoxycarbonylamino-ethoxy)-benzoic acid can be prepared in a similar manner to that described in Method L.
  • 3-tert-Butoxycarbonylmethoxy-benzoic acid can be prepared in a similar manner to that described in Method L: 1 H NMR (299.944 MHz, DMSO-D6) ⁇ 2.51 (9H, s), 4.74 (2H, s), 7.18 (1H, dq), 7.38 (1H, m), 7.41 (1H, m), 7.55 (1H, dt), 13.03 (1H, s).
  • 5-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid was prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (see Example 25) using the commercially available 5-methyl-1,8a-dihydro-imidazo[ 1,2-a]pyridine-2-carboxylic acid ethyl ester.
  • 6-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid and 6-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester were prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid and its ester above.
  • Step 1 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1,1,6-benzo[1,4]thiazine-6-carboxylic acid methyl ester
  • Step 2 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1,1,6-benzo[1,4]thiazine-6-carboxylic acid
  • Step a 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • Step b 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl
  • step a The product of step a was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (5 ml) was added. After 16 hours at room temperature the solution was evaporated to leave the title compound as a TFA salt.
  • the free base (0.7 g; oil; MS: APCI + (M+H) 339) was liberated by addition of aqueous NaOH (1M) and extraction with dichloromethane followed by evaporation of the solvent.
  • 3-Methanesulfonyl-5-nitro-benzoic acid and 3-cyano-5-methanesulfonyl-benzoic acid can be prepared according to a method described in EP-A1-556674.
  • 2-amino-5-MeSO 2 -benzoic acid can be prepared according to a method described in J. Org. Chem. (1953) 18 1380.
  • 3-Ethanesulfonyl-benzoic acid can be prepared according to a method described in J. Chem. Soc. 1946, 763.
  • 3-Methylsulfamoyl-benzoic acid and 3-dimethylsulfamoyl-benzoic acid can be repared according to a method described in DE2133038.
  • 3-Methylsulfamoyl-benzoic acid 1 H NMR: (399.98 MHz, DMSO-D6) ⁇ 7.42 (3H, d), 7.63 (1H, q), 7.76 (1H, t), 8.01 (1H, m), 8.18 (1H, dt), 8.31 (1H, t), 13.48 (1H, s).
  • Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended at 10 ⁇ 10 6 ml ⁇ 1 in RPMI containing 200 IU/ml penicillin, 200 ⁇ g/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.
  • Eosinophils (700 ⁇ l) were pre-incubated for 15 mins at 37° C. with 7 ⁇ l of either vehicle or compound (100 ⁇ required final concentration in 10% DMSO).
  • the chemotaxis plate (ChemoTx, 3 ⁇ m pore, Neuroprobe) was loaded by adding 28 ⁇ l of a concentration of eotaxin (0.1 to 100 nM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate.
  • the filter was then placed over the wells and 25 ⁇ l of eosinophil suspension were added to the top of the filter.
  • the plate was incubated for 1 hr at 37° C. in a humidified incubator with a 95% air/5% CO 2 atmosphere to allow chemotaxis.
  • the filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells.
  • PBS phosphate buffered saline
  • Cells that had migrated through the filter were pelleted by centrifugation (300 ⁇ g for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar).
  • the pelleted cells were lysed by the addition of 28 ⁇ l of PBS containing 0.5% Triton x100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant.
  • the number of eosinophils migrating was quantified according to the method of Strath et al., J Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.
  • Indomethacin (2.8 ⁇ M) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo-oxygenase products.
  • the tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders.
  • E/[A] histamine concentration effect

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Abstract

The present invention provides a compound of a formula (I):
Figure US20070179297A1-20070802-C00001
 wherein the variables are defined herein; to a process for preparing such a compound; and to the use of such a compound in the treatment of a chemokine (such as CCR3) or H1 mediated disease state.

Description

  • The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Pharmaceutically active piperidine derivatives are disclosed in WO99/38514, WO99/04794 and WO00/35877.
  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rôle in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or α) and Cys-Cys (C-C, or β) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).
  • Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
  • Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, H1, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. H1 antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
  • Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, GreiffL et al Allergy (1999) 54 (11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].)
  • The present invention provides a compound of formula (I):
    Figure US20070179297A1-20070802-C00002
    wherein:
    • q, s and t are, independently, 0 or 1;
    • n and r are, independently, 0, 1, 2, 3, 4 or 5;
    • m and p are, independently, 0, 1 or 2;
    • X is CH2, C(O), O, S, S(O), S(O)2 or NR37; provided that when m and p are both 1 then X is not CH2;
    • Y is NHR2 or OH;
    • T is C(O), C(S), S(O)2 or CH2;
    • R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl;
    • R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl);
    • R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, CR3aR3bR3c, C2-4 alkenyl {optionally substituted by aryl or heterocyclyl}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl, aryl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;
    • R3a is hydrogen, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl; R3b is aryl, heterocyclyl, S(O)2aryl or S(O)2heterocyclyl; and R3c is C1-4 alkyl, C1-4 haloalkyl, hydroxy, heterocyclyl(C1-4 alkyl) or aryl;
    • wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl {itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)}, NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy {itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)}, C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, SCN, CN, SO3H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; dis 0, 1 or 2;
    • R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
    • R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), C3-6 alkenyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
      or an N-oxide thereof; or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that:
    • when m and p are both 1, n, q and r are all 0, T and X are both S(O)2, and R1 is methoxyphenyl then R3 is not propyl; when m, p, q and r are all 1, n is 0, Y is NH2, T is CO and R1X is (CH3)2N then R3 is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R1 is 3-(4-fluorobenzyl)benzimidazol-2-yl then R3 is not 4-fluorophenyl.
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.
  • Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate. Another example of an addition salt is sulphate.
  • The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
  • Alkenyl group are, for example, vinyl or allyl.
  • Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl, cyclopentyl, cyclohexyl, norbomyl or camphoryl. The cycloalkyl ring is optionally fused to a benzene ring (for example forming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).
  • Cycloalkenyl is especially monocyclic and is, for example, cyclopentenyl or cyclohexenyl.
  • Aryl is preferably phenyl or naphthyl.
  • Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, fliryl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2, 1-b]thiazol-2-yl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • In one aspect of the invention heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example, furyl, thienyl, 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, quinoxaline, dihydro-1-benzopyrylium (for example a coumarin or a chromone), piperidine, morpholine, pyrrole, indole, 2,3-dihydroindole, quinoline, thiazole, pyrazole, isoxazole, imidazole, pyridine, benzofuryl, benzimidazole, pyrimidine or dibenzothiophene.
  • In a further aspect heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, pyriridinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1 -benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), quinolinyl, isoquinolinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • An N-oxide of a compound of formula (I) is, for example, a 1-oxy-[1,4′]bipiperidinyl-1′-yl compound.
  • In another aspect the present invention provides a compound of formula (I′):
    Figure US20070179297A1-20070802-C00003
    wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, CO, O, S, S(O), S(O)2 or NR37; provided that when m and p are both 1 then X is not CH2; Y is NHR2or OH; T is CO, CS, SO2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 is hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, SO2R38 or CONR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9COR10, CO2R11, CONR12R13, COR14, SOdR15, SO2NR42R43, NR44SO2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38 and R45 are, independently, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both SO2, and R1 is methoxyphenyl then R3 is not propyl; when m, p, q and r are all 1, n is 0, Y is NH2, T is CO and R1X is (CH3)2N then R3 is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R1 is 3-(4-fluorobenzyl)benzimidazol-2-yl then R3 is not 4-fluorophenyl.
  • In an further aspect the present invention provides a compound of formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, C(O), O, S, S(O), S(O)2 or NR37; provided that when m and p are both 1 then X is not CH2; Y is NHR2 or OH; T is C(O), C(S), S(O)2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)), NR41 C(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl) or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that: when m and p are both 1, n, q and r are all 0, T and X are both S(O)2, and R1 is methoxyphenyl then R3 is not propyl; when m, p, q and rare all 1, n is 0, Y is NH2, T is CO and R1X is (CH3)2N then R3is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or 1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q and r are all 0, T is CO, X is NH and R1 is 3-(4-fluorobenzyl)benzimidazol-2-yl then R3is not 4-fluorophenyl.
  • In another aspect the variables m and p are such that m +p is 0, 1 or 2 (for example 1 or 2).
  • In a further aspect n is 0 or 1.
  • In a still further aspect q and r are both 0.
  • In another aspect n, q and r are all 0.
  • In another aspect m, p and t are all 1.
  • In a further aspect s is 0.
  • In another aspect s is 1. In a further aspect q is 1. In a still further aspect n +r is equal to more than 1 (for example n +r is equal to 2, 3, 4 or 5).
  • In another aspect t +m +p is not equal to 3 (for example t +m +p is equal to 2).
  • In a still further aspect X is O.
  • In another aspect R1 is hydrogen, C1-6 alkyl, optionally substituted (as above) aryl or optionally substituted (as above) monocyclic heterocyclyl. In another aspect R1 is phenyl substituted with one or more of fluorine, chlorine, C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy).
  • In yet another aspect R1 is not phenyl substituted by cycloalkyl.
  • In a further aspect R1 is phenyl optionally substituted (for example with one, two or three) by halo (especially fluoro or chloro), C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy). In a still further aspect R1 is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
  • In another aspect R1 is one of the substituted phenyl groups exemplified in Method F below.
  • In a further aspect T is C(O), S(O)2 or CH2. In a still further aspect T is C(O). In another aspect T is S(O)2 or CH2.
  • In another aspect R3 is aryl or heterocyclyl either of which is optionally substituted as described above.
  • In a further aspect R3 is unsubstituted phenyl, mono-substituted phenyl or mono-substituted heterocyclyl, the substituents being chosen from those described above.
  • In a still further aspect R3 is oxo substituted heterocyclyl, said heterocyclyl optionally further substituted with one or more substituents chosen from those described above.
  • In another aspect R3 is a bicyclic heterocyclyl optionally substituted as described above. Bicyclic heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Bicyclic heterocyclyl is, for example, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for example in 1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in 2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (for example in a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in 2-dioxo-3,4-dihydro-1H-2, 1-benzothiazinyl), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in 3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl or in 1H-[1,8]naphthyridin-4-one-yl) or a benzothiazinyl (for example in 4H-benzo[1,4]thiazin-3-one-yl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • In yet another aspect R3 is: C1-6 alkyl {optionally substituted by CO2R16 or phthalimide}, C3-7 cycloalkyl {optionally substituted by oxo}, phenyl {optionally substituted by: halogen, OH, SH, C1-6 alkyl (itself optionally substituted by naphthyloxy (itself optionally substituted by halo or alkenyl) or NR17C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by CO2R18, NR19R20 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, C1-4 haloalkyl, OCF3, nitro, C3-7 cycloalkyl, NR21R22, NR23C(O)R24, CO2R25, C(O)NR26R27, S(O)2R28, phenyl (itself optionally substituted by NO2 or alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy, or adjacent substituents may join to form a dihydrophenanthrene moiety}, naphthyl {optionally substituted by NR29R30 or OH}, heterocyclyl {optionally substituted by halo, NO2, oxo, C1-6 alkyl (itself optionally substituted by OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or alkyl)), alkoxy, CF3, thioalkyl, C(O)R31, CO2R32, NR33C(O)R34, phenoxy, phenyl or nitrogen containing heterocyclyl;
    • R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 R27 , R29, R30, R31, R32, R33 and R34 are, independently, hydrogen, C1-6 alkyl or phenyl;
    • R28 is C1-6 alkyl; or a pharmaceutically acceptable salt thereof.
  • In another aspect R3 is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2(C1-4 alkyl), S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1 or 2 (preferably 2); and R46 is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl(C1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C1-4 haloalkylthio, C(O)NH2, NHS(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl) or S(O)2N(C1-4 alkyl)2.
  • In one aspect the variable R3 can be benzo[1,2,3]thiadiazolyl, thiophenyl or phenyl; the phenyl and thiophenyl rings being optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2(C1-4 alkyl), S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1 or 2 (preferably 2); and R46 is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl(C1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C1-4 haloalkylthio, C(O)NH2, NHS(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl) or S(O)2N(C1-4 alkyl)2.
  • In another aspect the variable R3 can be benzo[1,2,3]thiadiazolyl or phenyl (optionally substituted by: halo, hydroxy, nitro, cyano, amino, C1-4 alkyl (itself optionally substituted by S(O)2phenyl), C1-4 alkoxy, S(O)kR46 (wherein k is 0, 1or 2; and R46 is C1-4 alkyl or phenyl) or C1-4 haloalkylthio.
  • In a still further aspect the present invention provides a compound of formula (Ia″):
    Figure US20070179297A1-20070802-C00004
    wherein:
    • T is C(O), C(S), S(O)2 or CH2;
    • n is 0, 1, 2, 3, 4 or 5;
    • m and p are, independently, 0, 1 or 2(but are especially both 1);
    • R50 is hydrogen, cyano, S(O)2(C1-4 alkyl), S(O)2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR12′R13′, NR9′C(O)R10, S(O)2R15′, S(O)2NR42R43 or NR44S(O)2R45 group);
    • R5 and R52 are, independently, hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;
    • R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
    • wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
    • R4, R5, R6, R7, R8, R9, R9′, R10, R11, R12, R12′, R13, R13′, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or phenyl;
    • R15, R5′ and R45 are, independently, C1-6 alkyl or phenyl;
      or a pharmaceutically acceptable salt thereof.
  • In a further aspect R50, R51 and R52 are, independently, hydrogen, halogen, (especially fluoro or chloro), C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy).
  • In a still further aspect the present invention provides a compound of formula (Ia):
    Figure US20070179297A1-20070802-C00005
    wherein:
    • T is C(O), C(S), S(O)2 or CH2;
    • n is 0, 1, 2, 3, 4 or 5;
    • m and p are, independently, 0, 1 or 2 (but are especially both 1);
    • R35 is hydrogen, cyano, S(O)2(C1-4 alkyl), S(O)2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR12′R13′, NR9′C(O)R10′, S(O)2R15′, S(O)2NR42R43 or NR44S(O)2R45 group);
    • R36 is hydrogen, halogen or C1-4 alkyl;
    • R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
    • wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
    • R4, R5, R6, R7, R8, R9, R9′, R10, R10′, R11, R12, R12′, R13, R13′, R14, R42, R43 are, independently, hydrogen, C1-6 alkyl or phenyl;
    • R15, R15′ and R45 are, independently, C1-6 alkyl or phenyl;
      or a pharmaceutically acceptable salt thereof.
  • In another aspect the present invention provides a compound of formula (Ia′):
    Figure US20070179297A1-20070802-C00006
    wherein:
    • T is CO, CS, SO2 or CH2;
    • n is 0, 1, 2, 3, 4or 5;
    • m and p are, independently, 0, 1 or 2 (but are especially both 1);
    • R35 is hydrogen, cyano, SO2(C1-4 alkyl), SO2(C1-4 haloalkyl), halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or phenyl (optionally substituted by one or two halogen atoms or by one CONR12′R13′, NR9′COR10′, SO2R15′, SO2NR42R43 or NR44SO2R45 group);
    • R36 is hydrogen, halogen or C1-4 alkyl;
    • R3is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
    • wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9COR10, CO2R11, CONR12R13, COR14, SO2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
    • R4, R5, R6, R7, R8, R9, R9′, R10, R10′, R11, R12, R12′, R13, R13′, R14 , R42, R43 , R44are, independently, hydrogen, C1-6alkyl or phenyl;
    • R15, R15 ′ and R45 are, independently, C1-6alkyl or phenyl;
      or a pharmaceutically acceptable salt thereof.
  • In a further aspect R3 is heterocyclyl (such as thienyl, isoxazolyl or indolyl, or a naphthyridinyl, an imidazopyridinyl or an isoquinolinyl) optionally substituted by oxo, halogen or C1-6 alkyl.
  • In yet another aspect the present invention provides a compound of formula (Ia)
  • wherein:
    • T is C(O), C(S), S(O)2 or CH2;
    • n is 0, 1, 2, 3, 4 or 5;
    • m and p are, independently, 0, 1 or 2;
    • R35 is hydrogen, halogen or phenyl (optionally substituted by one or two halogen atoms or by one C(O)NR12′R13′, NR9C(O)R10′, S(O)2R15′, S(O)2NR42R43 or NR44S(O)2R45 group);
    • R36 is hydrogen or halogen;
    • R3is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, aryl or heterocyclyl;
    • wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo or C1-6 alkyl), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)2R15, phenyl (itself optionally substituted by NO2 or C1-6 alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring a dihydrophenanthrene moiety;
    • R4, R5, R6, R7, R8, R9, R9′, R10, R10′, R11, R12, R12′, R13, R13′, R14, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl;
    • R15, R15′ and R45 are, independently, C1-6 alkyl or aryl;
      or a pharmaceutically acceptable salt thereof.
  • In a further aspect R35 and R36 are, independently, hydrogen, halogen, (especially fluoro or chloro), C1-4 alkyl (especially methyl) or C1-4 alkoxy (especially methoxy). In another aspect R35 and R36 are both chlorine or both fluorine, especially 3,4 disposed on the phenyl ring to which they are attached.
  • In a further aspect the present invention provides a compound of formula (Ib):
    Figure US20070179297A1-20070802-C00007
    wherein T, n and R3 are as defined above.
  • In a still further aspect the present invention provides a compound of formula (Ic):
    Figure US20070179297A1-20070802-C00008
    wherein T, m, p and R3 are as defined above.
  • In another aspect the present invention provides a compound of formula (Id):
    Figure US20070179297A1-20070802-C00009
    wherein R3 is as defined above.
  • In yet another aspect the present invention provides a compound of formula (Ie):
    Figure US20070179297A1-20070802-C00010
    wherein R1, t, s and R3 are as defined above.
  • In a further aspect the present invention provides a compound of formula (If):
    Figure US20070179297A1-20070802-C00011
    wherein R1, n, t, s and R3 are as defined above.
  • In a still further aspect the present invention provides a compound of formula (Ig):
    Figure US20070179297A1-20070802-C00012
    wherein R1, X and R3 are as defined above.
  • A compound of formula (I), wherein s is 0, can be prepared by coupling a compound of formula (II):
    Figure US20070179297A1-20070802-C00013
    with a compound of formula (III):
    Figure US20070179297A1-20070802-C00014
    wherein L is a suitable leaving group, and the variables Y and T are optionally protected during the course of the reaction by standard protecting groups known in the art and deprotected in a separate step or during the reaction work-up. For example:
      • when T is carbonyl, L can be OH and the coupling can be carried out in the presence of a coupling agent (such as bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, (known as PYBROP™), oxalyl chloride, thionyl chloride or N,N′-carbonyl diimidazole, or another coupling agent known to a person skilled in the art); or,
      • when T is sulphonyl, L can be chloro and the coupling can be carrier out in the presence of a suitable base (such as potassium carbonate) in a suitable solvent (such as acetone).
  • A compound of formula (I), wherein s is 1, R47 is hydrogen and T is CO, can be prepared by reacting a compound of formula (II), wherein m and p are both 1, with an aromatic isocyanate of formula with an isocyanate O═C═N—(CH2)n—(CH2)r—R3.
  • A compound of formula (II) can be prepared by deprotecting a compound of formula (IV):
    Figure US20070179297A1-20070802-C00015
    for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane).
  • A compound of formula (IV), wherein X is O , can be prepared by reacting a compound of formula (V):
    Figure US20070179297A1-20070802-C00016
    with a compound of formula (VI):
    Figure US20070179297A1-20070802-C00017
    in the presence of NaBH(OAc)3 and acetic acid.
  • A compound of formula (IV), wherein X is CO or CH2, can be prepared by oxidising or reducing a compound of formula (VII):
    Figure US20070179297A1-20070802-C00018
  • A compound of formula (VII) can be prepared by reacting a compound of formula (VIII):
    Figure US20070179297A1-20070802-C00019
    with a compound of formula (VI) in the presence of NaBH(OAc)3 and acetic acid. A compound of formula (VIII) can be prepared by reduction of a compound of formula (IX):
    Figure US20070179297A1-20070802-C00020
  • A compound of formula (I) wherein X is NR37 can be prepared by reacting a compound of formula (X):
    Figure US20070179297A1-20070802-C00021
    with a compound of formula (XI):
    Figure US20070179297A1-20070802-C00022
    in the presence of NaBH(OAc)3 and acetic acid. A compound of formula (X) can be prepared by reacting NHR1R37 with a compound of formula (XII):
    Figure US20070179297A1-20070802-C00023
    in the presence of NaBH(OAc)3 and acetic acid and then deprotecting the piperidine nitrogen {for example using trifluoroacetic acid in a suitable solvent (such as dichloromethane) or using a source of hydrogen chloride in a suitable solvent (such as dioxane)}.
  • Alternatively, a compound of formula (I), wherein s, n, q and r are all 0 and T is CO, can be prepared by reacting a compound of formula (XIII):
    Figure US20070179297A1-20070802-C00024
    with an acid: R3CO2H. A compound of formula (XIII) can be prepared by deprotecting a compound of formula (XIV):
    Figure US20070179297A1-20070802-C00025
    wherein L* is BOC or a benzyl group. A compound of formula (XIV) can be prepared by performing a fluoride displacement reaction on FR1 in the presence of compound of formula (XV):
    Figure US20070179297A1-20070802-C00026
  • A compound of formula (XV) can be prepared by coupling a compound of formula (XVI) with a compound of formula (XVII):
    Figure US20070179297A1-20070802-C00027
  • Alternatively, a compound of formula (I) wherein s, n, q and r are all 0 and T is CO, can be prepared by performing a fluoride displacement reaction on FR1 in the presence of compound of formula (XVIII):
    Figure US20070179297A1-20070802-C00028
    provided that R47 is not hydrogen.
  • A compound of formula (XVIII) can be prepared by reacting a compound of formula (XIX):
    Figure US20070179297A1-20070802-C00029
    with an appropriate mixed anhydride (such as an anhydride of formula R3C(O)OC(O)(C1-6 alkyl), wherein alkyl is, for example, methyl, ethyl or iso-butyl). A compound of formula (XIX) can be prepared by deprotecting a compound of formula (XV).
  • Alternatively, a compound of formula (I) can be prepared by reductive ammination of a compound of formula (XX):
    Figure US20070179297A1-20070802-C00030
    with an amine of formula (XXI):
    Figure US20070179297A1-20070802-C00031
    under suitable conditions.
  • Further compounds of formula (I) can be prepared by adaptation of: the routes described above, methods described in the art or the Examples recited below.
  • Compounds of formula (V), (VI), (IX), (XI), (XII), (XVI) and (XVII) can be prepared by using or adapting methods described in the art.
  • In another aspect the present invention provides processes for the preparation of compounds of formula (I) (as defined above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (le), (If) and (Ig).
  • The intermediates of formula (II), (IV), (XIII), (XIV) and (XVII) defined herein are novel and these, and processes for their preparation, are provided as further features of the invention.
  • Examples of compounds of formula (Ib) are listed in Table I below.
    TABLE I
    Compound T n R3 M + H
    1 C(O) 0 C6H5 433
    2 C(O) 0 3,4-Cl2—C6H3 501
    3 C(O) 0 2,4-Cl2—C6H3 501
    4 C(O) 0 4-CH3—C6H4 447
    5 C(O) 0 4-CH3O—C6H4 463
    6 C(O) 0 4-CF3—C6H4 501
    7 C(O) 0 4-Cl—C6H4 467
    8 C(O) 0 4-NO2—C6H4 478
    9 C(O) 0 3,5-Cl2—C6H3 501
    10 C(O) 0 2-F-C6H4 451
    11 C(O) 0 4-cyclohexyl-C6H4 515
    12 C(O) 0 4-(n-butoxy)-C6H4 505
    13 C(O) 0 3-NMe2—C6H4 476
    14 C(O) 0 4-(NHC(O)Me)—C6H4 490
    15 C(O) 0 4-NEt2—C6H4 504
    16 C(O) 0 3-CO2Me—C6H4 491
    17 C(O) 0 2-C(O)NH2—C6H4
    18 C(O) 0 4-S(O)2Me—C6H4 511
    19 C(O) 0 2-I—C6H4 559
    20 C(O) 0 3-phenoxy-C6H4 525
    21 C(O) 0 2-Me—C6H4 447
    22 C(O) 0 3-Me—C6H4 447
    23 C(O) 0 3-I—C6H4 559
    24 C(O) 0 3-NH2-6-(NHC6H5)-C6H3 539
    25 C(O) 0 3,5-F2—C6H3 469
    26 C(O) 0 3-NO2-4-(tert-Bu)-C6H3 534
    27 C(O) 0 3-NO2-5-(CO2Me)-C6H3 536
    28 C(O) 0 2-Me-5-NO2—C6H3 492
    29 C(O) 0 3,5-(tert-Bu)2-C6H3 545
    30 C(O) 0 2-NO2-5-Me—C6H3 492
    31 C(O) 0 2-Br-5-MeO—C6H3 541
    32 C(O) 0 3-MeO-4-(CO2Me)-C6H3
    33 C(O) 0 2-(NHC(O)Me)-5-Br—C6H3 568
    34 C(O) 0 2-NO2-5-SCN—C6H3 535
    35 C(O) 0 3-MeO-4-Me—C6H3 477
    36 C(O) 0 4-CN—C6H4 458
    37 C(O) 0 3-CN—C6H4 458
    38 C(O) 0 2-phenoxy-4-Br—C6H3
    39 C(O) 0 2-NH2-5-I—C6H3 574
    40 C(O) 0 4-F-C6H4 451
    41 S(O)2 0 2-CF3O—C6H4 553
    42 S(O)2 0 3-NO2-4-Cl—C6H3 548
    43 S(O)2 0 Camphor-10-yl (alternatively named 7,7- 543
    dimethyl-bicyclo[2.2.1]beptan-2-on-1-yl)
    44 S(O)2 0 n-Pr 435
    45 S(O)2 0 C6Me5 539
    46 S(O)2 0 4-(n-Pr)-C6H4 511
    47 S(O)2 0 Naphth-2-yl 519
    48 S(O)2 0 2,6-Cl2—C6H3 537
    49 S(O)2 0 2,6-F2—C6H3 505
    50 S(O)2 0 4-NO2—C6H4 514
    51 S(O)2 0 3,4-Cl2—C6H3 537
    52 S(O)2 0 2,5-Cl2—C6H3
    53 S(O)2 0 5-(NMe2)-naphth-1-yl 562
    54 S(O)2 0 2,1,3-benzthiadiazol-4-yl 527
    55 S(O)2 0 4-Et-C6H4 497
    56 S(O)2 0 2,5-Cl2-thien-3-yl 543
    57 S(O)2 0 3,4-(MeO)2—C6H3 529
    58 S(O)2 0 3-CF3-6-Cl—C6H3 571
    59 S(O)2 0 5-Cl-thien-2-yl 509
    60 S(O)2 0 4-Cl—C6H4 503
    61 S(O)2 0 4-(iso-Pr)-C6H4 511
    62 S(O)2 0 2-Cl-4-CF3—C6H3 571
    63 S(O)2 0 Benzofuraz-4-yl (other name 2,1,3- 511
    benzoxadiazol-4-yl)
    64 S(O)2 0 3-Me—C6H4 483
    65 S(O)2 0 2,4-F2—C6H3 505
    66 S(O)2 0 2-Me-5-F-C6H3 501
    67 S(O)2 0 4-CF3O—C6H4 553
    68 S(O)2 0 iso-Pr 435
    70 S(O)2 0 4-(CO2H)—C6H4 513
    71 S(O)2 0 chromen-2-one-6-yl 537
    72 S(O)2 0 3,5-Cl2—C6H3 537
    73 S(O)2 0 2,3-Cl2—C6H3 537
    74 S(O)2 1 4-NO2—C6H4
    75 S(O)2 0 3-CF3—C6H4 537
    76 S(O)2 0 4-(tert-Bu)—C6H4 525
    77 S(O)2 0 3-CO2H-4-OH—C6H3 529
    78 S(O)2 0 2-NO2—C6H4 514
    79 S(O)2 0 2-F-C6H4 487
    80 S(O)2 0 3-NO2—C6H4 514
    83 S(O)2 0 Naphth-1-yl 519
    84 S(O)2 0 2-MeO-5-Cl—C6H3 533
    85 S(O)2 0 3-F-C6H4 487
    86 S(O)2 0 3-Cl-4-(NHC(O)Me)—C6H3 560
    87 S(O)2 1 C6H5 483
    88 S(O)2 0 2-NO2-4-MeO—C6H3 544
    89 S(O)2 0 2-Me-5-NO2—C6H3 528
    90 S(O)2 0 3-CO2H—C6H4 513
    91 S(O)2 0 2,4,6-Me3-C6H2 511
    92 S(O)2 0 Me
    93 S(O)2 0 3,4-Cl2—C6H3 537
    94 S(O)2 0 4-MeO—C6H4
    95 S(O)2 0 4-NHC(O)Me—C6H4 526
    96 S(O)2 0 2-CF3—C6H4 537
    97 S(O)2 0 (CH2)2CO2Me 479
    98 S(O)2 0 4-Me—C6H4 483
    99 S(O)2 0 4-CF3—C6H4 537
    100 S(O)2 0 4-CN—C6H4 494
    101 S(O)2 0 3-NO2-4-Me—C6H3 528
    102 S(O)2 0 1H-2-oxo-quinolin-6-yl
    103 S(O)2 0 2-(NHCOMe)-4-methylthiazol-5-yl 547
    104 S(O)2 0 Thien-2-yl 475
    105 S(O)2 0 Quinolin-8-yl
    106 S(O)2 0 2-OH-3,5-Cl2—C6H2 553
    107 S(O)2 0 2-(CO2Me)—C6H4 527
    108 S(O)2 0 2,5-(MeO)2—C6H3 529
    109 S(O)2 0 phenyl 469
    110 S(O)2 0 2-Me-4-NO2—C6H3 528
    111 S(O)2 0 5-(pyridin-2-yl)thien-2-yl 552
    112 S(O)2 0 1,3-Me2-5-Cl-pyrazol-4-yl 521
    113 S(O)2 0 3,5-Me2-isoxazol-4-yl 488
    114 S(O)2 0 2,3,6-Me3-4-MeO—C6H 541
    115 S(O)2 0 1-Me-imidazol-4-yl 473
    116 S(O)2 0 2-MeO-5-Me—C6H3 513
    117 S(O)2 0 5-(isoxazol-3-yl)thien-2-yl 542
    118 S(O)2 0 2-(CO2Me)thien-3-yl 533
    119 S(O)2 0 4-(1,1-dimethylprop-1-yl)-C6H4 539
    120 S(O)2 0 1-(N-phthalimido)-ethyl 566
    121 CH2 0 4-Me—C6H4 433
    122 CH2 0 4-(CO2H)—C6H4 463
    123 CH2 0 2-(CO2H)—C6H4 463
    124 CH2 0 4-(NHC(O)Me)—C6H4 476
    125 CH2 0 3-OH—C6H4 435
    126 CH2 0 4-MeO—C6H4 449
    127 CH2 0 5-Me-fur-2-yl 423
    128 CH2 0 2,5-F2—C6H3 455
    129 CH2 0 5-NO2-fur-2-yl
    130 CH2 0 4-NO2—C6H4
    131 CH2 0 4-iso-Pr-C6H4 461
    132 CH2 0 phenyl 419
    133 CH2 0 2-(SO3 −Na+)—C6H4 498
    134 CH2 0 4-F—C6H4 437
    135 CH2 0 2,6-Cl2—C6H3 487
    136 CH2 0 3,4-Cl2—C6H3 487
    137 CH2 0 2,4-Cl2—C6H3
    138 CH2 0 4-(OCH2CO2H)—C6H4 493
    139 CH2 0 Pyrid-2-yl 420
    140 CH2 0 3-methylthien-2-yl 439
    141 CH2 0 3-Cl—C6H4 453
    142 CH2 0 5-methylthien-2-yl 439
    143 CH2 0 3-OH-4-MeO—C6H3 465
    144 CH2 0 3-NO2-4-OH—C6H3 480
    145 CH2 0 Chromon-3-yl
    146 CH2 0 1,3-Me2-5-Cl-pyrazol-4-yl 471
    147 CH2 0 3,4-F2—C6H3 455
    148 CH2 0 4-Cl-pyrazol-3-yl 443
    149 C(O) 1 4-S(O)2Me—C6H4
    150 CH2 0 2,6-Cl2-pyridin-4-yl
    151 CH2 0 5-(4-NO2—C6H4)-fur-2-yl 530
    152 CH2 0 1-(4-methylbenzyl)-pyrazol-5-yl
    153 CH2 0 Benzfur-2-yl 459
    154 CH2 0 2-phenylimidazol-4-yl 485
    155 CH2 0 5-ethylthien-2-yl 453
    156 CH2 0 2-Cl-quinolin-3-yl 504
    157 CH2 0 6-methylpyridin-2-yl 434
    158 CH2 0 1-acetylindol-3-yl 500
    159 CH2 0 6-formyl-pyridin-2-yl 448
    160 CH2 0 Quinolin-3-yl
    161 CH2 0 5-(CH2OC(O)CH3)-fur-2-yl
    162 CH2 0
    Figure US20070179297A1-20070802-C00032
         		529
    163 CH2 0 Pyridin-4-yl 420
    164 CH2 0 3-OH-4-NO2—C6H3 480
    165 CH2 0 3,5-F2—C6H3 455
    166 CH2 0 3-CF3—C6H3 487
    167 CH2 0 2-F-6-Cl—C6H3 471
    168 CH2 0 2-(tert-butyl)S—C6H4
    169 CH2 0 4-Et-C6H4 447
    170 CH2 0 3-CO2H-4-OH—C6H4 479
    171 CH2 0 3-(OCH2CO2H)—C6H4 493
    172 CH2 0 2,3-methylenedioxyphenyl 463
    173 CH2 0 Thiazol-2-yl 426
    174 CH2 0 5-ethylfur-2-yl 437
    175 CH2 0 Quinolin-2-yl 470
    176 CH2 0 Quinolin-4-yl 470
    177 CH2 0 4-CH2CH(CH3)2—C6H4 475
    178 CH2 0 3-MeO-4-OH-5-CO2H—C6H2 509
    179 CH2 0 4-bromopyrazol-3-yl
    180 CH2 0 2-(OCH2CO2H)-3-MeO—C6H3 523
    181 CH2 0 4-(O(CH2)3N(CH3)2)-C6H4 520
    182 CH2 0 3-bromothien-2-yl 503
    183 CH2 0 3-phenoxythien-2-yl 517
    184 CH2 0 5-methylthio-thien-2-yl 471
    185 CH2 0 1-methyl-4-bromopyrazol-3-yl 501
    186 CH2 0 4-I—C6H4
    187 CH2 0 6,7-Me2-chromon-3-yl
    188 CH2 0 2-(OCH2CO2H)-5-NO2—C6H4 538
    189 CH2 0 2-(2,6-dichlorobenzyloxy)phenyl 593
    190 CH2 0 1-(4-chlorobenzyl)pyrazol-3-yl 533
    191 CH2 0 4-iso-propoxy-C6H4 477
    192 CH2 0 1-methylbenzimidazol-2-yl 473
    193 CH2 0 3-Me—C6H4 433
    194 CH2 0 Pyridin-3-yl 420
    195 CH2 0 2,4-(MeO)2-pyrimidin-5-yl
    196 CH2 0 3-Cl-5-CF3-pyridin-2-yl 522
    197 CH2 0 2,4-Me2—C6H3 447
    198 CH2 0 1-methylindol-3-yl 472
    199 CH2 0 2-methyl-3-(CO2Et)-fur-5-yl
    200 CH2 0 1-Me-4-Cl-pyrazol-3-yl 457
    201 C(O) 2 phenyl 461
    202 C(O) 1 4-Br—C6H4 525
    203 C(O) I 4-NH2—C6H4 462
    204 C(O) 1 2-Br—C6H4 525
    205 C(O) 1 4-F—C6H4 465
    206 C(O) 1 2-CF3—C6H4
    207 C(O) 1 3-Me—C6H4 461
    208 C(O) 1 2-Me—C6H4 461
    209 C(O) 1 3-Cl-4-OH—C6H3 497
    210 C(O) 3 9,10-dihydrophenanthren-2-yl 577
    211 C(O) I 2-NO2—C6H4 492
    212 C(O) 1 2-Cl—C6H4 481
    213 C(O) 1 4-Cl—C6H4 481
    214 C(O) 1 2-benzyloxy-C6H4 553
    215 C(O) 2 3,4-(OH)2—C6H3 493
    216 C(O) 1 4-NO2—C6H4 492
    217 C(O) 4 Phenyl 489
    218 C(O) 1 3,4-(MeO)2—C6H3 507
    219 C(O) 1 4-EtO—C6H4 491
    220 C(O) 1 3-F-4-OH—C6H3 481
    221 C(O) 3 Phenyl 475
    222 C(O) 1 3,4-methylenedioxyphenyl 491
    223 C(O) 3 4-MeO—C6H4 505
    224 C(O) 2 4-OH—C6H4 477
    225 C(O) 1 4-OH—C6H4 463
    226 C(O) 1 4-phenyl-C6H4 523
    227 C(O) 1 3,4-Cl2—C6H3 515
    228 C(O) 2 3-OH—C6H4 477
    229 C(O) 2 4-Me—C6H4 475
    230 C(O) 3 4-NO2—C6H4 520
    231 C(O) 2 3,4-(MeO)2—C6H3 521
    232 C(O) 3 4-Me—C6H4 489
    233 C(O) 2 C6F5 551
    234 C(O) 3 Dibenzothien-4-yl 581
    235 C(O) 1 4-Me—C6H4 461
    236 C(O) 2 4-SH—C6H4
    237 C(O) 1 4-CF3O—C6H4 531
    238 C(O) 1 4-CH2Br—C6H4
    239 C(O) 3 3,4-(MeO)2—C6H3 535
    240 C(O) 1 4-MeO—C6H4 477
    241 C(O) 1 4-(NMe2)—C6H4 490
    242 C(O) 2 4-MeO—C6H4 491
    243 C(O) 2 2-MeO—C6H4 491
    244 C(O) 1 3,4,5-(MeO)3—C6H2 537
    245 C(O) 2 3,4-methylenedioxyphenyl 505
    246 C(O) 2 Dibenzothien-4-yl
    247 C(O) 1 3-NH2—C6H4 462
    248 C(O) 1 Naphth-1-yl 497
    249 C(O) 1 3-MeO-4-OH—C6H3 493
    250 C(O) 1 Naphth-2-yl
    251 C(O) 1 3-(1-allyl-6-bromonaphth-2-yloxy)CH2—C6H4 721
    252 C(O) 1 4-NO2—C6H4
    253 C(O) 1 3-F-4-MeO—C6H3 495
    254 C(O) 4 3-Me—C6H4 503
    255 C(O) 1 3-OH—C6H4 463
    256 C(O) 1 4-benzyloxy-C6H4 553
    257 C(O) 1 4-(3-NO2—C6H4)—C6H4 568
    258 C(O) 1 2,5-(Me)2—C6H3 475
    259 C(O) 1 4-I—C6H4 573
    260 C(O) 1 4-(4-(1-Me-2-OH-4-(pyridin-3-yl)-butoxy)- 702
    C6H4)—C6H4
    261 C(O) 1 3-Br—C6H4 525
    262 C(O) 2 3-(n-Pr)-C6H4 503
    263 C(O) 1 4-(4-NO2—C6H4CH2O)-C6H4 598
    264 C(O) 1 2,5-(OH)2—C6H3
    265 C(O) 1 2-Me-3-NO2—C6H3 506
    266 C(O) 1 4-(CH2NHCO2CH2(fluoren-9-yl))-C6H4
    267 C(O) 1 3-OH-4-MeO—C6H4 493
    268 C(O) 1 3-F—C6H4 465
    269 C(O) 1 2-F—C6H4 465
    270 C(O) 1 3,5-(MeO)2—C6H3 507
    271 C(O) 1 3-Cl—C6H4 481
    272 C(O) 1 Phenyl 447
    273 C(O) 1 3,5-Me2—C6H3 475
    274 C(O) 2 3-MeO—C6H4 491
    275 C(O) 1 2,4-F2—C6H3 483
    276 C(O) 1 2-MeO—C6H4 477
    277 C(O) 1 3,4-F2—C6H3 483
    278 C(O) 1 3,5-F2—C6H3 483
    279 C(O) S phenyl 503
    280 S(O)2 0 5-(pyridin-2-yl)-thien-2-yl
    281 C(O) 0 3-S(O)2Me—C6H4 511
    282 C(O) 0 3-MeO-4-NH2—C6H3
    283 C(O) 0 3-MeO-4-F—C6H3 481
    284 C(O) 0 Benzthiazol-6-yl 490
    285 C(O) 0 3-MeO—C6H4 477
    286 C(O) 0 3-C6H5S(O)-C6H4 557
    287 C(O) 0 4-S(O)2Me—C6H4 511
    288 C(O) 0 2,4-Cl2—C6H3 501
    289 C(O) 0 4-NO2—C6H4 478
    290 C(O) 0 3-CN—C6H4 458
    291 C(O) 0 4-MeO—C6H4 463
    292 C(O) 0 4-CN—C6H4 458
    293 C(O) 0 2-S(O)2Me—C6H4 511
    294 C(O) 0 2-Cl-4-S(O)2Me—C6H3 545
    295 C(O) 0 3-(C6H5S(O)2OH2)-4-NO2—C6H3 632
    296 C(O) 0 2-(C6H5S(O)2OH2)-C6H4
    297 C(O) 0 Benzo[1,2,3]thiadiazol-5-yl 491
    298 C(O) 0 4-EtS—C6H4 493
    299 C(O) 0 3-CF3S—C6H4 533
    300 C(O) 0 4-CF3S—C6H4 533
    301 C(O) 0 3-CH3O(O)NH—C6H4 490
    302 C(O) 0 3-CH3-4-NH2—C6H3 462
    303 C(O) 0 Indol-7-yl 472
    304 C(O) 0 3-CH3CH2O-4-CH3O—C6H3 507
    305 C(O) 0 4-(2,5-dihydropyrrol-1-yl)-C6H4 500
    306 C(O) 1 3-Br-pyridin-5-yl 526
    307 C(O) 1 1-methyl-imidazol-4-yl 451
    308 C(O) 1 5-OH-indol-3-yl 502
    309 C(O) 1 Thiophen-3-yl 453
    310 C(O) 0 3-CH3CH2S(O)2—C6H4 525
    311 C(O) 0 3-CH3(CH2)2S(O)2—C6H4 539
    312 C(O) 0 3-(CH3)2CHCH2S(O)2—C6H4 553
    313 C(O) 0 3,4-(CH3S(O)2)2—C6H3 589
    314 C(O) 0 3-CH3CH2O-4-NH2—C6H3 492
    315 C(O) 1 Pyridin-4-yl 448
    316 C(O) 0 2-CH3S(O)2CH2—C6H4 525
    317 C(O) 0 2-NH2—C6H4 448
    318 C(O) 0 1-acetyl-indol-3-yl
    319 C(O) 0 Indol-3-yl
    320 C(O) 0 3-NH2(CH2)2O—C6H4
    321 C(O) 0 3-CH3NHS(O)2—C6H4
    322 C(O) 0 3-NH2S(O)2—C6H4
    323 C(O) 0 3-CH3O(CH2)2O—C6H4
    324 C(O) 0 3-(CH3)3COC(O)NH(CH2)2O—C6H4
    325 C(O) 0 1,2,3-benzothiadiazol-6-yl
    326 C(O) 0 3-HOC(O)CH2O—C6H4
    327 C(O) 0 2-CH3S(O)2-3-CN-thiophen-5-yl 542
    328 C(O) 0 3-CH3S(O)2-4-NH2—C6H3 526
    329 C(O) 0 2-CH3S(O)2-3-NH2C(O)-thiophen-5-yl 560
    330 C(O) 0 3-CF3O—C6H4 501
    331 C(O) 0 2-(CH3)2CHS(O)2-3-NH2-thiophen-4-yl 560
    332 C(O) 0 2-CH3S(O)2-thiophen-5-yl 517
    333 C(O) 0 3-CH3-5-(4-CH3-1,2,3-thiadiazol-5-yl)- 536
    isoxazol-4-yl
    334 C(O) 0 3-Cl-5-CF3-pyridin-2-yl 536
    335 C(O) 1 4-CF3O—C6H4 531
    336 C(O) 0 1H-benzotriazol-5-yl 474
    337 C(O) 0 4-CH3S(O)2CH2—C6H4 525
    338 C(O) 0 3-CH3S(O)2CH2—C6H4 525
    339 C(O) 0 2-CN—C6H4 458
    340 C(O) 0 Quinolin-6-yl 484
    341 C(O) 0 Quinoxalin-6-yl 485
    342 C(O) 0 3-NH2-4-CH3S(Oh-thiophen-2-yl 532
    343 C(O) 0
    Figure US20070179297A1-20070802-C00033
         		566
    344 C(O) 0
    Figure US20070179297A1-20070802-C00034
    345 C(O) 0 3-CF3O—C6H4 517
    346 C(O) 0 2,5-(CH3O)2—C6H3 493
    347 C(O) 0 1-(CH3)2CH-benzotriazol-5-yl
    348 C(O) 0
    Figure US20070179297A1-20070802-C00035
    349 C(O) 0 3-HO(CH2)2S(O)2—C6H4
    350 C(O) 0 2-HO(CH2)2S(O)2—C6H4
    351 C(O) 0 3-cyclopropylCH2S(O)2—C6H4
    352 C(O) 0 2-CH3S(O)2NH—C6H4 526
    353 C(O) 0 (CF3)(MeO)(C6H5)C 545
    354 C(O) 0 (C6H5)2CH 523
    355 C(O) 0 (4-Cl—C6H4)(CH3)2C 509
    356 C(O) 0 (C6H5)(cyclohexyl)CH 529
    357 C(O) 0 (4-F—C6H4(CH3)CH 479
    358 C(O) 1 3,4-methylenedioxy-C6H4 491
    359 C(O) 0 (C6H5)(cyclopentyl)CH 515
    360 C(O) 0 ((CH3)(CH3CH2)CH)(C6H5)CH 503
    361 C(O) 0 1-phenyl-cyclopentyl 501
    362 C(O) 0 1-(4-Cl—C6H4)cyclopentyl 535
    363 C(O) 0 1-phenyl-cyclopropyl 473
    364 C(O) 0 1-phenyl-cyclohexyl 515
    365 C(O) 0 (C6H5)(cyclohexyl)C(OH) 545
    366 C(O) 0 ((CH3)2CH)(C6H5)CH 489
    367 C(O) 1 pyrid-3-yl 448
    368 C(O) 1 pyrid-2-yl 448
    369 C(O) 1 5-Br-pyrid-3-yl 526
    370 C(O) 1 2,4-(MeO)2—C6H3 507
    371 C(O) 1 4-benzyloxy-phenyl 553
    372 C(O) 1 3-benzyloxy-phenyl 553
    373 C(O) 1
    Figure US20070179297A1-20070802-C00036
         		549
    374 C(O) 0 2-EtO—C6H4 491
    375 C(O) 0
    Figure US20070179297A1-20070802-C00037
         		549
    376 C(O) 1 4-n-butoxyphenyl 519
    377 C(O) 1 indol-1-yl 486
    378 C(O) 1 2-NO2-phenyl 492
    379 C(O) 1 thien-2-yl 453
    380 C(O) 1 3-Cl-4-OH-phenyl 497
    381 C(O) 1 2-Br-phenyl 525
    382 C(O) 1 3-Br-phenyl 525
    383 C(O) 1 3,5-F2-phenyl 483
    384 C(O) 1 3-aminophenyl 462
    385 C(O) 1 3,4-(OH)2-phenyl 479
    386 C(O) 1 2,5-(MeO)2-phenyl 507
    387 C(O) 1 4-Me-phenyl 461
    388 C(O) 0 5-(4-Cl—C6H4)-tetrazol-2-yl 549
    389 C(O) 1 4-MeS(O)2-phenyl 525
    390 C(O) 1 4-F-phenyl 465
    391 C(O) 1 5-Cl-benzo[b]thiophen-3-yl 537
    392 C(O) 1 4-CF3O-phenyl 531
    393 C(O) 1 3-Me-5-Cl-benzo[b]thiophen-2-yl 551
    394 C(O) 1 2-nitrophenyl 492
    395 C(O) 1 4-Cl-5-Me-3-NO2-pyrazol-1-yl 530
    396 C(O) 1 2-CF3-benzimidazol-1-yl 555
    397 C(O) 1 2-EtS-benzimidazol-1-yl 547
    398 C(O) 1 2-Me-4-(thien-2-yl)-thiazol-5-yl 550
    399 C(O) 1 4-Br-3,5-Me2-pyrazol-1-yl 543
    400 C(O) 1 5-Me-3,4-(NO2)2-pyrazol-1-yl 541
    401 C(O) 1 4-(3-methyl-butoxy)-phenyl 533
    402 C(O) 1 2-tert-butylthio-phenyl 535
    403 C(O) 1 4-Cl-3,5-Me2-pyrazol-1-yl 499
    404 C(O) 1
    Figure US20070179297A1-20070802-C00038
         		535
    405 C(O) 1 2,4-(NO2)2-imidazol-1-yl 527
    406 C(O) 1 3,5-Me2-pyrazol-1-yl 465
    407 C(O) 1 4-n-hexyl-phenyl 531
    408 C(O) 0 2-NH2-pyrid-5-yl 449
    409 C(O) 0 Pyrid-2-yl 434
    410 C(O) 0 2-EtS-pyrid-3-yl 494
    411 C(O) 0 2-OH-quinolin-4-yl 500
    412 C(O) 0 2-OH-pyrid-5-yl 450
    413 C(O) 0 2,6-(MeO)2-pyrid-3-yl 494
    414 C(O) 0 2-(imidazol-1-yl)-pyrid-5-yl 500
    415 C(O) 0 2-CO2CH3-pyrid-3-yl 492
    416 C(O) 0 2-Me-pyrid-5-yl 448
    417 C(O) 0 Quinolin-2-yl 484
    418 C(O) 0 6-Me-pyrid-2-yl 448
    419 C(O) 0 2-OH-6-Me-pyrid-3-yl 464
    420 C(O) 0 8-OH-quinolin-2-yl 500
    421 C(O) 1 3-F-phenyl 465
    422 C(O) 0 Imidazo[1,2-a]pyrid-2-yl 473
    423 C(O) 0 2-methyl-[1,8]naphthyridin-3-yl 499
    424 C(O) 0 [1,6]naphthyridin-2-yl 485
    425 C(O) 0 2-methyl-[1,6]naphthyridin-3-yl 499
    426 C(O) 0 1-methyl-1H-pyrid-2-one-5-yl 464
    427 C(O) 0 Quinolin-4-yl 484
    428 C(O) 0 Quinolin-6-yl 484
    429 C(O) 0 3-(CH3(CH2)2S(O)2)-C6H4 539
    430 C(O) 0 5-((pyrid-2-yl)SCH2)fur-2-yl 546
    431 C(O) 0 2-Me-3-OH-quinolin-4-yl 514
    432 C(O) 0 (pyrid-2-yl)CH═CH 460
    433 C(O) 0 (2-EtS-pyrid-5-yl)CH═CH 520
    434 C(O) 0 1-(5-CF3-pyrid-2-yl)-piperidin-4-yl 585
    435 C(O) 0 2,7-Me2-imidazo[1,2-a]pyrid-3-yl 501
    436 C(O) 0 (5-CF3-pyrid-2-yl)SO2CH(CH3) 594
    437 C(O) 1 3-(pyrid-2-yl)pyrazol-1-yl 514
    438 C(O) 0 3-NH2-4-CH3O—C6H3 478
    439 C(O) 0 2,5-(CH3O)2—C6H3 493
    440 C(O) 0 3-F-4-CH3—C6H3 465
    441 C(O) 0 3-phenyl-5-CH3-isoxazol-4-yl 514
    442 C(O) 0 1-phenyl-5-CH3-pyrazol-4-yl 513
    443 C(O) 0 3-CF3O—C6H4 517
    444 C(O) 0 2-CH3O-5-Cl—C6H3 497
    445 C(O) 0 2-CH3-3-F—C6H3 465
    446 C(O) 0 2-(2-phenyl-thiazol-4-yl)phenyl 592
    447 C(O) 0 3,4-methylenedioxyphenyl 477
    448 C(O) 0 5-phenyl-oxazol-4-yl 500
    449 C(O) 0 1H-indazol-3-yl 473
    450 C(O) 0 1-CH3-indol-3-yl 486
    451 C(O) 0 1-iso-propyl-benztriazol-5-yl 516
    452 C(O) 0
    Figure US20070179297A1-20070802-C00039
         		473
    453 C(O) 0 2-CH3-5-F—C6H3 465
    454 C(O) 0 3-CF3O-4-NH2—C6H3 532
    455 C(O) 0 3-CH3-5-CF3-isoxazol-4-yl 506
    456 C(O) 0 (1,2,4-triazol-1-yl)C(CH3)2 466
    457 C(O) 0 2-phenyl-thiazol-4-yl 516
    458 C(O) 0 2-CH3-4-CF3-thiazol-5-yl 522
    459 C(O) 0
    Figure US20070179297A1-20070802-C00040
         		529
    460 C(O) 0
    Figure US20070179297A1-20070802-C00041
         		558
    461 C(O) 0 3-F-4-CF3—C6H3 519
    462 C(O) 0
    Figure US20070179297A1-20070802-C00042
         		501
    463 C(O) 0 2-CH3-benzimidazol-5-yl 487
    464 C(O) 1
    Figure US20070179297A1-20070802-C00043
         		534
    465 C(O) 0 3-iso-propoxy-4-CH3O—C6H3 521
    466 C(O) 0
    Figure US20070179297A1-20070802-C00044
         		519
    467 C(O) 0
    Figure US20070179297A1-20070802-C00045
         		534
    468 C(O) 0 2-CH3O-5-F—C6H3 481
    469 C(O) 0 3-CH3CH2O—C6H4
    470 C(O) 0 2-(C6H5S(O)CH2)—C6H4
    471 C(O) 0 1H-indol-3-yl 472
    472 S(O)2 1 2-NO2—C6H4 528
    473 S(O)2 0 2-CN—C6H4 494
    474 C(O) 0 3-CH3S(O)2—C6H4 511
    475 C(O) 0 3-S(O)2NHCH3—C6H4 526
    476 C(O) 0 Benzo[1,2,3]thiadiazol-6-yl 491
    477 C(O) 0 3-CH3O(CH2)2O—C6H4 507
    478 C(O) 0 3,4-(CH3S(O)2)2—C6H3 589
    479 C(O) 0 3-CH3O—C6H4 463
    480 C(O) 0 3-CN—C6H4 458
    481 C(O) 0 4-F—C6H4 451
    482 C(O) 0 3-CH3O-4-F—C6H3 481
    483 C(O) 0 3H-benzothiazol-2-one-6-yl 506
    484 C(O) 0 2-CH3S(O)2-thien-5-yl 517
    485 C(O) 0 3-CH3-4-NH2—C6H3 462
    486 C(O) 0 Benzothiazol-6-yl 490
    487 C(O) 0 1H-5-CH3S(O)2-indol-2-yl 550
    488 C(O) 0 1H-5-CH3O-indol-2-yl 502
    489 C(O) 0 1H-indol-4-yl 472
    490 C(O) 0 1H-Benzimidazol-5-yl 473
    491 C(O) 0 3,4-methylenedioxyphenyl 477
    492 C(O) 0 1H-5-Cl-indol-2-yl 506
    493 C(O) 0 1H-5-OH-indol-2-yl 488
    494 C(O) 0
    Figure US20070179297A1-20070802-C00046
         		558
    495 C(O) 0 3,4-difluoromethylenedioxyphenyl 513
    496 C(O) 0 2-(pyrazol-1-yl)-pyridin-5-yl 500
    497 C(O) 0 4-CF3-pyridin-3-yl 502
    498 C(O) 0
    Figure US20070179297A1-20070802-C00047
         		576
    499 C(O) 0
    Figure US20070179297A1-20070802-C00048
         		459
    500 C(O) 0 3-n-propoxy-pyridin-2-yl 492
    501 C(O) 1 2-(2,4-F2—C6H3)thiazol-4-yl 566
    502 C(O) 0 1H-indol-2-yl 472
    503 C(O) 1 2-phenyl-5-CH3-thiazol-4-yl 544
    504 C(O) 0 2-S(O)2NH2-4-Cl—C6H3 546
    505 C(O) 0 2-CN—C6H4 458
    506 C(O) 0 1H-indol-7-yl 472
    507 C(O) 0 1H-5-F-indol-2-yl 490
    508 C(O) 0 1H-pyrazol-4-yl 423
    509 C(O) 0 1-CH3-pyrrol-2-yl 436
    511 C(O) 0 3-(pyrrol-1-yl)-4-CN-thien-2-yl 529
    512 C(O) 0 3-CH3O-4-NH2—C6H3 478
    513 C(O)C(O) 0 1H-indol-3-yl 500
    514 C(O) 0 4-(pyrrol-1-yl)phenyl 498
    515 C(O) 0 1-CH3-indol-2-yl 486
    516 C(O) 1 1H-indol-3-yl 486
    517 C(O) 1 1H-5-CH3O-indol-3-yl 516
    518 C(O) 0 2-(pyridin-2-yl)-thien-5-yl 516
    519 C(O) 0 1H-5-F-indol-2-yl 490
    520 C(O) 1 3-CH3-benzo[b]thiophen-2-yl 517
    521 C(O) 1 3,5-(CH3)2-4-NO2-pyrazol-1-yl 510
    522 C(O) 0 2-CF3-[1,6]-naphthyridin-3-yl 553
    523 C(O) 0 2-(1-CH3-5-CF3-pyrazol-3-yl)-thien-5-yl 587
    524 C(O) 0
    Figure US20070179297A1-20070802-C00049
         		638
    525 C(O) 1 3-Cl—C6H4 481
    526 C(O) 1 5-CH3-3-NO2-pyrazol-1-yl 496
    527 C(O) 1 2-CN—C6H4 472
    528 C(O) 0 Quinoxalin-2-yl 485
    529 C(O) 0 Pyrazin-2-yl 435
    530 C(O) 0
    Figure US20070179297A1-20070802-C00050
    531 C(O) 0 1-tert-butyl-3-CH3-pyrazol-5-yl 493
    532 C(O) 0 2-SH-pyridin-3-yl 466
    533 C(O) 0 Quinolin-3-yl 484
    534 C(O) 0
    Figure US20070179297A1-20070802-C00051
         		543
    535 C(O) 0 2-ethoxy-phenyl 477
    536 C(O) 1 4-NO2-imidazol-1-yl 482
    537 C(O) 0 4-CH3O-quinolin-2-yl 514
    538 C(O) 0 2-SCH2CH═CH2-pyridin-3-yl 506
    539 C(O) 0 1-iso-propyl-benztriazol-5-yl 516
    540 C(O) 0 [1,8]-naphthyridin-2-yl 485
    541 C(O) 1 2-CH3-4-phenyl-thiazol-5-yl 544
    542 C(O) 0 1-CH3-indol-2-yl 486
    543 C(O) 0 2-phenoxy-pyridin-5-yl-CH═CH 552
    544 C(O) 1 3,4-Cl2—C6H3 515
    545 C(O) 0 2-S(O)2CH3-3-CN-6-CH3-pyridin-4-yl 551
    546 C(O) 0 3H-Benzothiazol-2-one-6-yl 506
    547 C(O) 0 2-CH3O-pyridin-3-yl 464
    548 C(O) 0 Isoquinolin-1-yl 484
    549 C(O) 1 4-OH—C6H4 463
    550 C(O) 0 Quinolin-8-yl 484
    551 C(O) 0 2-CN—C6H4 458
    552 C(O) 0 2-CF3-[1,8]-naphthyridin-3-yl 553
    553 C(O) 0 2-CO2CH3-pyridin-6-yl 492
    554 C(O) 0 Isoquinolin-3-yl 484
    555 C(O) 0 3-CH2S(O)2CH3—C6H4 525
    556 C(O) 0 2-ethoxy-pyridin-3-yl 478
    557 C(O) 1
    Figure US20070179297A1-20070802-C00052
         		516
    558 C(O) 0 2-CH3O-pyridin-5-yl 464
    559 C(O) 0 Indan-1-one-3-yl 487
    560 C(O) 1 3-NO2-[1,2,4]-triazol-1-yl 483
    561 C(O) 0 1-(CH3)2CH-benzotriazol-5-yl 516
    562 C(O) 1 1H-2-CH3-indol-3-yl 500
    563 C(O) 0 3,5-(CH3)2-isoxazol-4-yl 452
    564 C(O) 0 1,5-(CH3)2-pyrazol-4-yl 451
    565 C(O) 0 Quinoxalin-6-yl 485
    566 C(O) 1 3-NO2-[1,2,4]triazol-1-yl 483
    567 C(O) 0 1H-indol-3-yl-CH═CH 498
    568 C(O) 1 4-(pyridin-2-yl)-pyrimidin-2-yl-S 558
    569 C(O) 0 3-S(O)2NH2—C6H4 512
    570 C(O) 1 1H-5-OH-indol-3-yl 502
    571 C(O) 0 4-CH2S(O)2CH3—C6H4 525
    572 C(O) 0
    Figure US20070179297A1-20070802-C00053
         		500
    573 C(O) 0 Isoxazol-5-yl 424
    574 C(O) 1 1-CH3-4-NO2-pyrazol-5-yl 496
    575 C(O) 0
    Figure US20070179297A1-20070802-C00054
         		645
    576 C(O) 0 3-ethoxy-4-amino-phenyl 492
    577 C(O) 1 1,4-(CH3)2-3-CO2H-pyrrol-2-yl 508
    578 C(O) 0
    Figure US20070179297A1-20070802-C00055
         		473
    579 C(O) 0
    Figure US20070179297A1-20070802-C00056
         		491
    580 C(O) 0 2-OH-quinolin-4-yl 500
    582 C(O) 0 3-amino-phenyl 448
    583 C(O) 0 3-NHS(O)2CH3—C6H4 526
    584 C(O) 0 3-C(CH3)3OC(O)NH(CH2)2O—C6H4 592
    585 C(O) 0 3-HO2CCH2O—C6H4 507
    586 C(O) 0 3-H2N(CH2)2O—C6H4 492
    587 C(O) 0 2-NHS(O)2CH3—C6H4 526
    588 C(O) 0 2-S(O)2CH2cyclopropyl-C6H4 551
    589 C(O) 0 3-S(O)2N(CH3)2—C6H4 540
    590 C(O) 0 3-NO2-5-S(O)2CH3—C6H3 556
    591 C(O) 0 3-NH2-5-S(O)2CH3—C6H3 526
    592 C(O) 0 1-S(O)2CH3-indol-3-yl
    593 C(O) 0 3-CN-5-S(O)2CH3—C6H3 536
    594 C(O) 0 1H-5-S(O)2CH3-indol-3-yl 550
    595 C(O) 0 CH(Phenyl)(CH2piperazin-1-yl) 545
    596 C(O) 1
    Figure US20070179297A1-20070802-C00057
         		518
    597 C(O) 0 3-S(O)2NH2-4-Cl—C6H3 546
    598 C(O) 0
    Figure US20070179297A1-20070802-C00058
         		474
    599 C(O) 0
    Figure US20070179297A1-20070802-C00059
         		487
    600 C(O) 0
    Figure US20070179297A1-20070802-C00060
         		507
    601 C(O) 0
    Figure US20070179297A1-20070802-C00061
         		487
    602 C(O) 0 2-NO2-5-S(O)2CH3—C6H3
    603 C(O) 0 2-NH2-5-S(O)2CH3—C6H3
  • Examples of compounds of formula (Ic) are listed in Table II below.
    TABLE II
    Compound m p T R3
    1 1 1 C(O) 3-MeO-4-NH2—C6H3
    2 0 2 C(O) 3-MeO-4-NH2—C6H3
    3 1 1 S(O)2 5-(pyridin-2-yl)-thien-2-yl
    4 0 1 C(O) 3-MeO-4-NH2—C6H3
    5 1 1 C(O) 3H-benzthiazol-2-one-6-yl
    6 1 1 C(O)
    Figure US20070179297A1-20070802-C00062
    7 1 1 C(O) [1,8]naphthyridin-2-yl
    8 1 1 C(O)
    Figure US20070179297A1-20070802-C00063
  • Examples of compounds of formula (Id) are listed in Table III below.
    TABLE III
    Compound R3
    1 4-F—C6H4
    2 Phenyl
    3 3,4-F2—C6H3
  • Examples of compounds of formula (If) are listed in Table IV below.
    TABLE IV
    (If)
    Figure US20070179297A1-20070802-C00064
    Compound R′ t s n
    1 2-CH3-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    2 3-Cl-4-F—C6H3 1 0 0 3-CH3S(O)2—C6H4
    3 3-F-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C684
    4 3-CH3O-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    5 2-CH3O-4-F—C6H3 1 0 0 3-CH3S(O)2—C6H4
    6 4-CH3O—C6H4 1 0 0 3-CH3S(O)2—C6H4
    7 4-CH3O—C6H4 0 0 0 3-CH3S(O)2—C6H4
    8 4-Cl—C6H4 0 0 0 3-CH3S(O)2—C6H4
    9 3,4-Cl2—C6H3 0 0 0 3-CH3S(O)2—C6H4
    10 4-CN—C6H4 0 0 0 3-CH3S(O)2—C6H4
    11 3,4-F2—C6H3 0 0 0 3-CH3S(O)2—C6H4
    12 4-F—C6H4 0 0 0 3-CH3S(O)2—C6H4
    13 4-CH3C(O)NH—C6H4 1 0 0 3-CH3S(O)2—C6H4
    14 4-CH3—C6H4 1 0 0 3-CH3S(O)2—C6H4
    15 3-CH3-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    16 4-Cl—C6H4 1 0 0 3-CH3S(O)2—C6H4
    17 4-F—C6H4 1 0 0 3-CH3S(O)2—C6H4
    18 2,4-Cl2—C6H3 1 0 0 3-CH3S(O)2—C6H4
    19 2-Cl-4-F—C6H3 1 0 0 3-CH3S(O)2—C6H4
    20 2,4-F2—C6H3 1 0 0 3-CH3S(O)2—C6H4
    21 2-F-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    22 2-CH3-4-F—C6H3 1 0 0 3-CH3S(O)2—C6H4
    23 2-CH3-4-Cl—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    24 3-F-4-Cl—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    25 2-CH3O-4-Cl—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    26 2-CH3O-4-F—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    27 4-CH3O—C6H4 1 0 0 3-CH3O-4-NH2—C6H3
    28 3-Cl-4-F—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    29 4-CH3—C6H4 1 0 0 3-CH3O-4-NH2—C6H3
    30 3-CH3-4-Cl—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    31 4-Cl—C6H4 1 0 0 3-CH3O-4-NH2—C6H3
    32 4-F—C6H4 1 0 0 3-CH3O-4-NH2—C6H3
    33 2,4-Cl2—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    34 2-Cl-4-F—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    35 2,4-F2—C6H3 1 0 0 3-CH,O-4-NH2—C6H3
    36 2-F-4-Cl—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    37 2-CH3-4-F—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    38 2-CH3-4-Cl—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    39 3-F-4-Cl—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    40 2-CH3O-4-Cl—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    41 2-CH3O-4-F—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    42 4-CH3O—C6H4 1 0 0 1,2,3-benzthiadiazol-5-yl
    43 3-Cl-4-F—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    44 4-CH3—C6H4 1 0 0 1,2,3-benzthiadiazol-5-yl
    45 3-Cl-4-CH3—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    46 4-Cl—C6H4 1 0 0 1,2,3-benzthiadiazol-5-yl
    47 4-F—C6H4 1 0 0 1,2,3-benzthiadiazol-5-yl
    48 2,4-Cl2—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    49 2-Cl-4-F—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    50 2,4-F2—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    51 2-F-4-Cl—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    52 2-CH3-4-F—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    53 3,4-Cl2—C6H3 1 1 0 3-CN—C6H4
    54 3,4-Cl2—C6H3 1 1 0 3-CH3S(O)2—C6H4
    55 2-CH3-4-Cl—C6H3 1 0 0 2-CH3S(O)2—C6H4
    56 3-Cl-4-F—C6H3 1 0 0 2-CH3S(O)2—C6H4
    57 3-F-4-Cl—C6H3 1 0 0 2-CH3S(O)2—C6H4
    58 3-CH3O-4-Cl—C6H3 1 0 0 2-CH3S(O)2—C6H4
    59 2-CH3O-4-F—C6H3 1 0 0 2-CH3S(O)2—C6H4
    60 4-CH3O—C6H4 1 0 0 2-CH3S(O)2—C6H4
    61 4-CH3C(O)NH—C6H4 1 0 0 2-CH3S(O)2—C6H4
    62 4-CH3—C6H4 1 0 0 2-CH3S(O)2—C6H4
    63 3-CH3-4-Cl—C6H3 1 0 0 2-CH3S(O)2—C6H4
    64 4-Cl—C6H4 1 0 0 2-CH3S(O)2—C6H4
    65 4-F—C6H4 1 0 0 2-CH3S(O)2—C684
    66 2,4-Cl2—C6H3 1 0 0 2-CH3S(O)2—C6H4
    67 2-Cl-4-F—C6H3 1 0 0 2-CH3S(O)2—C6H4
    68 2,4-F2—C6H3 1 0 0 2-CH3S(O)2—C6H4
    69 2-F-4-Cl—C6H3 1 0 0 2-CH3S(O)2—C6H4
    70 2-CH3-4-F—C6H3 1 0 0 2-CH3S(O)2—C6H4
    71 2-CH3-4-Cl—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    72 3-Cl-4-F—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    73 3-F-4-Cl—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    74 3-CH3O-4-Cl—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    75 2-CH3O-4-F—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    76 4-CH3O—C6H4 1 0 0 2-CH3S(O)2-thiophen-5-yl
    77 4-CH3C(O)NH—C6H4 1 0 0 2-CH3S(O)2-thiophen-5-yl
    78 4-CH3—C6H4 1 0 0 2-CH3S(O)2-thiophen-5-yl
    79 3-CH3-4-Cl—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    80 4-Cl—C6H4 1 0 0 2-CH3S(O)2-thiophen-5-yl
    81 4-F—C6H4 1 0 0 2-CH3S(O)2-thiophen-5-yl
    82 2,4-Cl2—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    83 2-CI-4-F—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    84 2,4-F2—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    85 2-F-4-Cl—C6H3 1 0 0 2-CH3S(O)2thiophen-5-yl
    86 2-CH3-4-F—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    87 3-Cl-4-CH3—C6H3 1 0 0 3-CH3S(O)2—C6H4
    88 3-Cl-4-CH3—C6H3 1 0 0 3-CH3O-4-NH2—C6H3
    89 3-CH3-4-Cl—C6H3 1 0 0 1,2,3-benzthiadiazol-5-yl
    90 3-Cl-4-CH3—C6H3 1 0 0 2-CH3S(O)2—C6H4
    91 3-Cl-4-CH3—C6H3 1 0 0 2-CH3S(O)2-thiophen-5-yl
    92 2-CH3-4-Cl—C6H3 1 0 0 Quinolin-6-yl
    93 2-CH3-4-Cl—C6H3 1 0 0 3-(CH3O(CH2)2O)—C6H4
    94 2-CH3-4-Cl—C6H3 1 0 0 3,4-(CH3S(O)2)2—C6H3
    95 2-CH3-4-Cl—C6H3 1 0 0 3-CH3O—C6H4
    96 2-CH3-4-Cl—C6H3 1 0 0 3-CN—C6H4
    97 2-CH3-4-Cl—C6H3 1 0 0 4-F—C6H4
    98 2-CH3-4-Cl—C6H3 1 0 0 Indol-7-yl
    99 2-CH3-4-Cl—C6H3 1 0 0 5-CH3S(O)2-indol-2-yl
    100 2-CH3-4-Cl—C6H3 1 0 0 Benzimidazol-5-yl
    101 2-CH3-4-Cl—C6H3 1 0 0 3,4-methylenedioxy-C6H3
    102 2-CH3-4-Cl—C6H3 1 0 0 5-F-indol-2-yl
    103 2-CH3-4-Cl—C6H3 1 0 0 5-CF3-thieno[3,2-b]pyridin-6-yl
    104 2-CH3-4-Cl—C6H3 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl
    105 3-CH3-4-Cl—C6H3 1 0 0 Quinolin-6-yl
    106 3-CH3-4-Cl—C6H3 1 0 0 2-CN—C6H4
    107 3-CH3-4-Cl—C6H3 1 0 0 3-(CH,O(CH2)2O)-C6H4
    108 3-CH3-4-Cl—C6H3 1 0 0 3,4-(CH3S(O)2)2—C6H3
    109 3-CH3-4-Cl—C6H3 1 0 0 3-CH3O—C6H4
    110 3-CH3-4-Cl—C6H3 1 0 0 3-CN—C6H4
    111 3-CH3-4-Cl—C6H3 1 0 0 4-F—C6H4
    112 3-CH3-4-Cl—C6H3 1 0 0 5-CH3S(O)2-thien-2-yl
    113 3-CH3-4-Cl—C6H3 1 0 0 Indol-7-yl
    114 3-CH3-4-Cl—C6H3 1 0 0 5-CH3S(O)2-indol-2-yl
    115 3-CH3-4-Cl—C6H3 1 0 0 3-EtO-4-NH2—C6H3
    116 3-CH3-4-Cl—C6H3 1 0 0 5-CH3O-indol-2-yl
    117 3-CH3-4-Cl—C6H3 1 0 0 3,4-methylenedioxy-C6H3
    118 3-CH3-4-Cl—C6H3 1 0 0 5-F-indol-2-yl
    119 3-CH3-4-Cl—C6H3 1 0 0 5-CF3-thieno[3,2-b]pyridin-6-yl
    120 3-CH3-4-Cl—C6H3 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl
    121 2-CH3-4-Cl—C6H3 1 0 0 2-NH2-4-MeO—C6H3
    122 2-CH3-4-Cl—C6H3 1 0 0 Pyrazin-2-yl
    123 2-CH3-4-Cl—C6H3 1 0 0 3-phenyl-5-Me-isoxazol-4-yl
    124 2-CH3-4-Cl—C6H3 1 0 0 3-CF3O—C6H4
    125 2-CH3-4-Cl—C6H3 1 0 0 2-MeO-5-Cl—C6H3
    126 2-CH3-4-Cl—C6H3 1 0 0 2-Me-3-F—C6H3
    127 2-CH3-4-Cl—C6H3 1 0 0 2-EtO—C6H4
    128 2-CH3-4-Cl—C6H3 1 0 0 5-phenyl-oxazol-4-yl
    129 2-CH3-4-Cl—C6H3 1 0 0 5-F-1H-indol-2-yl
    130 2-CH3-4-Cl—C6H3 1 0 0 2H-isoquinolin-1-one-4-yl
    131 2-CH3-4-Cl—C6H3 1 0 0 3H-benzothiazol-2-one-6-yl
    132 2-CH3-4-Cl—C6H3 1 0 0 Bicyclo[4.2.0]octa-1,3,5-trien-7-yl
    133 2-CH3-4-Cl—C6H3 1 0 0 1-iso-propylbenztriazol-5-yl
    134 2-CH3-4-Cl—C6H3 1 0 0 1-phenylcyclopropyl
    135 2-CH3-4-Cl—C6H3 1 0 0 3-NH2S(O)2-4-Cl—C6H3
    136 2-CH3-4-CI—C6H3 1 0 0 3-CF3O-4-NH2—C6H3
    137 2-CH3-4-Cl—C6H3 1 0 0 3-(pyrrol-1-yl)-4-CN-thien-2-yl
    138 2-CH3-4-Cl—C6H3 1 0 0 2-(CH3O(CH2)2O)-5-NH2—C6H3
    139 2-CH3-4-Cl—C6H3 1 0 0 1-(1-CH3-5-CF3-pyrazol-3-yl)-
    thien-5-yl
    140 2-CH3-4-Cl—C6H3 1 0 0 (1,2,4-triazol-1-yl)C(CH3)2
    141 2-CH3-4-Cl—C6H3 1 0 0 2-phenyl-thiazol-4-yl
    142 2-CH3-4-Cl—C6H3 1 0 0 2-CH3-4-CF3-thiazol-5-yl
    143 2-CH3-4-Cl—C6H3 1 0 0 [1,8]-naphthyndin-2-yl
    144 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00065
    145 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00066
    146 2-CH3-4-Cl—C6H3 1 0 0 3-F-4-CF3—C6H3
    147 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00067
    148 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00068
    149 2-CH3-4-Cl—C6H3 1 0 0 2-CH3-benzimidazol-5-yl
    150 2-CH3-4-Cl—C6H3 1 0 1
    Figure US20070179297A1-20070802-C00069
    151 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00070
    152 2-CH3-4-Cl—C6H3 1 0 0 1,5-dimethyl-pyrazol-3-yl
    153 2-CH3-4-Cl—C6H3 1 0 0 2-CH3O-5-F—C6H3
    154 3-CH3-4-Cl—C6H3 1 0 0 3-NH2-4-CH3O—C6H3
    155 3-CH3-4-Cl—C6H3 1 0 0 2,5-(CH3O)2—C6H3
    156 3-CH3-4-Cl—C6H3 1 0 0 3-F-4-CH3—C6H3
    157 3-CH3-4-Cl—C6H3 1 0 0 Pyrazin-2-yl
    158 3-CH3-4-Cl—C6H3 1 0 0 3-phenyl-5-CH3-isoxazol-4-yl
    159 3-CH3-4-Cl—C6H3 1 0 0 1-phenyl-5-CH3-pyrazol-4-yl
    160 3-CH3-4-Cl—C6H3 1 0 0 3-CF3O—C6H4
    161 3-CH3-4-Cl—C6H3 1 0 0 2-CH3O-5-Cl—C6H3
    162 3-CH3-4-Cl—C6H3 1 0 0 2-CH3-3-F—C6H3
    163 3-CH3-4-Cl—C6H3 1 0 0 2-CH3CH2O—C6H4
    164 3-CH3-4-Cl—C6H3 1 0 0 2-(2-phenyl-thiazol-4-yl)-phenyl
    165 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00071
    166 3-CH3-4-Cl—C6H3 1 0 0 3,4-methylenedioxyphenyl
    167 3-CH3-4-Cl—C6H3 1 0 0 5-phenyl-oxazol-4-yl
    168 3-CH3-4-Cl—C6H3 1 0 0 Quinoxalin-2-yl
    169 3-CH3-4-Cl—C6H3 1 0 0 1H-Pyrazol-4-yl
    170 3-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-3-yl
    171 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00072
    172 3-CH3-4-Cl—C6H3 1 0 0 1-iso-propyl-benztriazol-5-yl
    173 3-CH3-4-Cl—C6H3 1 0 0 3-n-propoxy-pyridin-2-yl
    174 3-CH3-4-Cl—C6H3 1 0 0 2-CH3-5-F—C6H3
    175 3-CH3-4-Cl—C6H3 1 0 1 (2-S(O)2NHCH3—C6H4)S
    176 3-CH3-4-Cl—C6H3 1 0 0 3-CH3-5-CF3-isoxazol-4-yl
    177 3-CH3-4-Cl—C6H3 1 0 1 2-(2,4-F2—C6H3)thiazol-4-yl
    178 3-CH3-4-Cl—C6H3 1 0 0 2-(CH3O(CH2)2O)-5-NH2—C6H3
    179 3-CH3-4-Cl—C6H3 1 0 0 2-phenyl-thiazol-4-yl
    180 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00073
    181 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00074
    182 3-CH3-4-Cl—C6H3 1 0 0 3-F-4-CF3—C6H3
    183 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00075
    184 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00076
    185 3-CH3-4-Cl—C6H3 1 0 0 3-iso-propoxy-C6H4
    186 3-CH3-4-Cl—C6H3 1 0 0 2-CH3-benzimidazol-5-yl
    187 3-CH3-4-Cl—C6H3 1 0 1
    Figure US20070179297A1-20070802-C00077
    188 3-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-3-yl
    189 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00078
    190 3-CH3-4-Cl—C6H3 1 0 0 1-tert-butyl-3-CH3-pyrazol-5-yl
    191 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00079
    192 3-CH3-4-Cl—C6H3 1 0 0 2-CH3O-5-F—C6H3
    193 3-CH3-4-Cl—C6H3 1 0 0 3-NH2-4-CH3O—C6H3
    194 3-CH3-4-Cl—C6H3 1 0 0 2,5-(CH3O)2—C6H3
    195 2-CH3-4-Cl—C6H3 1 0 0 2-CN—C6H4
    196 2-CH3-4-Cl—C6H3 1 0 0 2-CH3O-4-F—C6H3
    197 3-CH3-4-Cl—C6H3 1 0 0 1-CH3-pyrrol-2-yl
    198 2-CH3-4-Cl—C6H3 1 0 0 3-S(O)2CH3-4-NH2—C6H3
    199 2-CH3-4-Cl—C6H3 1 0 0 1H-5-F-indol-2-yl
    200 3-CH3-4-Cl—C6H3 1 0 0 1H-5-CH3O-indol-3-yl
    201 2-CH3-4-Cl—C6H3 1 0 0 3-F-4-CH3—C6H3
    202 2-CH3-4-Cl—C6H3 1 0 0 1-phenyl-5-CH3-pyrazol-4-yl
    203 2-CH3-4-Cl—C6H3 1 0 0 2-(2-phenyl-thiazol-4-yl)-phenyl
    204 3-CH3-4-Cl—C6H3 1 0 0 1H-5-F-indol-2-yl
    205 3-CH3-4-Cl—C6H3 1 0 0 3-CF3O-4-NH2—C6H3
    206 3-CH3-4-Cl—C6H3 1 0 0 3-iso-propoxy-4-CH3O—C6H3
    207 2-CH3-4-Cl—C6H3 1 0 0 1H-5-CH3O-indol-2-yl
    208 2-CH3-4-Cl—C6H3 1 0 0 1H-indol-4-yl
    209 2-CH3-4-Cl—C6H3 1 0 0 4-CF3-pyridin-3-yl
    210 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00080
    211 2-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-3-yl
    212 2-CH3-4-Cl—C6H3 1 0 0 3-iso-propoxy-4-CH3O—C6H3
    213 3-CH3-4-Cl—C6H3 1 0 1 1H-indol-3-yl
    214 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00081
    215 2-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-2-yl
    216 3-CH3-4-Cl—C6H3 1 0 0 3-S(O)2NH2-4-Cl—C6H3
    217 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00082
    218 3-CH3-4-Cl—C6H3 1 0 0 3-(pyrrol-1-yl)-3-CN-thien-2-yl
    219 2-CH3-4-Cl—C6H3 1 0 0 4-(pyrrol-1-yl)phenyl
    220 3-CH3-4-Cl—C6H3 1 0 0 1H-indazol-3-yl
    221 2-CH3-4-Cl—C6H3 1 0 0 3-CH3O-NH2—C6H3
    222 2-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-2-yl
    223 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00083
    224 2-CH3-4-Cl—C6H3 1 0 0 4-S(O)2CH3—C6H4
    225 3-CH3-4-Cl—C6H3 1 0 0 2-(1-CH3-S—CF3-pyrazol-3-yl)-
    thien-5-yl
    226 2-CH3-4-Cl—C6H3 1 0 0 2-CH3-5-F—C6H3
    227 2-CH3-4-Cl—C6H3 1 0 0 4-CH2S(O)2CH3—C6H4
    228 2-CH3-4-Cl—C6H3 1 0 0 Quinoxalin-2-yl
    229 2-CH3-4-Cl—C6H3 1 0 0 1H-5-Cl-indol-2-yl
    230 3-CH3-4-Cl—C6H3 1 0 0 3-CH2S(O)2CH3—C6H4
    231 2-CH3-4-Cl—C6H3 1 0 1 2-(2,4-F2—C6H3)thiazol-4-yl
    232 2-CH3-4-Cl—C6H3 1 0 0 3-S(O)2NH2—C6H4
    233 2-CH3-4-Cl—C6H3 1 0 1 1H-indol-3-yl
    234 3-CH3-4-Cl—C6H3 1 0 0 4-S(O)2CH3—C6H4
    235 3-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-2-yl
    236 2-CH3-4-Cl—C6H3 1 0 0 3-CH3-5-CF3-isoxazol-4-yl
    237 3-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-2-yl
    238 4-S(O)2CH3—C6H3 1 0 0 3,4-Cl2—C6H3
    239 2-CH3-4-Cl—C6H3 1 0 0 1-CH3-indol-3-yl
    240 3-CH3-4-Cl—C6H3 1 0 0 [1,8]-naphthyridin-2-yl
    241 2-CH3-4-Cl—C6H3 1 0 0 3-S(O)2CH3—C6H4
    242 3-CH3-4-Cl—C6H3 1 0 0 3-OH—C6H4
    243 3-CH3-4-Cl—C6H3 1 0 0 3H-Benzthiazol-2-one-6-yl
    244 2-CH3-4-Cl—C6H3 1 0 0 3-n-propoxy-pyridin-2-yl
    245 2-CH3-4-Cl—C6H3 1 0 0 3H-Benzthiazol-2-one-6-yl
    246 2-CH3-4-Cl—C6H3 1 0 0 Isoxazol-5-yl
    247 2-CH3-4-Cl—C6H3 1 0 0 2,5-(CH3O)2—C6H3
    248 2-CH3-4-Cl—C6H3 1 0 0 1H-pyrazol-4-yl
    249 3-CH3-4-Cl—C6H3 1 0 0 Benzothiazol-6-yl
    250 2-CH3-4-Cl—C6H3 1 0 0 3,5-(CH3)2-isoxazol-4-yl
    251 3-CH3-4-Cl—C6H3 1 0 0 4-CF3-pyridin-3-yl
    252 3-CH3-4-Cl—C6H3 1 0 0 1H-indol-4-yl
    253 3-CH3-4-Cl—C6H3 1 0 0 1,5-(CH3)2-pyrazol-3-yl
    254 2-CH3-4-Cl—C6H3 1 0 0 1H-indazol-3-yl
    255 3-CH3-4-Cl—C6H3 1 0 0 3-S(O)2NH2—C6H4
    256 2-CH3-4-Cl—C6H3 1 0 1 4-S(O)2CH3—C6H4
    257 2-CH3-4-Cl—C6H3 1 0 0 Benzthiazol-6-yl
    258 2-CH3-4-Cl—C6H3 1 0 0 1H-5-OH-indol-2-yl
    259 2-CH3-4-Cl—C6H3 1 0 0 3-CH2S(O)2CH3—C6H4
    260 2-CH3-4-Cl—C6H3 1 0 0 3,4-methylenedioxyphenyl
    261 2-CH3-4-Cl—C6H3 1 0 0 1-CH3-pyrrol-2-yl
    262 2-CH3-4-Cl—C6H3 1 0 0 3-CH3-4-NH2—C6H3
    263 3-CH3-4-Cl—C6H3 1 0 0 Isoxazol-5-yl
    264 2-CH3-4-Cl—C6H3 1 0 0 3-OH—C6H4
    265 2-CH3-4-Cl—C6H3 1 0 0 1H-5-OH-indol-3-yl
    266 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00084
    267 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00085
    268 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00086
    269 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00087
    270 3-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00088
    271 2-CH3O-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    272 2,6-(CH3)2-4-Cl—C6H2 1 0 0 3-CH3S(O)2—C6H4
    273 2,3-Cl2—C6H3 1 0 0 3-CH3S(O)2—C6H4
    274 2,5-Cl2—C6H3 1 0 0 3-CH3S(O)2—C6H4
    275 2-Cl-4-CH3—C6H3 1 0 0 3-CH3S(O)2—C6H4
    276 2-Cl-5-CH,-C6H3 1 0 0 3-CH3S(O)2—C6H4
    277 2-CH3-4-C(O)CH3— 1 0 0 3-CH3S(O)2—C6H4
    C6H3
    278 2-(morpholin-4-yl)- 1 0 0 3-CH3S(O)2—C6H4
    C6H4
    279 3-CH3CH2-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    280 Naphth-7-yl 1 0 0 3-CH3S(O)2—C6H4
    281 2-tert-butyl-C6H4 1 0 0 3-CH3S(O)2—C6H4
    282 Indan-5-yl 1 0 0 3-CH3S(O)2—C6H4
    283 2-cyclohexyl-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    284 2-C(O)NH2-4-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    285 2-isoxazol-5-yl-4-Cl- 1 0 0 3-CH3S(O)2—C6H4
    C6H3
    286 2-CH3-5-Cl—C6H3 1 0 0 3-CH3S(O)2—C6H4
    287 phenyl 1 0 0 3-CH3S(O)2—C6H4
    288 2,4-Cl2-6-CH3—C6H2 1 0 0 3-CH3S(O)2—C6H4
    289 3-Cl-4-CH3—C6H3 1 0 0 3-CH3S(O)2—C6H4
    290 2-CN-4-CH3—C6H3 1 0 0 3-CH3S(O)2—C6H4
    291 2-CN-4-CF3—C6H3 1 0 0 3-CH3S(O)2C6H4
    292 2-CH3-pyridin-6-yl 1 0 0 3-CH3S(O)2—C6H4
    293 Pyrimidin-2-yl 1 0 0 3-CH3S(O)2—C6H4
    294 2-Cl-4-F—C6H3 1 0 0 2-Cl-4-CH3S(O)2—C6H3
    295 2-CH3-4-Cl—C6H3 1 0 0 2-CH3S(O)2—C6H4
    296 2-CH3-4-Cl—C6H3 1 0 0 2-Cl-4-CH3S(O)2—C6H3
    297 2-CH3-4-Cl—C6H3 1 0 0 3-S(O)2NH2-4-Cl—C6H3
    298 2-CH3-4-Cl—C6H3 1 0 0
    Figure US20070179297A1-20070802-C00089
    299 2,4-Cl2-3-CH3—C6H2 1 0 0 3-S(O)2CH3—C6H4
    300 2-ethyl-4-F—C6H3 1 0 0 3-S(O)2CH3—C6H4
    301 2-CH3-4-Cl—C6H3 1 0 0 1H-5-S(O)2CH3-indol-2-yl
    302 2-CH3-4-Cl—C6H3 1 0 1
    Figure US20070179297A1-20070802-C00090
    303 3-CH3-4-Cl—C6H3 1 0 1
    Figure US20070179297A1-20070802-C00091
    304 2,4-Cl2-3-CH3—C6H2 1 0 0
    Figure US20070179297A1-20070802-C00092
    305 2,4-Cl2-3-CH3—C6H2 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl
    306 2,4-Cl2-3-CH3—C6H2 1 0 0 2-S(O)2CH3-thien-5-yl
    307 2,4-Cl2-3-CH3—C6H2 1 0 0 4-S(O)2CH3—C6H4
    308 5-CF3-pyridin-2-yl 1 0 0 3-S(O)2CH3—C6H4
    309 3,4-Cl2—C6H3 1 1 0 phenyl
    310 3,4-Cl2—C6H3 1 1 0 4-OCH3—C6H4
    311 3,4-Cl2—C6H3 1 1 0 4-F—C6H4
    312 3,4-Cl2—C6H3 1 1 0 3-SCH3—C6H4
    313 3,4-Cl2—C6H3 1 1 1 phenyl
    314 3,4-Cl2—C6H3 1 1 1 4-OCH3—C6H4
    315 3,4-Cl2—C6H3 1 1 1 4-F—C6H4
  • Examples of compounds of formula (Ig) are listed in Table V below.
    TABLE V
    R1 X R3
    1 3,4-Cl2—C6H3 CH2 3-S(O)2CH3—C6H4
    2 3,4-Cl2—C6H3 NH 3-S(O)2CH3—C6H4
    3 3,4-Cl2—C6H3 C(O) 3-S(O)2CH3—C6H4
    4 3,4-Cl2—C6H3 S(O)2 4-S(O)2CH3—C6H4
    5 3,4-Cl2—C6H3 S(O)2 C6H5
  • The compounds of formula (I):
    Figure US20070179297A1-20070802-C00093
    wherein:
    • q, s and t are, independently, 0 or 1;
    • n and r are, independently, 0, 1, 2, 3, 4 or 5;
    • m and p are, independently, 0, 1 or 2;
    • X is CH2, C(O), O, S, S(O), S(O)2 or NR37;
    • Y is NHR2 or OH;
    • T is C(O), C(S), S(O)2 or CH2;
    • R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl;
    • R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl);
    • R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, CR3aR3bR3c, C2-4 alkenyl {optionally substituted by aryl or heterocyclyl}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl, aryl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;
    • R3a is hydrogen, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl; R3b is aryl, heterocyclyl, S(O)2aryl or S(O)2heterocyclyl; and R3c is C1-6 alkyl, C1-4 haloalkyl, hydroxy, heterocyclyl(C1-4 alkyl) or aryl;
    • wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl {itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)}, NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy {itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)}, C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, SCN, CN, SO3H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;
    • d is 0, 1 or 2;
    • R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43, and R44 are, independently, hydrogen, C1-6 alkyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
    • R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl), C3-6 alkenyl, aryl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy);
    • or an N-oxide thereof; or a pharmnaceutically acceptable salt thereof; or a solvate thereof; have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR3) activity, and may be used in the treatment of autoinmmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
  • In one aspect examples of these conditions are:
    • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis)}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneurnonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;
    • (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behqet's disease, Sjogren's syndrome or systemic sclerosis;
    • (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
    • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
    • (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
    • (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
  • In another aspect examples of these conditions are:
    • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;
    • (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
    • (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
    • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
    • (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
    • (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
  • In a further aspect examples of these conditions are:
    • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;
    • (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
    • (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous 5 dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
    • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
    • (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
    • (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
  • The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, are also H1 antagonists and may be used in the treatment of allergic disorders.
  • The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).
  • Thus, in a further aspect the present invention provides a compound of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, which is both a modulator of chemokine receptor (especially CCR3) activity and an H1 antagonist.
  • According to a further feature of the invention there is provided a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
  • According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • According to another feature of the present invention there is provided a method for antagonising H1 in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • The invention also provides a compound of the formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.
  • In another aspect the invention provides the use of a compound of formula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).
  • In a further aspect the present invention provides the use of a compound of the formula (I), wherein: q, s and t are, independently, 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, C(O), O, S, S(O), S(O)2 or NR37; Y is NHR2 or OH; T is C(O), C(S), S(O)2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 and R47 are, independently, hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by oxo, C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)), NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl (itself optionally substituted by halo, C1-6 alky, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 , or 2; R4, R5, R6, R7, R8, R9, 10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38, R45 and R48 are, independently, C1-6 alkyl (optionally substituted by halogen, hydroxy or C3-10 cycloalkyl) or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising H1 in a warm blooded animal, such as man, or both).
  • In another aspect the present invention provides the use of a compound of the formula (I′):
    Figure US20070179297A1-20070802-C00094
    wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1 or 2; X is CH2, CO, O, S, S(O), S(O)2 or NR37; Y is NHR2 or OH; T is CO, CS, SO2 or CH2; R1 is hydrogen, C1-6 alkyl, aryl or heterocyclyl; R2 is hydrogen, C1-6 alkyl, aryl(C1-4)alkyl or CO(C1-6 alkyl); R3 is C1-6 alkyl {optionally substituted by halogen, CO2R4 or phthalimide}, C3-7 cycloalkyl {optionally substituted by C1-4 alkyl or oxo}, C3-7 cycloalkenyl {optionally substituted by C1-6 alkyl or aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl (itself optionally substituted by halogen, OC(O)C1-6 alkyl, phenyl (itself optionally substituted by halo (such as one or two chlorine or fluorine atoms), C1-6 alkyl, SO2R38 or CONR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl) or NR4C(O)OCH2(fluoren-9-yl)), NR41 C(O)OCH2(fluoren-9-yl), C1-6 alkoxy (itself optionally substituted by halogen, CO2R4, NR5R6 or phenyl (itself optionally substituted by halogen or NO2)), C1-6 alkylthio, nitro, C3-7 cycloalkyl, NR7R8 , NR9COR10, CO2R11, CONR12R13, COR14, SOdR15, SO2NR42R43, NR44SO2R45, phenyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 or C1-6 alkoxy (itself optionally substituted by halo, OH or pyridinyl)), heterocyclyl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), phenoxy (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy), SCN, CN, SO3H (or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2; R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R37, R39, R40, R41, R42, R43 and R44 are, independently, hydrogen, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); R15, R38 and R45 are, independently, C1-6 alkyl or aryl (itself optionally substituted by halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy); or a pharmaceutically acceptable salt thereof; or a solvate thereof; in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) in a warm blooded animal, such as man).
  • The invention further provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
    • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farner's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;
    • (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
    • (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
    • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema);
    • (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
    • (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle;
      in a warm blooded animal, such as man.
  • In a further aspect a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}.
  • In a still further aspect a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.
  • The invention also provides the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection).
  • The present invention also provides a the use of a compound of formula (I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
  • The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) or an H1 mediated disease state (such as an allergic disorder) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • The present invention also provides a method of treating a sign and/or symptom of a cold (for example a sign and/or symptom of common cold or influenza or other associated respiratory virus infection) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising H1, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
  • In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg−1 to 100 mgkg−1 of the compound, preferably in the range of 0.1 mgkg−1 to 20 mgkg−1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically-acceptable salt thereof (hereafter Compound X), for therapeutic or prophylactic use in humans:
    (a)
    Tablet I mg/tablet
    Compound X 100
    Lactose Ph.Eur. 179
    Croscarmellose sodium 12.0
    Polyvinylpyrrolidone 6
    Magnesium stearate 3.0
  • (b)
    Tablet II mg/tablet
    Compound X 50
    Lactose Ph.Eur. 229
    Croscarmellose sodium 12.0
    Polyvinylpyrrolidone 6
    Magnesium stearate 3.0
  • (c)
    Tablet III mg/tablet
    Compound X 1.0
    Lactose Ph.Eur. 92
    Croscarmellose sodium 4.0
    Polyvinylpyrrolidone 2.0
    Magnesium stearate 1.0
  • (d)
    Capsule mg/capsule
    Compound X 10
    Lactose Ph.Eur. 389
    Croscarmellose sodium 100
    Magnesium stearate 1.0
  • (e)
    Injection I (50 mg/ml)
    Compound X 5.0% w/v
    Isotonic aqueous solution to 100%
  • Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β-cyclodextrin may be used to aid formulation.
  • The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
    • (i) when given, 1H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6 (CD3SOCD3) or CDCl3 as the solvent unless otherwise stated;
    • (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (EI) or fast atom bombardment (FAB); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion—(M+H)+;
    • (iii) the title and sub-titled compounds of the examples and methods were named using the AUTONOM program from Beilstein informations system GmbH;
    • (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, NovaPak or Ex-Terra reverse phase silica column; and
  • (v) the following abbreviations are used:
    RPHPLC reverse phase HPLC THF tetrahydrofuran
    RT room temperature DCM dichloromethane
    DEAD diethyl-azodicarboxylate TFA trifluoroacetic acid
    NMP N-methylpyrrolidone m.pt. melting point
    CDI N,N′-carbonyl diimidazole DMSO dimethylsulfoxide
    MTBE tert-butyl methyl ether Ac Acetate
    DMF N,N-dimethylformamide aq aqueous
    Boc or BOC tert-butoxycarbonyl IPA iso-propyl alcohol
    HPLC high pressure liquid equiv. equivalents
    chromatography
    PYBROP ™ bromo-tris-pyrrolidino-
    phosphonium
    hexafluorophosphate
    • EXAMPLE 1
  • This Example illustrates the preparation of 4-(3,4-dichlorophenoxy)piperidine.
    • Step a: tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate
  • Diethyl azodicarboxylate (41.0 ml) was added to a solution of triphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After 15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15 minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) in tetrahydrofuran (400 ml) was added dropwise over 30 min. The solution was stirred at room temperature for 16 hours and concentrated to a small volume. Purification by chromatography (ethyl acetate:iso-hexane 95:5) gave the sub-title compound as an oil (61.3 g).
  • MS: APCI(+ve): 246 (M-BOC+2H)
    • Step b: 4-(3,4-Dichlorophenoxy)piperidine
  • The product from Step a was dissolved in dichloromethane (600 ml) and trifluoroacetic acid (300 ml) was added. After 24 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (36.6 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the title compound as a gum (25 g).
  • 1H NMR: δ(CDCl3) 1.77 (1H, br s), 2.05-2.26 (4H, m), 3.20-3.49 (4H, m), 4.61 (1H, s), 6.69-7.52 (3H, m).
    • EXAMPLE 2
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate (acetate salt of Compound 281 in Table 1).
    • Step a: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • 4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in 1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g) followed by NaBH(OAc)3 (1.81 g) and acetic acid (0.37 g). After 18 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO4 and concentrated. Purification by silica chromatography (dichloromethane:methanol 92:8) gave the sub-title product (1.97 g).
  • MS: APCI(+ve): 429 (M+H)
    • Step b: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine
  • The product of Step a was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (15 ml) was added. After 4 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the trifluoroacetate salt of the sub-titled product as a solid (1.15 g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the sub-title compound as a solid (0.68 g).
  • 1H NMR: δ(CDCl3) 1.38-1.51 (2H, m), 1.74-2.02 (6H, m), 2.38-2.50 (3H, m), 2.56-2.61 (2H, m), 2.79-2.86 (2H, m), 3.14-3.18 (2H , m), 4.22-4.28 (1H, m), 6.73-7.32 (3H, m).
    • Step c: [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone acetate
  • The product of Step b (0.15 g) was dissolved in THF (4 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.235 g), 3-methylsulphonylbenzoic acid (0.091 g) and N,N-di-iso-propylethylamine (0.238 ml) were added. After 18 hours at room temperature ethyl acetate and aqueous NaHCO3 solution were added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na2SO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)) gave the title compound (0.095 g).
  • 1H NMR: δ(DMSO-D6) 1.44-1.94 (8H, m), 2.37-2.77 (5H, m), 3.07-3.55 (6H, m), 4.40 (1H, m), 4.50-4.53 (1H, m), 6.96-8.02 (7H, m).
  • Melting point: 60-61° C. becomes a gum.
  • Melting point of free base: 154° C.
    • EXAMPLE 3
  • This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone acetate (Compound 282 of Table I).
  • The compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.016 g).
  • 1H NMR: δ(DMSO-D6) 1.32-2.01 (8H, m), 2.28-2.88 (5H, m), 3.32 (4H, br s), 3.77 (3H , s), 4.13 (2H, br s), 4.39-4.44 (1H, m), 6.59-7.50 (6H, m).
  • Melting point: 171° C. becomes a gum.
    • EXAMPLE 4
  • This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone (Compound 4 of Table II).
    • Step a: tert-Butyl 4-(3,4-difluorophenoxy)-1-piperidinecarboxylate
  • This compound was prepared according to the method of Example 1 Step a using 3,4-difluorophenol to afford the compound as an oil (5.4 g).
  • MS: ESI(+ve): 213 (M-BOC+H)
    • Step b: 4-(3,4-Difluorophenoxy)piperidine
  • This compound was prepared according to the method of Example 1 Step b to afford the compound as a pale yellow oil (3 g).
  • MS: ESI(+ve): 214 (+H)
    • Step c: 3-[4-(3,4-Difluoro-phenoxy)piperidin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester
  • The product of Step b (0.5 g) was dissolved in 1,2-dichloroethane (7 ml). tert-Butyl 3-oxo-1-pyrrolidinecarboxylate (0.43 g) was added followed by NaBH(OAc)3 (0.7 g) and acetic acid (0.08 g). After 24 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO4 and concentrated. Purification by silica chromatography (100% ethyl acetate) gave the sub-title product (0.79 g).
  • MS: ESI(+ve): 383 (M+H)
    • Step d: 3,4-Difluorophenyl 1-(3-pyrrolidinyl)-4-piperidinyl ether
  • The product of Step c was dissolved in dioxane (10 ml) and HCl (6N) (10 ml) was added and the reaction stirred for 3 hrs. Organic solvent was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na2SO4 and concentrated to give the sub-title product as an oil (0.54 g).
  • 1H NMR: δ(CDCl3) 1.60-2.39 (9H, m), 2.70-3.13 (6H, m), 4.19-4.22 (1H, m), 6.58-7.52 (3H, m).
    • Step e: (4-Amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone
  • This compound was prepared by the method of Example 2 Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a solid (0.151 g).
  • 1H NMR: δ(CDCl3) 1.95-2.43 (5H, m), 2.69-2.81 (3H, m), 3.42-3.91 (10H, m), 4.19-4.23 (1H, m), 6.56-7.25 (6H, m).
  • Melting point: 138-139° C.
    • EXAMPLE 5
  • This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (Compound 1 in Table II).
    • Step a: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • This compound was prepared by the method of Example 2, Step a using 4-(3,4-difluorophenoxy)piperidine to give the sub-title compound as a solid (0.48 g).
  • MS: APCI(+ve): 397 (M+H)
    • Step b: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl
  • This compound was prepared by the method of Example 2, Step b to give the sub-title compound as a solid (0.36 g).
  • MS: APCI(+ve): 297 (M+H)
    • Step c: (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone
  • This compound was prepared by the method of Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.133 g).
  • 1H NMR: δ(CDCl3) 1.50-1.60 (2H, m), 1.85-1.93 (4H, m), 2.04-2.08 (2H, m), 2.58-2.62 (2H, m), 2.69-2.75 (1H, m), 2.86-2.90 (4H, m), 3.86 (3H, s), 3.86 (2H, m), 4.25-4.30 (1H, m), 6.50-6.61 (1H, m), 6.65 (1H, dd), 6.70-6.75 (1H. m), 6.85 (1H, dt), 6.94 (1H, s), 7.01-7.09 (1H, m).
    • EXAMPLE 6
  • This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone (Compound 2 in Table II).
    • Step a: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • This compound was prepared by the method of Example 2, Step a using 3-oxo-piperidine-1-carboxylic acid tert-butyl ester to give the sub-title compound as a solid (0.946 g).
  • MS: APCI(+ve): 397 (M+H)
    • Step b: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl
  • This compound was prepared by the method of Example 2, Step b to give the sub-title compound as a solid (0.706).
  • MS: ESI(+ve): 297 (M+H)
    • Step c: (4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone
  • This compound was prepared by the same method as Example 2, Step c using 4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.070 g).
  • 1H NMR: δ(CDCl3) 1.41-1.67 (4H, m), 1.73-1.80 (2H, m), 1.86-2.00 (2H, m), 2.44 (3H, m), 3.00-3.13 (2H, m), 2.79-2.91 (2H, m), 3.82 (3H, s), 3.97-4.01 (1H, d), 4.14-4.17 (1H, d), 4.32 (1H, sept), 4.89 (2H, s), 6.67 (1H, d), 6.75-6.79 (1H, m), 6.80 (1H, dd), 6.87 (1H, s), 6.98-7.06 (1H, m), 7.27 (1H, q).
    • EXAMPLE 7
  • This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl (Compound 280 in Table I).
  • The product of Example 2, Step b (0.2 g) was dissolved in acetone (4 ml). Potassium carbonate [0.134 g dissolved in H2O (1.2 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.168 g) and the reaction left to stir for 1 hr. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried with Na2SO4 and concentrated. Purification reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4O Acaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)) gave the title compound as a solid (0.077 g).
  • 1H NMR: δ(DMSO-D6) 1.45-1.58 (4H, m), 1.79-1.90 (4H, m), 2.28-2.46 (5H, m), 2.66-2.73 (2H, m), 3.67-3.71 (2H, m), 4.35-4.43 (1H, m), 6.93-8.60 (9H, m).
  • Melting point: 139-140° C.
    • EXAMPLE 8
  • This Example illustrates the preparation of 4-(3,4-difluoro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl (Compound 3 in Table II).
  • This compound was prepared by the method of Example 7 using product of Example 5, step b to give the title compound as a solid (0.095 g).
  • 1H NMR: δ(CDCl3) 1.67-1.80 (4H, m), 1.87-2.01 (1H, t), 2.30 (1H, t), 2.39-2.50 (2H, m), 2.74-2.78 (2H, m), 3.89 (2H, d), 4.16-4.20 (1H, m), 6.56-6.60 (1H, m), 6.67-6.63 (1H, m), 7.03 (1H, q), 7.26 (1H, t), 7.52 (1H, d), 7.53 (1H, d), 7.70(1H, d), 7.76 (1H, dt), 8.60 (1H, d).
  • Melting point: 128-129° C.
    • EXAMPLE 9
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone (Compound 293 Table I).
    • Step 1: Preparation of 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • To 1-tert-butoxycarbonyl-4-piperidone (200 g, 1.01 mol) in tetrahydrofuran (THF) (1500 ml) was added 4-hydroxypiperidine (78.1 g, 0.77 mol). The resultant slurry was stirred for 30 minutes before cooling the reaction mixture with ice/water, acetic acid (47 ml) is then added (exotherm) which caused precipitation. The slurry was allowed to warm to room temperature before the addition of sodium triacetoxyborohydride (236 g, 1.12 mol) which was washed in with THF (500 ml). The resultant slurry was stirred overnight at room temperature. To the reaction mixture was added water (2000 ml) to give a solution. The solution was then extracted with diethyl ether (3×1800 ml). The aqueous phase was basified with 10% aq NaOH (950 ml) and extracted with dichloromethane (DCM) (3×1500 ml). The combined DCM layers are dried (MgSO4), filtered and the solvent removed to give the sub-titled compound as a yellow viscous oil, (177 g, 81%; MS: (M+H) 285).
    • Step 2: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • To a solution of potassium tert-butoxide (139.0 g, 1.24 mol) in THF (500 ml) was added a solution of the product of Step 1 (176.2 g, 0.62 mol) in THF (1000 ml). The reaction mixture was stirred 10 minutes before the additon of 3,4 dichlorofluorobenzene (122.8 g, 0.74 mol), this caused a green colouration that subsequently faded. The reaction mixture was then heated at reflux for 90 minutes. The reaction mixture was then cooled to room temperature before the addition of saturated NaHCO3 (1600 ml). The layers were separated and the organic layer stripped to leave an orange semi-solid. The solid was dissolved in DCM (1500 ml) and dried (MgSO4), filtered and the solvent removed. To the resultant solid was added methyl tert-butyl ether (MTBE) (54 ml) and iso-hexane (1000 ml) to give a slurry which was stirred overnight. The slurry was then filtered and washed with isohexane (200 ml) and the solid dried in vacuo at 50° C. to give the sub-titled compound as a pale powder, (211.6 g, 80%; MS: (M+H) 429).
    • Step 3: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidine
  • The product of Step 2 (10.15 g, 23.6 mmol) was dissolved in dichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol) added and the resultant solution stirred. After 90 minutes the dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resultant oil was partitioned between ethyl acetate (100 ml) and 2M aq NaOH (100 ml). The layers were separated and the organics extracted with 10% aq citric acid (100 ml). The layers were separated and the aqueous basified with 2M aq NaOH and extracted with ethyl acetate (200 ml). The organics were dried (MgSO4), filtered and the solvent removed to give the sub-titled product as a pale oil which solidified on standing (4.62 g, 59%; MS: (M+H) 329).
    • Step 4: Preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone
  • Oxalyl chloride (55 ml, 0.63 mol) was added dropwise over 10 minutes to a stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) in DCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for 2 hours at room temperature. The solution was then evaporated to give a solid that was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (275 ml ) and was added over 10 minutes to a stirred solution of the product of Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) in dichloromethane (125 ml). The resultant solution was stirred at room temperature for 16 hours. The solution was then washed with water (500 ml), 1M aq NaOH (500 ml) and water (2×500 ml). The organic phase was dried (MgSO4), filterered and the solvent removed to give a pale yellow foam. The foam was triturated with diethyl ether to give the title compound (12.96 g, 76%).
  • Melting point 141° C.
  • 1H NMR: (400 MHz, CDCl3) δ 1.39-1.63 (1H, m), 1.72-2.04 (6H, m), 2.42-2.68 (2H, m), 2.73-2.92 (3H, m), 3.00-3.08 (1H, m), 3.23 (1H, s), 3.28 (2H, s), 3.34-3.40 (1H, m), 3.46-3.52 (1H, m), 4.21-4.30 (1H, m), 4.62-4.68 (1H, m), 4.80-4.86 (1H, m), 6.72-6.76 (1H, m), 6.97-7.00 (1H, m), 7.28-7.32 (1H, m), 7.32-7.37 (1H, m), 7.56-7.61 (1H, m), 7.64-7.70 (1H, m), 8.05-8.10 (1H, m).
    • EXAMPLE 10
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone (Compound 281 Table I).
  • Oxalyl chloride (30 mls, 0.35 mol) was added dropwise over 10 minutes to a stirred suspension of 3-methanesulfonyl-benzoic acid (6 g, 0.03) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 4 hours at room temperature. The solution was then evaporated under high vacuum to give a solid which was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (100 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (9.3 g, 0.028 mol) and triethylamine (8.4 ml, 0.06 mol) in dichloromethane (100 ml). The resultant solution was stirred at room temperature for 3 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) and water (2×100 ml). The organic phase was dried (MgSO4), filterered and the solvent removed to give a pale yellow foam. The foam was dissolved in methanol (100 ml) and allowed to crystallise. The crystals were filtered, washed with methanol and then dried to give the title compound (12.2 g, 84%).
  • Melting point 157° C.
  • 1H NMR: (400 MHz, CDCl3) δ 1.40-1.65 (2H, m), 1.75-1.85 (3H, m), 1.93-2.03 (3H, m), 2.42-2.51 (2H, m), 2.58 (1H, tt), 2.74-2.91 (3H, m), 3.00-3.14 (1H, m), 3.07 (3H, s), 3.62-3.76 (1H, m), 4.27 (1H, septet), 4.69-4.80 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.31 (1H, d), 7.64 (1H, t), 7.69 (1H, dt), 7.97-7.98 (1H, m), 8.00 (1H, dt).
  • The hydrochloride salt (melting point 159° C.) was prepared by evaporation to dryness of a clear solution of Compound 281 of Table I and HCl in ethanol.
    • EXAMPLE 11
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-thiophen-5-yl)-methanone (Compound 332 of Table I).
  • Oxalyl chloride (32 ml, 0.37 mol) was added dropwise over 10 minutes to a stirred suspension of 5-(methylsulfonyl)-2-thiophenecarboxylic acid (6.64 g, 0.032) in DCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for 2 hours at room temperature. The solution was then removed to give a solid which was redissolved in dichloromethane and the solvent again removed to give a yellow solid. The solid acid chloride was dissolved in DCM (150 ml) and was added over 10 minutes to a stirred solution of the product of step 3 of Example 9 (10 g, 0.03 mol) and triethylamine (9 ml, 0.065 mol) in dichloromethane (300 ml). The resultant solution was stirred at room temperature for 2 hours. The solution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) and water (300 ml). The organic phase was dried (MgSO4), filterered and the solvent removed to give an orange foam. The solid was dissolved in dichloromethane (200 ml) and purified by chromatography using ethyl acetate and then acetone as the eluant. The purified material was precipitated from acetone by the addition of iso-hexane. The crystals were filtered, washed with isohexane and then dried to give the title compound (11.5 g, 74%).
  • Melting point: 153-154° C.
  • 1H NMR (399.98 MHz, DMSO-D6) δ 1.42-1.48 (2H, m), 1.56-1.62 (2H, m), 1.77-1.84 (2H, m), 1.90-1.96 (2H, m), 2.37-2.43 (2H, m), 2.56-2.63 (2H, m), 2.75-2.80 (2H, m), 2.89-3.14 (2H, m), 3.29-3.32 (1H, m), 3.41 (3H, s), 4.41-4.45 (1H, m), 6.98 (1H, dd), 7.25 (1H, d), 7.49 (2H, q), 7.77 (1H, d).
    • EXAMPLE 12
  • This Example illustrates the preparation of [4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone (Compound 1 of Table IV)
  • A solution of 4-(2-methyl-4-chloro-phenoxy)-piperidine (0.87 mmol) and 1-(3-methanesulfonyl-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml) and glacial acetic acid (1 mmol) was stirred at room temperature for 1 hour after which sodium triacetoxy borohydride (2 mmol) was added. The resulting mixture was stirred at RT for 24 hours, evaporated on to silica (2 g) and placed on to a Mega Bond elut cartridge (10 g Silica). The product was eluted with DCM/MeOH mixtures and further purified by Reverse Phase preparative chromatography, MeOH/aqueous TFA gradient on a Symmetry column. The free base was isolated by dissolving in EtOAc and washing with sodium bicarbonate solution, drying the organic layer with MgSO4 and evaporation left the product as a white solid (0.047 g; M.pt. 83-84° C.).
  • 1H NMR (300 MHz, DMSO-D6) δ 1.2-2.8 (bm, 14H), 2.15 (s, 3H), 3.1 (bm, 1H), 3.25 (s, 3H), 3.5 (bm, 1H), 4.4 (bm, 1H), 4.5 (bm, 1H), 7.0 (d, 1H), 7.12 (m, 1H), 7.2 (d, 1H), 7.7 (m, 2H), 7.9 (s, 1H), 8.0 (dd, 1H).
    • EXAMPLE 13
  • This Example illustrates the preparation of (4-amino-3-methoxy-phenyl)-[4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone ditrifluoroacetate (Compound 23 of Table IV).
  • A solution of the 4-(4-chloro-2-methyl-phenoxy)-piperidine (0.87 mmol) and 1-(4-nitro-3-methoxy-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml) and glacial acetic acid (1 mmol) was stirred at RT for 1 hour after which sodium triacetoxy borohydride (2 mmol) was added. The resulting mixture was stirred at RT for 24 hours, evaporated on to silica (2 g) and placed on to a Mega Bond elut cartridge (10 g Si). The product was eluted with DCM/MeOH mixtures and further purified by SCX, eluting the product with 10% aq NH3 in MeOH. The nitro compound was dissolved in THF (10 ml) and hydrogenated over 10% Pd on C at 3 atmospheres in Peteric apparatus. The mixture was filtered and the filtrate evaporated, the residue was then purified by RPHPLC, using a Symmetry column and eluting with MeOH/aqueous TFA mixtures. The product was isolated as the trifluoroacetate by evaporation of the appropriate HPLC fractions (0.046 g; m.pt. 84-85° C.).
  • 1H NMR (400 MHz, DMSO-D6) δ 1.4-2.4 (m, 13H), 2.9 (m, 2H), 3.15 (m, 2H), 3.4 (m, 1H), 3.55 (m, 2H), 3.8 (s, 3H), 4.2 (bs, 2H), 4.55 and 4.8 (2 bm, 1H), 6.68 (d, 1H), 6.82 (d, 1H), 6.85 (s, 1H), 7.0-7.22 (m, 2H), 7.25 (s, 1H), 9.5 (bm, 1H).
    • EXAMPLE 14
  • This Example illustrates the preparation of 2-[1′-(3-methanesulfonyl-benzoyl)-[1,4′]bipiperidinyl-4-yloxy]-5-trifluoromethyl-benzonitrile trifluoroacetate (Compound 291 of Table IV).
  • The product of Method E (183 mg, 0.5 mmol) was dissolved in DMSO (2 ml) and treated with sodium hydride (22 mg 1 equiv. of 60%) under an inert atmosphere. After stirring the mixture at RT for 1 hour, 2-fluoro-5-trifluoromethyl-benzonitrile (1 equiv.) was added. After stirring at RT for 24 hours, the reaction mixture was acidified (glacial acetic acid) and filtered. The filtrate was purified by RPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as the trifluoroacetate salt (0.06 g; m.pt. 110-111° C.).
  • 1H NMR (400 MHz, DMSO-D6) δ 1.0-3.8 (m, 20H), 4.5-5.3 (m, 2H), 7.5 (d, 1H), 7.75 (m, 3H), 8.02 (m, 2H).
    • EXAMPLE 15
  • This Example illustrates the preparation of (3-methanesulfonyl-phenyl)-[4-(6-methyl-pyridin-2-yloxy)-[1,4′]bipiperidinyl-1′-yl]-methanone trifluoroacetate (Compound 292 of Table IV).
  • The product of Method E (1 mmol) and potassium tert-butoxide (2 mmol ) were stirred together in dry THF (20 ml) at RT. After 10 mins 2-fluoro-6-methyl-pyridine (1 mmol) was added and the reaction mixture stirred at reflux overnight. The reaction mixture was cooled, diluted with water and extracted into ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was purified by RPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as the trifluoroacetate salt (0.03 g; m.pt. 61-62° C.).
  • 1H NMR (400 MHz, DMSO-D6) δ 1.6-3.8 (m, 15H), 2.4 (s, 3H), 3.3 (s, 3H), 4.5-5.4 (m, 3H), 6.6 (m, 1H), 6.02 (dd, 1H), 7.6 (q, 1H), 7.82 (m, 2H), 7.95 (s, 1H), 8.02 (m, 1H), 9.7 (bs, 1H)
    • EXAMPLE 16
  • This Example illustrates the preparation of N-{3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide (Compound 583 of Table I).
  • To (3-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.133 g) in pyridine (2 mL) was added methanesulfonyl chloride (0.024 ml) and the reaction left to stir for 5 minutes. The solvent was evaporated, water (0.5 mL) added and the solvent re-evaporated. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) gave the title compound (0.050 g; m.pt. 94-95° C.).
  • 1H NMR (399.978 MHz, CDCl3) δ 1.59-2.09 (8H, m), 2.22 (2H, br s), 2.54-2.60 (1H, m), 2.81 (2H, br s), 3.02 (5H, br s), 3.51-3.75 (1H, br m), 4.25-4.28 (1H, m), 4.29 (1H, br s), 6.70-7.52 (8H, m).
    • EXAMPLE 17
  • This Example illustrates the preparation of N-{2-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide (Compound 587 of Table I).
  • To a solution of (2-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.2 g) in pyridine (2 ml) at 0° C. was added methane sulphonyl chloride (0.039 ml). The mixture was allowed to warm to room temperature and the pyridine removed by evaporation. The residue was azeotroped with water and the product purified by RPHPLC (Symmetry column, eluting 25% to 95% MeCN/0.1% NH4OAc aq at 20 ml/min over 6 minutes) to give the product as a colourless solid (0.09 g).
  • 1H NMR: (399.978 MHz, CDCl3) δ 1.49-1.69 (5H, m), 1.77-1.84 (2H, m), 1.87-1.94 (1H, m), 1.95-2.02 (2H, m), 2.43-2.50 (2H, m), 2.59 (1H, tt), 2.78-2.84 (2H, m), 2.87-3.03 (1H, m), 3.08 (3H, s), 3.17 (1H, sextet), 4.27 (1H, septet), 6.75 (1H, dd), 6.99 (1H, d), 7.15 (1H, td), 7.24 (1H, d), 7.31 (1H, d), 7.43 (1H, td), 7.62 (1H, d).
    • EXAMPLE 18
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(1-methanesulfonyl-1H-indol-3-yl)-methanone hydrochloride (Compound 592 of Table I).
  • To a solution of Compound 471 of Table I (0.17 g) in dimethylformamide (3 ml) at 0° C. under an atmosphere of nitrogen, was added sodium hydride (0.014 g of a 60% suspension in oil). The mixture was stirred for 5 minutes then methanesulphonyl chloride (0.027 ml in 1 ml of dimethylformamide) was added and then mixture allowed to warm to room temperature over 12 hours. The reaction mixture was partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by RPHPLC (Symmetry, 25% to 95% MeCN/0.1% NH4OAc aq over 6 minutes, 20 ml/min, 220 nm) to give a colourless solid (0.062 g; m.pt. 173-175° C.).
  • 1H NMR: (299.944 MHz DMSO-D6) δ 1.72-1.87 (2H, m), 2.01-2.34 (5H, m), 2.48-2.55 (1H, m), 2.98-3.13 (2H, m), 3.13-3.27 (2H, m), 3.39-3.47 (2H, m), 3.53-3.62 (2H, m), 3.64 (3H, s), 4.35-4.58 (1H, m), 4.65-4.76 (1H, m), 7.12 (1H, dd), 7.39-7.48 (2H, m), 7.52 (1H, t), 7.61 (1H, t), 7.79 (1H, d), 7.88 (1H, s), 7.95 (1H, d).
    • EXAMPLE 19
  • This Example illustrates the preparation of 1-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-2-phenyl-3-piperazin-1-yl-propan-1-one (Compound 595 of Table I).
  • Compound 575 of Table I (0.1 78 g) was treated with 6N hydrochloric acid (5 ml) and stirred at room temperature for 24 hours. 2N Sodium hydroxide solution was added and the reaction mixture extracted with ethyl acetate. The organic extracts were combined, washed with water, dried (MgSO4) and evaporated to give a white solid. Purification was by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)). (Any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with MgSO4 and evaporation of solvent.) The title compound was a white solid (0.087 g).
  • 1H NMR (399.98 MHz, DMSO-D6) δ 1.20-1.95 (9H, m), 2.10-2.53 (9H, m), 2.59-2.65 (2H, m), 2.70-2.77 (1H, m), 2.89-3.12 (4H, m), 4.02-4.47 (4H, m), 6.89-7.00 (1H, m), 7.16-7.32 (6H, m), 7.44-7.52 (1H, m).
    • EXAMPLE 20
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-1-oxy-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone.
  • The product Example 10 (0.100 g) in dichloromethane (5 ml) was treated with m-chloroperbenzoic acid (0.043 g) and the reaction stirred at room temperature for 0.5 hours. Saturated aqueous sodium hydrogencarbonate was added and the reaction mixture extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4) and evaporated to give a brown foam. Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) gave the title compound as a white solid (0.021 g).
  • 1H NMR (299.946 MHz, DMSO-D6) δ 1.70-2.91 (15H, m), 3.24-3.44 (3H, m), 3.55-3.68 (1H, m), 4.55-4.76 (2H, m), 6.99-7.06 (1H, m), 7.29-7.33 (1H, m), 7.53 (1H, dd), 7.71-7.79 (2H, m), 7.93 (1H, s), 7.99-8.05 (1H, m).
    • EXAMPLE 21
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 1 of Table I).
  • To a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.1 g, see step b of Example 2) in dichloromethane (5 ml) and triethylamine (0.2 ml) was added benzoyl chloride (0.045 ml) and the reaction mixture was stirred for 2 hours. The mixture was washed with water, dried (MgSO4), filtered and the solvents evaporated to leave a gum. Purification by RPHPLC [with an eluent system (50% MeCN/0.1% NH4OAc aq), any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with MgSO4 and evaporation of solvent] and trituration of the resulting product with diethyl ether gave a solid which was filtered and dried to give the title compound (0.120 g; m.pt. 122° C.).
  • 1H NMR (299.944 MHz CDCl3) δ 1.42-1.62 (2H, m), 1.78-1.82 (3H, m), 1.95-2.01 (3H, m), 2.39-2.69 (3H, m), 2.69-3.09 (4H, m), 3.63-3.95 (1H, m), 4.24-4.29 (1H, m), 4.62-4.89 (1H, m), 6.73-6.77 (1H, m), 6.99 (1H, d), 7.26-7.29 (1H, m), 7.39 (5H, s).
    • EXAMPLE 22
  • This Example illustrates the preparation of [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone (Compound 4 of Table V).
    • Step 1: 4-(3,4-dichloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester
  • 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.18 g) and 3,4-dichlorothiophenol (6.15 ml) were stirred together in acetonitrile (200 ml) and potassium carbonate (8.86 g) was added. The mixture was heated at reflux for 18 hours after which water was added and the resulting mixture extracted with dichloromethane. The organic extracts were combined, washed with water, dried (MgSO4) and evaporated to give the sub-title compound (14.58 g).
  • 1H NMR (299.944 MHz, CDCl3) δ 1.45 (9H, s), 1.49-1.62 (2H, m), 1.87-1.96 (2H, m), 2.89-2.98 (2H, m), 3.16-3.26 (1H, m), 3.91-4.01 (2H, m), 7.21-7.57 (3H, m).
    • Step 2: 4-(3,4-dichloro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester
  • The product from Step 1 (1 g) and m-chloroperbenzoic acid (1.19 g) were stirred at ambient temperature in dichloromethane (10 ml) for 18 hours. Sodium metabisulphite (1.19 g) in water (5 ml) was added and stirring was continued for 0.5 hours after which the reaction mixture was extracted with dichloromethane. The combined organics were washed with saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to give the sub-title compound (0.34 g).
  • 1H NMR (399.978 MHz, CDCl3) δ 1.45 (9H, s), 1.56-1.65 (2H, m), 1.94-2.00 (2H, m), 2.62-2.70 (2H, m), 3.01-3.09 (1H, m), 4.21-4.30 (2H, m), 7.66-7.00 (2H, m), 7.93-7.98 (1H, m).
    • Step 3: 4-(3,4-dichloro-benzenesulfonyl)-piperidine
  • The product of step 2 was deprotected following the procedure of Example 1 step b. 1H NMR (299.944 MHz, CDCl3) δ 1.64-1.71 (2H, m), 1.96-2.05 (2H, m), 2.55-2.64 (2H, m), 2.99-3.10 (1H, m), 3.19-3.27 (2H, m), 7.66-7.71 (2H, m), 7.92-7.98 (1H, m).
    • Step 4: 4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • The product of step 3 was used in a reductive amination with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure of Example 2 step a.
    • Step 5: 4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl
  • The product of step 4 was deprotected following the procedure of Example 2 step b. 1H NMR (299.946 MHz, DMSO-D6) δ 1.22-1.61 (7H, m), 1.77-1.83 (2H, m), 2.09-2.16 (1H, m), 2.25-2.45 (3H, m), 2.87-2.98 (4H, m), 3.35-3.43 (1H, m), 7.81 (1H, dd), 7.96 (1H, d), 8.05 (1H, d)
    • Step 6: [4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone
  • The product of step 5 was coupled to 4-methanesulfonyl-benzoic acid following the procedure of Example 2 step c.
  • 1H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.62 (5H, m), 1.70-1.85 (4H, m), 2.13 (3H, t), 2.72-3.04 (4H, m), 3.27 (3H, s), 3.37-3.48 (1H, m), 4.44-4.52 (1H, m), 7.63 (2H, d), 7.81 (1H, dd), 7.95-8.00 (3H, m), 8.06 (1H, d).
  • [4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 5 of Table V). The product of step 5 was coupled to benzoic acid following the procedure of Example 2 step c. 1H NMR (299.946 MHz, DMSO-D6) δ 1.31-1.69 (5H, m), 1.82 (3H, d), 2.15 (2H, d), 2.69-2.75 (1H, m), 2.90-2.97 (4H, m), 3.33-3.43 (1H, m), 3.48-3.63 (1H, m), 4.42-4.53 (1H, m), 7.39 (5H, dt), 7.81 (1H, dd), 7.96 (1H, d), 8.06 (1H, d).
    • EXAMPLE 23
  • This Example illustrates the preparation of 3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-1-ethyl-7-methyl-1H-[1,8]naphthyridin-4-one (Compound 534 of Table I).
  • 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (0.155 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) %)) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.184 g; m.pt. 189-190° C.)
  • MS: APCI+(M+H) 543
  • 1H NMR (299.946 MHz, DMSO-D6) δ 1.37 (3H, t), 1.47-1.69 (5H, m), 1.78-1.84 (1H, m), 1.89-1.97 (2H, m), 2.36-2.41 (2H, m), 2.49-2.56 (1H, m), 2.66 (3H, s), 2.70-2.79 (3H, m), 2.95 -3.04 (1H, m), 3.52-3.59 (1H, m), 4.38-4.57 (4H, m), 6.95-6.99 (1H, m), 7.22-7.24 (1H, m), 7.35-7.40 (1H, m), 7.46-7.51 (1H, m), 8.37 (1H, s), 8.43-8.45 (1H, m).
    • EXAMPLE 24
  • This Example illustrates the preparation of 4-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-2H-isoquinolin-1-one (Compound 572 of Table I).
  • 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 1-oxo-1,2-dihydro-isoquinoline4-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by RPHPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%))) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with Magnesium sulfate and evaporation of solvent) gave the title compound (0.153 g).
  • MS: APCI+ (M+H) 500
  • 1H NMR (299.944 MHz CDCl3) δ 1.37-1.66 (2H, m), 1.73-1.88 (3H, m), 1.93-2.05 (3H, m), 2.41-2.51 (2H, m), 2.52-2.63 (1H, m), 2.75-2.86 (2H, m), 2.86-3.09 (2H, m), 3.71-3.90 (1H, m), 4.23-4.32 (1H, m), 4.77-4.93 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.27-7.32 (3H, m), 7.54-7.67 (1H, m), 7.57 (1H, t), .7.74 (1H, t), 8.46 (1H, d).
    • EXAMPLE 25
  • This Example illustrates the preparation of [4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone (Compound 579 of Table 1).
    • Step a: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
  • To a solution of 2-amino-5-fluoropyridine (1.12 g) in diethyl ether (25 ml) was added ethyl bromopyruvate (1.25 ml). the mixture was stirred for I hour. The resultant solid was filtered off, suspended in ethanol and heated at reflux for 4hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium bicarbonate solution (100 ml). The organic layer was separated, dried, (magnesium sulfate) and the solvent removed by evaporation. The residue was purified by flash chromatography (silica) eluting with ethyl acetate: hexane (3:1) to give the sub-title compound as a colourless solid (1.12 g).
  • MS: ES+ (M+H) 209
  • 1H NMR (399.98 MHz, CDCl3) δ 1.44 (3H, t), 4.46 (2H, q), 7.19 (1H, ddd), 7.68 (1H, dd), 8.07-8.09 (1H, m), 8.19 (1H, s).
    • Step b: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid
  • A solution of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1 g) in 4N HCl was refluxed for 4 hours. The solvent was evaporated to give the sub-title compound as a white solid (0.86 g).
  • MS: ES+ (M+H) 181
  • 1H NMR (399.98 MHz, DMSO-D6) δ 7.81-7.89 (2H,m), 8.71 (1H,s), 9.03 (1H,s).
    • Step c: [4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone
  • 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with magnesium sulfate and evaporation of solvent) gave the title compound (0.104 g).
  • MS: APCI+ (M+H) 491
  • 1H NMR (399.978 MHz, CDCl3) δ 1.61 (1H, qd), 1.75-2.02 (7H, m), 2.42-2.51 (2H, m), 2.59-2.67 (1H, m), 2.75-2.86 (3H, m), 3.12-3.21 (1H, m), 4.23-4.29 (1H, m), 4.76-4.85 (1H, m), 5.23-5.32 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.16 (1H, ddd), 7.30 (1H, d), 7.58 (1H, dd), 8.07 (2H, s).
    • EXAMPLE 26
  • This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid phenylamide (Compound 309 of Table IV).
  • Phenylisocyanate(0.078 ml) was added to a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see Example 2 step b) in dichloromethane (5 ml). The mixture was stirred at 23° C. for 16 hours. The resulting precipitate was filtered, washed with dichloromethane (2×5 ml) then crystallised from acetonitrile to afford the title compound as a solid (0.2 g; melting point 215-216° C.).
  • 1H NMR (DMSO-D6) 5 1.35 (2H, qd), 1.53-1.62 (2H, m), 1.72-1.78 (2H, m), 1.89-1.96 (2H, m), 2.36-2.42 (2H, m), 2.44-2.52 (IH, m), 2.72-2.78 (4H, m), 4.15 (2H, d), 4.39-4.45 (1H, m), 6.91 (1H, tt), 6.98 (1H, dd), 7.19-7.23 (2H, m), 7.25 (1H, d), 7.43-7.46 (2H, m), 7.49 (1H, d), 8.46 (1H, s).
  • 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbothioic acid phenylamide was prepared using the methodology of Example 26 and employing phenylisothiocyanate, (melting point 162-163° C.). 1′H NMR: (DMSO-d6) δ 1.39-1.49 (2H, m), 1.53-1.62 (2H, m), 1.79 (2H, d), 1.89-1.96 (2H, m), 2.39 (2H, t), 2.54-2.63 (1H, m), 2.73-2.80 (2H, m), 3.04 (2H, t), 4.39-4.46 (1H, m), 4.72 (2H, d), 6.98 (1H, dd), 7.06-7.10 (1H, m), 7.23-7.30 (5H, m), 7.49 (1H, d), 9.24 (1H, s).
    • EXAMPLE 27
  • This Example illustrates the preparation of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid (3-methanesulfonyl-phenyl)-amide (Compound 54 of Table IV).
  • Hydrogen peroxide (100 μl, 30%) was added to a cooled (0° C.) solution of Compound 312 of Table IV (0.13 g) in trifluoroacetic acid(1 ml). The mixture was allowed to reach ambient temperature and stirred for a further 1 hour. The solution was quenched with water(5 ml), basified to pH11 with 2M sodium hydroxide solution and extracted with ethyl acetate. The organic solution was separated, washed with water (2×5 ml), dried (MgSO4), filtered and the filtrate evaporated to leave a gum. The gum was dissolved in acetonitrile and purified by RPHPLC (Nova Pak column) eluting with acetonitrile/0.1% ammonium acetate aq (1:1). The required fractions were evaporated and then lyophilised to give the title compund as a colourless powder (0.03 g).
  • 1H NMR (DMSO-D6) δ 1.31-1.42 (2H, m), 1.53-1.62 (2H, m), 1.77 (2H, d), 1.89-1.96 (2H, m), 2.36-2.43 (3H, m), 2.74-2.82 (4H, m), 3.16 (3H, s), 4.18 (2H, d), 4.42 (1H, septet), 6.98 (1H, dd), 7.25 (1H, d), 7.44-7.52 (3H, m), 7.80-7.83 (1H, m), 8.09 (1H, t), 8.90(1H, s).
  • Selected proton NMR data and/or melting point data are provided for certain further compounds in Tables VI and VII below.
    TABLE VI
    Compound
    (Table no.) NMR data
     3 (I) δ(D2O) 1.97-1.69(2H, m), 2.21-2.08(2H, m), 2.51-2.23(4H, m),
    3.07-2.96(1H, m), 3.31-3.17(2H, m), 3.45-3.32(2H, m),
    3.56-3.45(1H, m), 3.75-3.56(2H, m), 4.88-4.70(3H, m), 7.07-7.02(1H, m),
    7.36-7.30(1H, m), 7.46-7.37(1H, m), 7.55(2H, d), 7.74-7.72(1H,
    m)
     8 (I) δ(CDCl3) 1.67-1.41(2H, m), 1.86-1.76(3H, m), 2.04-1.93(3H, m),
    2.51-2.42(3H, m), 2.62-2.56(1H, m), 2.88-2.76(3H, m), 3.06(1H,
    t), 3.66(1H, d), 4.28(1H, septet), 4.76(1H, d), 6.75(1H, dd), 6.99(1H,
    d), 7.31(1H, d), 7.56(2H, d), 8.28(2H, d)
     18 (I) δ(CD3OD) 1.59-1.41(2H, m), 1.83-1.68(2H, m), 2.08-1.93(4H, m),
    2.56-2.48(4H, m), 2.68-2.61(1H, m), 2.91-2.80(3H, m),
    3.15-3.02(1H, m), 3.71-3.57(1H, m), 4.23-4.14(1H, m), 4.40(1H, septet),
    4.50(3H, s), 4.75-4.57(1H, m), 6.91(1H, dd), 7.12(1H, d), 7.40(1H, d),
    7.66(2H, d), 8.04(2H, d)
     36 (I) δ(CD3OD) 1.62-1.42(2H, m), 1.94-1.72(3H, m), 2.11-1.98(3H, m),
    2.61-2.52(2H, m), 2.95-2.82(3H, m), 3.15(1H, t), 3.68-3.63(1H,
    m), 4.42(1H, septet), 4.71-4.67(2H, m), 6.91(1H, dd), 7.11(1H, d),
    7.40(1H, d), 7.60(2H, d), 7.86(2H, d)
     37 (I) δ(CD3OD) 2.06-1.76(3H, m), 2.45-2.12(5H, m), 3.05-2.88(1H, m),
    3.42-3.25(3H, m), 3.71-3.50(2H, m), 3.93-3.74(1H, m), 4.63(1H,
    septet), 4.94-4.82(2H, m), 7.03-6.95(1H, m), 7.24(1H, dd),
    7.47-7.42(1H, m), 7.71-7.66(1H, m), 7.78(1H, td), 7.90-7.86(2H, m)
    149 (I) δ(CDCl3) 1.50-1.27(2H, m), 1.90-1.75(5H, m), 2.02-1.92(2H, m),
    2.56-2.39(4H, m), 2.63(1H, t), 2.81-2.72(2H, m), 3.09-3.01(3H,
    m), 3.82(2H, s), 3.91(1H, d), 4.25(1H, septet), 4.67(1H, d), 6.75(1H,
    dd), 6.99(1H, d), 7.31(1H, dd), 7.45(2H, d), 7.90(2H, d)
    203 (I) δ(DMSO-D6) 1.61-1.44(2H, m), 2.24-2.01(4H, m), 2.61-2.53(2H,
    m), 3.16-2.99(2H, m), 3.60-3.30(5H, m), 3.67(2H, s), 3.77(3H, s),
    4.13(1H, d), 4.53(1H, d), 4.69-4.60(1H, m), 7.05(1H, ddd), 7.14(1H,
    d), 7.42-7.25(3H, m), 7.55(2H, dd), 10.98-10.78(3H, m)
    205 (I) δ((CD3)2CO) 1.26(2H, quintet), 1.76-1.58(4H, m), 1.98-1.90(2H, m),
    2.42-2.35(2H, m), 2.58-2.45(2H, m), 2.81-2.71(2H, m), 3.00(1H,
    t), 3.70(2H, s), 4.00(1H, d), 4.39(2H, septet), 4.51(1H, d), 6.92(1H,
    dd), 7.07-7.01(2H, m), 7.13(1H, d), 7.30-7.25(2H, m), 7.40(1H, d)
    220 (I) δ(DMSO-D6) 1.58-1.44(2H, m), 2.28-1.97(5H, m), 2.59-2.53(2H,
    m), 3.18-2.93(3H, m), 3.34-3.25(1H, m), 3.51-3.36(2H, m),
    3.66-3.56(2H, m), 4.11(1H, d), 4.53(1H, d), 4.64(1H, septet),
    6.92-6.82(2H, m), 6.99(1H, d), 7.10-7.03(1H, m), 7.36(1H, dd), 7.55(1H, ddd),
    10.99-10.87(1H, m)
    225 (I) δ((CD3)2CO) 1.71-1.51(2H, m), 2.13-2.08(2H, m), 2.40-2.21(3H,
    m), 2.61-2.54(1H, m), 3.05(1H, t), 3.55-3.15(6H, m),
    3.69-3.61(2H, m), 4.16(1H, d), 4.76-4.63(2H, m), 4.91-4.86(1H, m),
    6.78-6.76(2H, m), 7.12-7.02(3H, m), 7.32(1H, dd), 7.51(1H, dd)
    244 (I) δ(DMSO-D6) 1.55-1.42(2H, m), 2.25-1.96(6H, m), 2.66-2.54(2H,
    m), 3.14-2.96(2H, m), 3.32-3.26(1H, m), 3.51-3.35(2H, m),
    3.62(3H, s), 3.71-3.64(2H, m), 3.74(6H, s), 4.14(1H, d), 4.54(1H, d),
    4.66-4.58(1H, m), 6.53(2H, s), 7.04(1H, dd), 7.35(1H, d), 7.54(1H, tt)
    253 (I) δ(CDCl3) 1.47-1.19(2H, m), 2.00-1.76(6H, m), 2.62-2.37(4H, m),
    2.80-2.70(2H, m), 2.98(1H, t), 3.65(2H, s), 3.88(3H, s),
    3.92-3.89(1H, m), 4.25(1H, septet), 4.68(1H, d), 6.77-6.72(1H, m), 6.89(1H,
    d), 6.94-6.92(2H, m), 7.01-6.96(2H, m), 7.30(1H, dd)
    258 (I) δ(DMSO-D6) 1.40-1.26(3H, m), 1.78-1.59(5H, m), 1.98-1.92(1H,
    m), 2.17(3H, s), 2.21(3H, s), 2.45-2.37(2H, m), 2.60-2.48(3H, m),
    3.01(1H, t), 3.70-3.57(2H, m), 3.89(1H, d), 4.39(1H, septet), 4.55(1H,
    d), 7.00(1H, d), 7.13(1H, d), 7.41(1H, d), 7.95-7.89(3H, m)
    267 (I) δ(CDCl3) 1.74-1.61(2H, m), 2.21-2.09(3H, m), 2.32-2.25(1H, m),
    2.48(1H, t), 2.67-2.53(2H, m), 2.89(1H, t), 3.31-3.05(5H, m),
    3.71(4H, s), 3.82(2H, s), 4.08(1H, d), 4.59-4.53(1H, m), 4.94(1H, d),
    6.89(1H, dd), 6.93(1H, dd), 6.97(1H, d), 7.34(1H, d), 7.40(1H, d),
    7.58-7.54(1H, m),
    268 (I) δ(CDCl3) 1.24(1H, dq), 1.41(1H, dq), 1.88-1.72(4H, m),
    2.00-1.91(2H, m), 2.53-2.37(3H, m), 2.59(1H, dt), 2.78-2.70(2H, m),
    2.98(1H, t), 3.73(2H, s), 3.89(1H, d), 4.24(1H, septet), 4.68(1H, d),
    6.74(1H, dd), 7.03-6.91(4H, m), 7.29-7.25(1H, m), 7.30(1H, d)
    272 (I) δ(CDCl3) 1.18(1H, dq), 1.40(1H, dq), 1.86-1.68(4H, m),
    2.00-1.91(2H, m), 2.43-2.35(2H, m), 2.48(1H, td), 2.57(1H, dt),
    2.77-2.68(2H, m), 2.95(1H, dt), 3.74(2H, s), 3.91(1H, d), 4.23(1H, septet),
    4.69(1H, d), 6.74(1H, dd), 6.98(1H, d), 7.35-7.23(6H, m)
    274 (I) δ(DMSO-D6) 1.74-1.59(5H, m), 1.77(3H, dq), 2.65-2.36(4H, m),
    2.86-2.74(6H, m), 2.95(1H, t), 3.74(3H, s), 3.93(1H, d), 4.40(1H, septet),
    4.53(1H, d), 6.73-6.70(1H, m), 6.80-6.78(2H, m), 6.93(1H, dd),
    7.18-7.13(2H, m), 7.41(1H, d)
    276 (I) δ((CD3)2CO) 1.63-1.51(2H, m), 2.02-1.98(2H, m), 2.21-2.15(2H,
    m), 2.58-2.31(4H, m), 2.96(1H, t), 3.40-3.03(4H, m),
    3.60-3.49(2H, m), 3.72(3H, s), 4.02(1H, d), 4.63-4.55(1H, m), 4.77-4.72(1H,
    m), 6.76(1H, t), 6.84(1H, d), 6.96-6.93(1H, m), 7.03(1H, d),
    7.11-7.07(1H, m), 7.16-7.15(1H, m), 7.37-7.31(1H, m)
    286 (I) δ(CD3OD) 1.90-1.63(2H, m), 2.49-2.05(6H, m), 3.28-2.87(7H, m),
    3.84-3.44(5H, m), 4.69-4.56(1H, m), 4.85-4.78(2H, m),
    7.04-6.94(1H, m), 7.28-7.21(1H, m), 7.45(1H, t), 7.60-7.55(3H, m),
    7.64-7.61(1H, m), 7.66(1H, t), 7.77-7.73(2H, m), 7.85-7.81(2H, m)
    291 (I) δ(CD3OD) 1.98-1.71(3H, m), 2.46-2.11(5H, m), 3.18-2.98(1H, m),
    3.45-3.26(2H, m), 3.70-3.46(4H, m), 3.86(3H, s), 4.66-4.56(1H,
    m), 4.84-4.80(2H, m), 7.04-6.94(3H, m), 7.27-7.20(1H, m),
    7.47-7.42(3H, m)
    293 (I) δ(CD3OD) 1.88-1.73(2H, m), 2.22-1.92(5H, m), 2.31(1H, d),
    2.87-2.79(1H, m), 3.06-2.97(1H, m), 3.17(3H, s), 3.57-3.31(5H, m),
    4.55-4.44(1H, m), 4.73-4.65(2H, m), 6.92-6.82(1H, m), 7.12(1H, td),
    7.40-7.31(2H, m), 7.63(1H, dt), 7.75-7.68(1H, m), 7.99(1H, dt)
    294 (I) δ(CD3OD) 1.98-1.70(2H, m), 2.45-2.08(6H, m), 2.97(1H, t),
    3.21(3H, s), 3.41-3.21(3H, m), 3.72-3.49(3H, m), 4.67-4.56(1H, m),
    4.95-4.81(2H, m), 7.03-6.94(1H, m), 7.27-7.20(1H, m),
    7.47-7.42(1H, m), 7.74-7.62(1H, m), 8.02(1H, ddd), 8.13(1H, dd)
    295 (I) δ(CD3OD) 2.04-1.74(3H, m), 2.36-2.12(4H, m), 2.48-2.40(1H, m),
    3.03-2.87(1H, m), 3.43-3.15(3H, m), 3.80-3.47(3H, m),
    4.68-4.58(1H, m), 4.85-4.80(2H, m), 5.13(2H, s), 7.03-6.96(1H, m),
    7.27-7.21(1H, m), 7.46-7.42(1H, m), 7.63-7.56(3H, m), 7.79-7.69(4H,
    m), 8.12(1H, d)
    296 (I) δ(CD3OD) 2.46-1.75(8H, m), 2.96(1H, t), 3.32(2H, s),
    3.72-3.19(4H, m), 3.97-3.92(1H, m), 4.69-4.56(1H, m), 4.98-4.79(2H, m),
    7.03-6.94(1H, m), 7.24(1H, d), 7.69-7.35(10H, m)
    297 (I) δ(CD3OD) 1.66-1.51(2H, m), 1.89-1.69(3H, m), 2.08-1.96(3H, m),
    2.71-2.50(3H, m), 3.01-2.81(3H, m), 3.24-3.10(1H, m),
    3.84-3.71(1H, m), 4.46-4.38(1H, m), 4.79-4.67(1H, m), 6.92(1H, dd),
    7.14(1H, d), 7.41(1H, d), 7.81(1H, dd), 8.39(1H, d), 8.71(1H, s)
    298 (I) δ(CD3OD) 1.33(3H, t), 1.62-1.41(2H, m), 1.95-1.74(3H, m),
    2.11-1.98(3H, m), 2.73-2.52(3H, m), 2.95-2.79(3H, m), 3.03(2H, q),
    3.26-3.09(1H, m), 3.93-3.78(1H, m), 4.48-4.39(1H, m), 4.78-4.56(1H,
    m), 6.91(1H, dd), 7.11(1H, d), 7.42-7.34(5H, m)
    299 (I) δ(CD3OD) 1.99-1.72(3H, m), 2.36-2.11(4H, m), 2.44(1H, d),
    3.06-2.87(1H, m), 3.42-3.23(2H, m), 3.71-3.46(4H, m), 3.95-3.77(1H,
    m), 4.67-4.55(1H, m), 4.84-4.80(1H, m), 7.03-6.94(1H, m),
    7.27-7.20(1H, m), 7.47-7.43(1H, m), 7.66-7.61(2H, m), 7.87-7.81(2H,
    m)
    300 (I) δ(CD3OD) 1.96-1.72(3H, m), 2.33-2.09(4H, m), 2.46-2.41(1H, m),
    3.02-2.87(1H, m), 3.43-3.22(3H, m), 3.72-3.47(3H, m),
    3.93-3.78(1H, m), 4.66-4.56(1H, m), 4.84-4.80(1H, m), 7.03-6.94(1H, m),
    7.28-7.21(1H, m), 7.47-7.43(1H, m), 7.59(2H, d), 7.83(2H, d)
    301 (I) (500.076MHz, DMSO-D6) δ 1.33-1.44(m, 2H), 1.55-1.60(m, 2H),
    1.66-1.73(m, 1H), 1.78-1.86(m, 1H), 1.91(s, 3H), 1.91-1.96(m, 2H),
    2.05(s, 3H), 2.39(t, 2H), 2.55(t, 1H), 2.74-2.79(m, 3H), 2.94-3.04(m,
    1H), 3.56-3.66(m, 1H), 4.42(septet, 1H), 4.45-4.52(m, 1H), 6.98(dd,
    2H), 7.02(d, 2H), 7.25(d, 1H), 7.35(t, 1H), 7.49(d, 1H), 7.58(d, 1H),
    7.66(s, 1H)
    302 (I) (500.076MHz, DMSO-D6) δ 1.36(dq, 2H), 1.54-1.60(m, 2H),
    1.72-1.75(m, 2H), 1.91(s, 3H), 1.91-1.95(m, 2H), 2.05(s, 3H), 2.39(t,
    2H), 2.74-2.78(m, 2H), 2.80-2.87(m, 1H), 4.05-4.19(m, 2H),
    4.42(septet, 1H), 5.22(s, 2H), 6.58(d, 1H), 6.97-6.99(m, 2H), 7.00(s, 1H),
    7.25(d, 1H), 7.49(d, 1H)
    303 (I) (500.076MHz, DMSO-D6) δ 1.54-1.63(m, 4H), 1.69-1.82(m, 4H),
    1.91-1.96(m, 2H), 1.91(s, 3H), 2.35-2.44(m, 2H), 2.73-3.04(m,
    7H), 4.39-4.46(m, 2H), 6.48-6.49(m, 1H), 6.98(d, 1H),
    7.02-7.07(m, 3H), 7.26(s, 1H), 7.34(t, 1H), 7.49(d, 1H), 7.62(d, 1H)
    304 (I) (500.076MHz, DMSO-D6) δ 1.33(t, 3H), 1.36-1.43(m, 2H),
    1.54-1.60(m, 2H), 1.70-1.80(m, 2H), 1.91-1.96(m, 2H), 1.91(s, 3H),
    2.39(t, 2H), 2.51-2.55(m, 1H), 2.74-2.79(m, 2H), 3.79(s, 3H),
    4.01-4.05(m, 1H), 4.02(q, 2H), 4.42(septet, 1H), 4.47-4.53(m, 1H), 6.94(s,
    2H), 6.97-6.99(m, 2H), 7.25(d, 1H), 7.49(d, 1H)
    305 (I) (500.076MHz, DMSO-D6) δ 1.37-1.46(m, 2H), 1.54-1.61(m, 2H),
    1.67-1.83(m, 2H), 1.91-1.96(m, 2H), 1.91(s, 3H), 2.40(t, 2H),
    2.53-2.58(m, 1H), 2.74-2.80(m, 2H), 2.99-3.10(m, 1H), 3.63-3.74(m,
    1H), 4.42(septet, 1H), 4.46-4.54(m, 1H), 6.29-6.30(m, 1H), 6.98(dd,
    1H), 7.25(d, 1H), 7.43-7.44(m, 1H), 7.48(t, 3H), 7.64(d, 2H)
    306 (I) (500.076MHz, DMSO-D6) δ 1.22-1.40(m, 2H), 1.54-1.61(m, 2H),
    1.75(t, 2H), 1.91-1.96(m, 2H), 2.38(t, 2H), 2.53-2.60(m, 1H),
    2.71-2.77(m, 2H), 3.03(t, 1H), 3.79(s, 2H), 3.98-4.03(m, 1H),
    4.36-4.40(m, 1H), 4.40-4.45(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.50(d, 1H),
    8.34(s, 1H), 8.40(s, 1H), 8.57(d, 1H)
    307 (I) (500.076MHz, DMSO-D6) δ 1.17-1.31(m, 2H), 1.53-1.59(m, 2H),
    1.69(t, 2H), 1.88-1.94(m, 2H), 2.35(t, 2H), 2.45-2.52(m, 1H),
    2.68-2.74(m, 2H), 2.95(t, 1H), 3.50(s, 2H), 3.59(s, 3H), 4.06-4.10(m, 1H),
    4.36-4.43(m, 2H), 6.88(s, 1H), 6.97(dd, 1H), 7.25(d, 1H), 7.45(s, 1H),
    7.49(d, 1H)
    308 (I) (500.076MHz, DMSO-D6) δ 1.03(dq, 1H), 1.18(dq, 1H),
    1.49-1.58(m, 3H), 1.68(d, 1H), 1.83-1.90(m, 2H), 1.91(s, 3H), 2.23-2.30(m,
    2H), 2.41-2.49(m, 3H), 2.57-2.67(m, 2H), 2.90(t, 1H), 3.66(q, 2H),
    4.01(d, 1H), 4.38(septet, 1H), 4.43(d, 1H), 6.58(dd, 1H), 6.88(d, 1H),
    6.96(dd, 1H), 7.07(d, 1H), 7.12(d, 1H), 7.23(d, 1H), 7.49(d, 1H),
    8.58(s, 1H)
    309 (I) (500.076MHz, DMSO-D6) δ 1.46-1.56(m, 2H), 1.89-1.98(m, 2H),
    2.03-2.18(m, 4H), 2.23(d, 1H), 2.55-2.61(m, 1H), 3.02-3.17(m,
    4H), 3.42-3.51(m, 2H), 3.98(s, 2H), 4.16(d, 1H), 4.54(d, 1H),
    4.60-4.66(m, 1H), 6.93-6.97(m, 1H), 7.01-7.09(m, 1H), 7.15(s, 1H),
    7.25(s, 1H), 7.34-7.38(m, 1H), 7.54-7.58(m, 1H)
    310 (I) (500.076MHz, DMSO-D6) δ 1.11(t, 3H), 1.39-1.48(m, 2H),
    1.55-1.60(m, 2H), 1.65-1.72(m, 1H), 1.81-1.87(m, 1H), 1.90-1.95(m,
    2H), 1.90(s, 3H), 2.39(t, 2H), 2.53-2.59(m, 1H), 2.74-2.83(m, 2H),
    3.03-3.10(m, 1H), 3.36(q, 2H), 3.47-3.55(m, 1H), 4.42(septet, 1H),
    4.46-4.54(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H),
    7.72-7.78(m, 2H), 7.86(s, 1H), 7.96(d, 1H)
    311 (I) (500.076MHz, DMSO-D6) δ 0.92(t, 3H), 1.40-1.49(m, 2H),
    1.55-1.64(m, 2H), 1.57(sextet, 2H), 1.65-1.73(m, 1H), 1.81-1.88(m, 1H),
    1.91(s, 3H), 1.91-1.96(m, 2H), 2.36-2.44(m, 2H), 2.54-2.61(m,
    1H), 2.73-2.84(m, 2H), 3.02-3.11(m, 1H), 3.45-3.53(m, 1H),
    4.40-4.46(m, 1H), 4.50-4.54(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d,
    1H), 7.72-7.78(m, 2H), 7.86(s, 1H), 7.96(d, 1H)
    312 (I) (500.076MHz, DMSO-D6) δ 0.98(d, 6H), 1.39-1.49(m, 2H),
    1.54-1.61(m, 2H), 1.64-1.71(m, 1H), 1.81-1.87(m, 1H), 1.90-1.95(m,
    2H), 1.91(s, 3H), 2.02(septet, 1H), 2.39(t, 2H), 2.53-2.59(m, 1H),
    2.74-2.79(m, 2H), 3.03-3.11(m, 1H), 3.45-3.52(m, 1H),
    4.42(septet, 1H), 4.47-4.53(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d,
    1H), 7.71-7.77(m, 2H), 7.88(s, 1H), 7.98(d, 1H)
    313 (I) (500.076MHz, DMSO-D6) δ 1.41-1.53(m, 2H), 1.54-1.62(m, 2H),
    1.66-1.74(m, 1H), 1.84-1.89(m, 1H), 1.91-1.96(m, 2H), 1.91(s,
    3H), 2.36-2.44(m, 2H), 2.54-2.62(m, 1H), 2.73-2.87(m, 4H),
    3.10(t, 1H), 3.50(s, 3H), 3.52(s, 3H), 3.52-3.58(m, 1H), 4.40-4.46(m,
    1H), 4.48-4.54(m, 1H), 6.97-7.00(m, 1H), 7.23-7.29(m, 1H),
    7.50(d, 1H), 8.06(d, 1H), 8.16(s, 1H), 8.29(d, 1H)
    314 (I) (500.076MHz, DMSO-D6) δ 1.34(t, 3H), 1.35-1.41(m, 2H),
    1.54-1.60(m, 2H), 1.74(d, 2H), 1.90-1.96(m, 2H), 1.90(s, 3H), 2.39(t, 2H),
    2.50-2.55(m, 1H), 2.73-2.79(m, 2H), 2.80-2.89(m, 1H), 4.01(q,
    2H), 4.08-4.19(m, 2H), 4.42(septet, 2H), 5.06(s, 2H), 6.62(d, 1H),
    6.77(d, 1H), 6.81(s, 2H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H)
    315 (I) (DMSO-D6) δ 1.53-1.82(m, 2H), 2.02-2.36(m, 5H), 2.60-2.67(m,
    1H), 3.07-3.15(m, 2H), 3.31-3.38(m, 1H), 3.43-3.53(m, 2H),
    4.12-4.19(m, 4H), 4.51(d, 1H), 4.68(septet, 1H), 4.85(s, 1H), 7.06(ddd, 1H),
    7.37(dd, 1H), 7.56(t, 1H), 7.94(d, 2H), 8.86(d, 2H), 11.47(s, 1H)
    316 (I) (DMSO-D6) δ 1.58-2.28(m, 4H), 2.67-2.84(m, 1H), 2.91-3.04(m,
    2H), 2.97(s, 2H), 3.06-3.26(m, 2H), 3.24-3.42(m, 1H),
    3.44-3.67(m, 3H), 3.57(s, 3H), 4.55-4.77(m, 2H), 4.83(s, 1H), 7.00-7.09(m, 2H),
    7.35-7.58(m, 5H)
    317 (I) (DMSO-D6) δ 1.52(dq, 2H), 1.74-1.92(m, 2H), 1.93-2.04(m, 4H),
    2.42-2.50(m, 2H), 2.55(tt, 1H), 2.77-2.85(m, 2H), 2.87-2.96(m,
    2H), 4.22-4.30(m, 3H), 6.69-6.74(m, 2H), 6.76(d, 1H), 6.99(d, 1H),
    7.07(dd, 1H), 7.16(dt, 1H), 7.29(s, 2H), 7.32(s, 1H)
    318 (I) (DMSO-D6) δ 1.71(m, 2H), 2.18(m, 3H), 2.70(s, 3H), 3.02(m, 1H),
    3.15(m, 2H), 3.32(m, 3H), 3.50(m, 2H), 4.63(m, 1H), 7.05(ddd, 1H),
    7.36(m, 4H), 7.56(t, 1H), 7.66(d, 1H), 8.11(s, 1H), 8.37(d, 1H)
    319 (I) (DMSO-D6) δ 1.40(m, 2H), 1.57(m, 2H), 1.79(m, 2H), 1.90(m, 2H),
    2.40(m, 2H), 2.58(m, 1H), 2.79(m, 2H), 2.87(m, 2H), 4.30(d, 2H),
    4.43(m, 1H), 6.97(dd, 1H), 7.13(m, 2H), 7.25(d, 1H), 7.43(d, 1H), 7.49(d,
    1H), 7.65(m, 2H)
    321 (I) (DMSO-D6) δ 1.67-1.78(m, 2H), 1.95-2.09(m, 3H), 2.18-2.27(m,
    2H), 2.44(d, 3H), 2.77-2.88(m, 1H), 3.08-3.19(m, 3H),
    3.33-3.52(m, 5H), 3.59-3.67(m, 1H), 4.60-4.68(m, 1H), 4.84(s, 1H),
    7.05(ddd, 1H), 7.14-7.27(m, 1H), 7.37(dd, 1H), 7.55(t, 1H), 7.61(q, 1H),
    7.70-7.71(m, 2H), 7.78-7.80(m, 1H), 7.86-7.89(m, 1H)
    322 (I) (DMSO-D6) δ 1.65-1.80(m, 2H), 1.99-2.09(m, 2H), 2.19-2.30(m,
    3H), 2.77-2.90(m, 1H), 3.07-3.21(m, 3H), 3.30-3.37(m, 3H),
    3.47-3.57(m, 2H), 3.59-3.71(m, 1H), 4.59-4.69(m, 1H), 4.82-4.86(m,
    1H), 7.05(ddd, 1H), 7.37(dd, 1H), 7.49(s, 2H), 7.55(t, 1H),
    7.64-7.69(m, 2H), 7.84-7.86(m, 1H), 7.92(td, 1H)
    323 (I) (DMSO-D6) δ 1.64-1.78(m, 2H), 1.99-2.09(m, 2H), 2.17-2.29(m,
    3H), 2.70-2.85(m, 1H), 3.04-3.19(m, 3H), 3.28-3.38(m, 3H),
    3.31(s, 3H), 3.46-3.55(m, 2H), 3.66(t, 2H), 4.12(t, 2H), 4.56-4.68(m,
    1H), 4.81-4.86(m, 1H), 6.94-6.97(m, 2H), 7.04(dd, 1H), 7.05(ddd,
    1H), 7.34-7.39(m, 2H), 7.55(t, 1H)
    324 (I) (CDCl3) δ 1.45(s, 9H), 1.48-1.67(m, 4H), 1.75-1.85(m, 2H),
    1.90-2.03(m, 3H), 2.42-2.51(m, 2H), 2.56(m, 1H), 2.71-2.84(m, 3H),
    2.91-3.06(m, 1H), 3.54(q, 2H), 3.75-3.88(m, 1H), 4.03(t, 2H),
    4.27(septet, 1H), 4.68-4.82(m, 1H), 4.93-5.01(m, 1H), 6.75(dd, 1H),
    6.90-7.00(m, 3H), 7.25-7.32(m, 3H)
    325 (I) (DMSO-D6) δ 1.70-1.84(m, 2H), 2.00-2.09(m, 2H), 2.20-2.29(m,
    3H), 2.81-2.91(m, 1H), 3.09-3.21(m, 3H), 3.28-3.38(m, 3H),
    3.48-3.57(m, 2H), 3.61-3.70(m, 1H), 4.61-4.72(m, 1H), 4.82-4.86(m,
    1H), 7.05(ddd, 1H), 7.14-7.27(m, 1H), 7.37(dd, 1H), 7.56(t, 1H),
    7.76-7.79(m, 1H), 8.51(s, 1H), 8.80(d, 1H)
    326 (I) (DMSO-D6) δ 1.70-1.78(m, 2H), 2.00-2.09(m, 2H), 2.18-2.26(m,
    2H), 3.05-3.17(m, 2H), 3.24-3.40(m, 2H), 3.97-4.06(m, 2H),
    4.44-4.52(m, 2H), 4.59-4.70(m, 2H), 4.73(s, 2H), 4.81-4.86(m, 1H),
    4.91-4.93(m, 2H), 6.90-6.93(m, 1H), 6.96-7.04(m, 1H), 7.07-7.11(m,
    1H), 7.17-7.20(m, 1H), 7.34-7.43(m, 2H), 7.52-7.55(m, 1H)
    327 (I) (CDCl3) δ 1.52-1.63(m, 4H), 1.77-1.86(m, 2H), 1.92-2.03(m, 4H),
    2.44-2.50(m, 2H), 2.58-2.67(m, 1H), 2.77-2.83(m, 2H), 3.05(bs,
    1H), 3.36(s, 3H), 4.26-4.31(m, 2H), 6.74-6.77(m, 1H),
    6.99-7.01(m, 1H), 7.30-7.33(m, 1H), 7.47(s, 1H)
    328 (I) (CDCl3) δ 1.43-1.67(m, 4H), 1.73-1.91(m, 4H), 1.95-2.02(m, 2H),
    2.42-2.50(m, 2H), 2.52-2.62(m, 1H), 2.77-2.85(m, 2H), 2.92(bs,
    2H), 3.06(s, 3H), 4.23-4.30(m, 1H), 5.26(s, 2H), 6.73-6.79(m, 2H),
    6.99-7.00(m, 1H), 7.29-7.32(m, 1H), 7.47-7.50(m, 1H),
    7.82-7.82(m, 1H)
    329 (I) (CDCl3) δ 1.50-1.69(m, 4H), 1.77-1.86(m, 2H), 1.92-2.02(m, 4H),
    2.45-2.49(m, 2H), 2.59-2.65(m, 1H), 2.79-2.83(m, 2H), 3.02(bs,
    1H), 3.39(s, 3H), 4.26-4.30(m, 2H), 5.88(bs, 1H), 6.74-6.77(m, 1H),
    6.99-7.00(m, 1H), 7.30-7.32(m, 1H), 7.46(bs, 1H), 7.65(s, 1H)
    330 (I) (DMSO-D6) δ 1.73-3.63(m, 17H), 4.57-4.70(m, 1H), 7.01-7.88(m,
    7H)
    331 (I) (DMSO-D6) δ 1.21(d, 6H), 1.37-2.03(m, 8H), 2.33-3.42(m, 7H),
    4.15-4.19(m, 1H), 4.37-4.45(m, 1H), 5.89(s, 2H), 6.96-8.34(m, 4H)
    332 (I) (DMSO-D6) δ 1.41-1.94(m, 8H), 2.37-2.78(m, 8H), 3.32(s, 3H),
    4.38-4.46(m, 1H), 6.96-7.78(m, 5H)
    333 (I) (CDCl3) δ 1.80-1.96(m, 5H), 2.38(s, 4H), 2.41-3.00(m, 12H),
    3.57-3.60(m, 1H), 4.26(s, 1H), 4.73-4.76(m, 1H), 6.73-7.32(m, 3H)
    334 (I) (DMSO-D6) δ 1.33-1.93(m, 8H), 2.33-3.27(m, 7H), 4.39-4.45(m,
    1H), 4.49-4.53(m, 1H), 6.96-8.98(m, 5H)
    335 (I) (CDCl3) δ 1.16-1.30(m, 1H), 1.33-1.48(m, 1H), 1.76-2.75(m,
    12H), 2.96-3.05(m, 1H), 3.72(s, 2H), 3.89-3.93(m, 1H),
    4.21-4.30(m, 1H), 4.66-4.71(m, 1H), 6.72-7.32(m, 7H)
    336 (I) (DMSO-D6) δ 1.37-2.83(m, 17H), 4.38-4.47(m, 1H), 5.76(s, 1H),
    6.96-7.96(m, 6H)
    337 (I) (DMSO-D6) δ 1.33-1.99(m, 8H), 2.36-2.60(m, 4H), 2.73-2.82(m,
    2H), 2.94(s, 3H), 2.98-3.09(m, 1H), 3.55-3.66(m, 1H),
    4.38-4.46(m, 1H), 4.56(s, 2H), 6.96-7.00(m, 1H), 7.23-7.27(m, 1H),
    7.41-7.52(m, 5H)
    338 (I) (DMSO-D6) δ 1.35-1.99(m, 8H), 2.37-2.46(m, 2H), 2.55-2.63(m,
    2H), 2.73-2.85(m, 2H), 2.92(s, 3H), 2.97-3.06(m, 1H),
    3.55-3.65(m, 1H), 4.41-4.49(m, 1H), 4.56(s, 2H), 6.96-7.01(m, 1H),
    7.25-7.27(m, 1H), 7.39-7.52(m, 5H)
     1 (III) δ(DMSO-D6) 1.57-1.36(2H, m), 2.25-1.87(5H, m), 2.45-2.33(2H,
    m), 3.16-2.97(2H, m), 3.37-3.17(4H, m), 3.45-3.40(1H, m),
    4.12(0H, t), 4.53(1H, d), 4.67-4.58(1H, m), 4.84-4.77(1H, m), 5.45(1H,
    d), 7.03(1H, ddd), 7.19(2H, t), 7.42-7.33(3H, m), 7.55(1H, m),
    10.59-10.38(1H, m)
     2 (III) δ(DMSO-D6) 1.60-1.36(2H, m), 2.27-1.93(5H, m), 2.61-2.57(1H,
    m), 2.90-2.73(1H, m), 3.13-2.94(2H, m), 3.41-3.23(3H, m),
    4.17-3.85(2H, m), 4.68-4.47(2H, m), 4.84-4.77(1H, m), 5.43(1H, d),
    7.09-6.99(1H, m), 7.40-7.27(6H, m), 7.55(1H, t), 11.13-10.92(1H, m)
     3 (III) δ(DMSO-D6) 1.27-1.07(1H, m), 1.57-1.36(1H, m), 2.24-1.89(5H,
    m), 2.66-2.56(1H, m), 2.93-2.79(1H, m), 3.16-3.00(2H, m),
    3.51-3.39(2H, m), 4.18(1H, t), 4.67-4.46(2H, m), 4.84-4.78(1H, m),
    5.51-5.43(1H, m), 6.05(1H, s), 7.04(1H, dd), 7.24-7.17(1H, m),
    7.48-7.33(3H, m), 7.55(1H, dd), 10.41-10.23(1H, m)
  • TABLE VII
    Compound MP
    (Table) MS (° C.) 1H NMR Can be prepared using:
     3 (IV) 495(M+H) 181-182 (DMSO-D6) δ 1.2-2.8(bm, 14H), 3.1(bm, 1H), 3.35(s, 3H), 3.5(bm, Example 12
    1H), 4.4(m, 1H), 4.5(bm, 1H), 6.82(dd, 1H), 7.1(dd, 1H), 7.4(t, 1H),
    7.7(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)
     2 (IV) 495(M+H) 111-112 (DMSO-D6) δ 1.6-2.3(bm, 8H), 3.0-3.6(bm, 8H), 3.3(s, 3H), Example 12 and final product
    4.5-4.8(m, 2H), 6.9-7.1(m, 1H), 7.2-7.4(m, 2H), 7.8(m, 2H), 7.94(d, 1H), isolated as Hydrochloride by
    8.03(d, 1H), 10.9(bm, 1H) treatment with a solution of
    HCl in dioxan and
    evaporation.
     7 (IV) 459(M+H) 149-150 (DMSO-D6) δ 1.2-3.7(bm, 16H), 3.75(s, 3H), 3.85(bm, 1H), 4.6(bm, As for 2 (IV) above
    1H), 5.05(bm, 1H), 6.9(m, 4H), 7.78(m, 2H), 7.92(d, 1H), 8.05(m,
    1H), 11.0 and 11.8(bm, 1H)
     8 (IV) 463(M+H) 126-127 (DMSO-D6) δ 1.2-3.6(bm, 16H), 3.9(bm, 1H), 4.6 bm, 1H), As for 2 (IV) above
    5.14(bm, 1H), 7.0(d, 2H), 7.38(d, 2H), 7.75(m, 2H), 7.9(m, 1H), 8.05(m,
    1H), 11.3 and 11.95(bm, 1H)
     9 (IV) 497(M+H) 78-80 (DMSO-D6) δ 1.2-4.0(bm, 17H), 4.6(bm, 1H), 5.2(bm, 1H), 7.0(dd, As for 2 (IV) above
    1H), 7.3(m, 1H), 7.58(d, 1H), 7.78(d, 2H), 7.95(d, 1H), 8.05(m,
    1H)11.0 and 11.65(bm, 1H)
     10 (IV) 454(M+H) 78-80 (DMSO-D6) δ 1.2-3.6(m, 17H), 4.25(bm, 1H), 4.98(m, 1H), 7.03(d, Example 12
    2H), 7.72(m, 4H), 7.9(s, 1H), 8.0(m, 1H)
     11 (IV) 465(M+H) 82-83 (DMSO-D6) 1.2-3.4(m, 16H), 3.5(bm, 1H), 4.3(bm, 1H), 4.85(m, Example 12
    1H), 6.7(m, 1H), 7.0(m, 1H), 7.3(q, 1H), 7.7(m, 2H), 7.9(s, 1H),
    8.0(m, 1H)
     12 (IV) 447(M+H) 64-65 (DMSO-D6) δ 1.2-3.3(m, 16H), 3.45(bm, 1H), 4.25(m, 1H), 4.8(m, Example 12
    1H), 6.9(m, 2H), 7.1(t, 2H), 7.75(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)
     13 (IV) 500(M+H) 110-111 (DMSO-D6) δ 1.2-4.8(bm, 24H), 6.95(dd, 2H), 7.5(m, 2H), 7.8(m, As for 2 (IV) above
    2H), 7.95(s, 1H), 8.02(d. 1H), 9.85(d, 1H), 10.7(bm, 1H)
     14 (IV) 457(M+H) 140-142 (DMSO-D6) δ 1.2-4.8(m, 24H), 6.86(bm, 2H), 7.02(m, 2H), Example 12
    7.75(bm, 2H), 7.90(s, 1H), 8.03(bm, 1H)
     15 (IV) 491(M+H) 94-95 (DMSO-D6) δ 1.2-4.8(bm, 24H). 6.8(bd, 1H), 7.0(bs, 1H), 7.3(d, Example 12
    1H), 7.75(m, 2H), 7.9(s, 1H), 8.0(m, 1H)
     16 (IV) 477(M+H) 150-152 (DMSO-D6) δ 1.2-4.6(bm, 21H), 7.0(bm, 2H), 7.3(bm, 2H), Example 12.
    7.75(m, 2H), 7.9(s, 1H), 8.0(m, 1H)
     17 (IV) 461(M+H) 219-220 (DMSO-D6) δ 1.2-4.8(bm, 21H), 6.9-7.3(m, 4H), 7.75(m, 2H), As for 2 (IV) above
    7.92(s, 1h), 8.02(m, 1H).
     18 (IV) 511(M+H) 104-105 (DMSO-D6) δ 1.2-5.0(bm, 21H), 7.3(d, 1H) 7.4(dd, 1H), 7.6(dd, Example 12 and final product
    1H), 7.75(m, 2H), 7.95(s, 1H), 8.0(d, 1H), 9.5 and 9.7(bs, 1H) isolated as trifluoroacetate by
    evaporation of Reverse Phase
    HPLC fractions.
     19 (IV) 495(M+H) 76-77 (DMSO-D6) δ 1.2-5.0(bm, 21H), 7.2(m, 1H), 7.3(m, 1H), 7.45(m, As for 18 (IV) above
    1H), 7.75(m, 2H), 7.95(s, 1H), 8.05(m, 1H), 9.5(bm, 1H)
     20 (IV) 479(M+H) 230-232 (DMSO-D6) δ 1.2-3.7(bm, 19H), 4.4-4.7(bm, 2H), 7.02(t, 1H), As for 2 (IV) above
    7.3(m, 2H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H)
     21 (IV) 495(M+H) 69-70 (DMSO-D6) 1.2-4.0(m, 19H), 4.4-4.8(m, 2H), 7.3(m, 2H), 7.5(m, As for 18 (IV) above
    1H), 7.75(m, 2H), 7.98(s, 1H), 8.0(m, 1H), 9.5(bm, 1H)
     22 (IV) 475(M+H) 130-132 (CDCl3) δ 1.0-3.6(m, 19H), 3.7(s, 3H), 4.6(m, 2H), 6.6-6.9(m, 3H), As for 2 (IV) above
    7.7(m, 2H), 8.0(m, 2H)
     24 (IV) 462(M+H) 72-73 (DMSO-D6) 1.6(m, 2H), 1.8(m, 1H), 2.01(m, 4H), 2.3(m, 1H), Example 13
    2.55(m, 2H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), 3.58(m, 2H), 3.8(s,
    3H), 4.3(bs, 2H), 4.6 and 4.8(m, 1H), 6.7(d, 1H), 6.8-7.0(m, 3H),
    7.2(m, 1H), 7.5(m, 1H), 9.5(bs, 1H)
     26 (IV) 458(M+H) 111-112 (DMSO-D6) δ 1.4-3.6(m, 17H), 3.8(2s, 6H), 4.2-4.5(m, 3H), 6.7(m, Example 13
    2H), 6.82(m, 2H), 6.9-7.2(m, 2H)
     27 (IV) 440(M+H) 73-75 (DMSO-D6) δ 1.6-1.9(m, 3H), 2.0-2.3(m, 5H), 2.4-2.6(m, 2H), Example 13
    2.9(m, 2H), 3.18(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.7(s, 3H), 3.8(s,
    3H), 4.2(bs, 2H), 4.4 and 4.6(2m, 1H), 6.7(d, 1H), 6.9(m, 5H),
    7.0(d, 1H), 9.7(bm, 1H)
     28 (IV) 462(M+H) 81-83 (DMSO-D6) δ 1.6(m, 2H), 1.8(m, 1H), 2.05(m, 4H), 2.3(m, 1H), Example 13
    2.5(m, 1H), 2.9(m, 2H), 3.2(m, 2H), 3.3(m, 2H), 3.4(m, 1H), 3.55(m,
    2H), 3.8(s, 3H), 4.3(bs, 2H), 4.6 and 4.8(m, 1H), 6.62(d, 1H),
    6.81(d, 1H), 6.9(s, 1H), 7.05(m, 1H), 7.35(m, 2H), 9.76(bm, 1H)
     29 (IV) 424(M+H) 97-99 (DMSO-D6) δ 1.4-2.6(m, 14H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), Example 13
    3.55(m, 2H), 3.8(s, 3H), 4.3(bs, 2H), 4.5 and 4.7(m, 1H), 6.65(d,
    1H), 6.9(m, 4H), 7.1(m, 1H), 9.5(bs, 1H)
     30 (IV) 458(M+H) 78-79 (DMSO-D6) δ 1.5-2.6(m, 13H), 2.3(s, 3H), 2.9(m, 2H), 3.2(m, 2H), Example 13
    3.4(m, 1H), 3.55(m, 2H), 4.3(bs, 2H), 4.55 and 4.75(m, 1H),
    6.67(d, 1H), 6.85(m, 3H), 7.0(dd, 1H), 7.32(t, 1H), 9.5(bs, 1H)
     31 (IV) 444(M+H) 100-101 (DMSO-D6) δ 1.6(m, 2H), 1.8(m, 1H), 2.0(m, 4H), 2.3(m, 1H), Example 13
    2.5(m, 2H), 2.9(m, 2H), 3.18(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.8(s,
    3H), 4.2(bs, 2H), 4.6 and 4.8(m, 1H), 6.62(d, 1H), 6.8(m, 2H),
    7.0(m, 2H), 7.36(m, 2H), 9.7(bs, 1H)
     32 (IV) 428(M+H) 74-75 (DMSO-D6) 1.6(m, 2H), 1.8(m, 1H), 2.0(m, 4H), 2.3(m, 1H), Example 13
    2.5(m, 2H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.8(s,
    3H), 4.2(bs, 2H), 4.5 and 4.7(m, 1H), 6.7(d, 1H), 6.85(d, 1H), 6.9(s,
    1H), 7.02(m, 1H), 7.04(m, 1H), 7.18(m, 2H), 9.6(m, 1H)
     33 (IV) 478(M+H) 117-119 (DMSO-D6) δ 1.6-3.6(m, 17H), 3.8(s, 3H), 4.25(bs, 2H), 4.6 and Example 13
    4.9(m, 1H), 6.6(d, 1H), 6.8(m, 2H), 7.3(m, 1H), 7.4(m, 1H), 7.6(m,
    1H), 9.5(bs, 1H)
     34 (IV) 462(M+H) 109-110 (DMSO-D6) δ 1.6-3.6(m, 17H), 3.8(s, 3H), 4.25(bs, 2H), 4.55 and Example 13
    4.85(m, 1H), 6.6(d, 1H), 6.8(m, 2H), 7.2(m, 1H), 7.3(m, 1H),
    7.45(m, 1H), 9.5(bs, 1H)
     37 (IV) 442(M+H) 89-90 (DMSO-D6) δ 1.6-3.6(m, 20H), 3.8(s, 3H), 4.25(bs, 2H), 4.45 and Example 13
    4.75(m, 1H), 6.6(d, 1H), 6.8(m, 2H), 7.0(m, 3H), 9.6(bs, 1H)
     38 (IV) 471(M+H) 143-145 (DMSO-D6) δ 1.6-3.6(m, 19H), 4.2-4.8(m, 2H), 7.0(m, 1H), 7.2(d, As for 18 (IV) above
    1H), 7.22(s, 1H), 7.8(d, 1H), 8.5(d, 1H), 8.8(s, 1H)
     39 (IV) 475(M+H) 141-142 (DMSO-D6) δ 1.6-3.6(m, 16H), 4.2-4.8(m, 2H), 6.9(m, 1H), 7.2(m, As for 18 (IV) above
    1H), 7.5(m, 1H), 7.8(d, 1H), 8.5(d, 1H), 8.8(d, 1H)
     41 (IV) 471(M+H) 160-162 (DMSO-D6) δ 1.6-3.6(m, 16H), 3.8(s, 3H), 4.2-4.8(m, 2H), 6.7(m, As for 18 (IV) above
    1H), 6.9-7.2(m, 2H), 7.8(d, 1H), 8.5(d, 1H), 8.8(d, 1H)
     42 (IV) 453(M+H) 116-118 (DMSO-D6) δ 1.6-3.6(m, 16H), 3.7(s, 3H), 4.2-4.8(m, 2H), As for 18 (IV) above
    6.8-7.1(m, 3H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H), 9.6(bs, 1H)
     43 (IV) 475(M+H) 109-110 (DMSO-D6) δ 1.6-3.6(m, 16H), 4.2-4.8(m, 2H), 7.07(m, 1H), As for 18 (IV) above
    7.35(m, 2H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H), 9.6(bs, 1H)
     44 (IV) 437(M+H) 136-137 (DMSO-D6) δ 1.6-3.2(m, 15H), 3.3(s, 3H), 3.6(m, 1H), 4.22(m, Example 12
    1H), 4.5(m, 1H), 6.8(d, 2H), 7.10(d, 2H), 7.82(d, 1H), 8.52(d, 1H),
    8.8(d, 1H)
     89 (IV) 471(M+H) 100-102 (DMSO-D6) δ 1.0-4.2(m, 21H), 6.0(m, 1H), 6.18(m, 1H), 6.42(m, As for 18 (IV) above
    1H), 7.02(d, 1H), 7.6(d, 1H), 7.85(d, 1H)
     47 (IV) 441(M+H) 133-136 (DMSO-D6) δ 1.6-4.8(m, 18H), 6.9-7.2(m, 4H), 7.82(d, 1H), 8.52(d, As for 18 (IV) above
    1H), 8.8(d, 1H)
     48 (IV) 491(M+H) 105-106 (DMSO-D6) δ 1.6-4.8(m, 18H), 6.3(d, 1H), 6.4(d, 1H), 6.58(s, 1H), As for 18 (IV) above
    6.9(d, 1H), 7.52(d, 1H), 7.8(d, 1H)
     49 (IV) 475(M+H) 123-125 (DMSO-D6) δ 1.6-4.8(m, 18H), 7.2(m, 1H), 7.3(m, 1H), 7.45(m, As for 18 (IV) above
    1H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H)
     50 (IV) 459(M+H) 93-94 (DMSO-D6) δ 1.6-4.8(m, 18H), 7.05(m, 1H), 7.3(m, 2H), 7.82(d, As for 18 (IV) above
    1H), 8.52(d, 1H), 8.8(d, 1H), 9.7(bm, 1H)
    271 (IV) 507(M+H) 102-103 (DMSO-D6) δ 1.6-3.8(m, 16H), 3.3(s, 3H), 3.8(d, 3H), 4.4-4.7(m, Example 12
    2H), 6.95(m, 1H), 7.1(m, 2H), 7.78(m, 2H), 7.95(s, 1H), 8.03(d,
    1H)
    272 (IV) 505(M+H) 97-98 (DMSO-D6) δ 1.6-4.8(m, 27H), 7.1(s, 2H), 7.6(m, 2H), 7.95(s, 1H), As for 18 (IV) above
    8.03(d, 1H)
    273 (IV) 511(M+H) 110-112 (DMSO-D6) δ 1.4-3.8(m, 16H), 3.3(s, 3H), 4.4-5.0(m, 2H), 7.22(m, As for 18 (IV) above
    2H), 7.3(m, 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H)
    274 (IV) 511(M+H) 114-115 (DMSO-D6) δ 1.4-3.8(m, 16H), 3.3(s, 3H), 4.4-5.0(m, 2H), 7.02(m, Example 12
    1H), 7.4(m, 2H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H)
    275 (IV) 491(M+H) 88-89 (DMSO-D6) δ 1.4-3.8(m, 16H), 2.25(s, 3H), 3.3(s, 3H), 4.2-4.8(m, Example 12
    2H), 7.02(m, 2H), 7.22(m, 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d,
    1H)
    276 (IV) 491(M+H) 182-183 (DMSO-D6) δ 1.4-3.8(m, 16H), 2.25(s, 3H), 3.3(s, 3H), 4.4-4.6(m, Example 12
    2H), 6.74(d, 1H), 7.02(s, 1H), 7.22(d, 1H), 7.75(m, 2H), 7.90(s,
    1H), 8.0(d, 1H)
    277 (IV) 499(M+H) 162-164 (DMSO-D6) δ 1.6-3.8(m, 19H), 2.25(s, 3H), 3.3(s, 3H), 4.5-5.0(m, As for 2 (IV) above
    2H), 7.14(t, 1H), 7.8(m, 4H), 7.95(m, 1H), 8.02(d, 1H), 10.9(bm,
    1H)
    278 (IV) 528(M+H) 120-122 (DMSO-D6) δ 1.5-5.0(m, 29H), 6.9-7.2(m, 4H), 7.75(m, 2H), As for 2 (IV) above
    7.95(s, 1H), 8.02(d, 1H), 10.2(bs, 1H), 11.0-11.3(bm, 1H)
    279 (IV) 505(M+H) 97-99 (DMSO-D6) δ 1.18(t, 3H), 1.6-3.7(m, 17H), 2.62(q, 2H), 3.3(s, 3H), Example 12
    4.4-4.8(m, 1H), 6.8-7.1(m, 2H), 7.3(m, 1H), 7.75(m, 2H), 7.95(s,
    1H), 8.02(m, 1H), 9.4(bs, 1H)
    280 (IV) 494(M+H) 138-140 (DMSO-D6) δ 1.8(m, 2H), 2.1-4.4(m, 14H), 3.3(s, 3H), 4.62(bm, As for 2 (IV) above
    1H), 4.9 and 5.1(m, 1H), 7.65(m, 1H), 7.8(m, 2H), 7.85(m, 2H),
    7.95(d, 1H), 8.01(d, 1H), 8.3(t, 1H), 9.0(t, 1H), 9.15(t, 1H), 10.35(bs,
    1H), 11.5(bs, 1H)
    281 (IV) 499(M+H) 98-99 (DMSO-D6) δ 1.2(s, 9H), 1.3-3.6(m, 20H), 4.5(m, 1H), 6.8(t, 1H), Example 12
    6.9(d, 1H), 7.1(t, 1H), 7.2(d, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.0(d,
    1H)
    282 (IV) 483(M+H) 79-80 (DMSO-D6) δ 1.2-3.6(m, 22H), 3.3(s, 3H), 4.22 and 4.5(m, 2H), Example 12
    6.67(d, 1H), 6.8(s, 1H), 7.08(d, 1H), 7.75(m, 2H), 7.9(s, 1H), 8.0(d,
    1H)
    283 (IV) 559(M+H) 113-115 (DMSO-D6) δ 1-1.48(m, 29H), 3.3(s, 3H), 7.0(m, 1H), 7.18(m, 2H), Example 12
    7.75(m, 2H), 7.9(s, 1H), 8.0(m, 1H)
    284 (IV) 520(M+H) 111-112 (DMSO-D6) δ 1.6-4.0(m, 19H), 4.6 and 4.9(m, 2H), 7.2(m, 1H), As for 18 (IV) above
    7.4-7.8(m, 6H) 7.95(s, 1H), 8.02(d, 1H), 9.5(bm, 1H)
    285 (IV) 544(M+H) 111-112 (DMSO-D6) δ 1.6-3.2(m, 15H), 3.3(s, 3H), 3.5(m, 1H), 4.5 and Example 12
    4.6(m, 2H), 6.9(d, 1H), 7.35(d, 1H), 7.5(dd, 1H), 7.75(m, 2H), 7.81(d,
    1H), 7.9(s, 1H), 8.0(dd, 1H), 8.68(d, 1H)
    286 (IV) 491(M+H) 115-117 (DMSO-D6) δ 1.6-3.2(m, 16H), 3.3(s, 3H), 3.35-3.6(m, 3H), Example 12
    4.4-4.9(m, 2H), 6.9(m, 1H), 7.0-7.2(m, 2H), 7.75(m, 2H), 7.92(s, 1H),
    8.02(m, 1H)
    287 (IV) 443(M+H) 142-144 (DMSO-D6) δ 1.6-3.4(m, 14H), 3.3(s, 3H), 3.4-3.7(m, 2H), Example 12
    4.6-4.8(m, 2H), 7.0(m, 3H), 7.3(m, 2H), 7.75(m, 2H), 7.92(s, 1H), 8.04(dd,
    1H)
    288 (IV) 525(M+H) 84-86 (DMSO-D6) δ 1.6-3.4(m, 22H), 4.2-4.7(m, 2H), 7.38(d, 1H), 7.5(d, As for 18 (IV) above
    1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(m, 1H)
    289 (IV) 491(M+H) 149-151 (DMSO-D6) δ 1.3-2.0(m, 8H), 2.22(s, 3H), 2.3-2.6(m, 4H), 2.8(m, Example 12
    2H), 3.1(m, 1H), 3.3(s, 3H), 3.5(m, 1H), 4.3-4.6(m, 2H), 6.84(dd,
    1H), 7.0(d, 1H), 7.2(m, 1H), 7.75(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)
    290 (IV) 502(M+H) 93-95 (DMSO-D6) δ 1.6-4.0(m, 16H), 3.3(s, 3H), 4.4-5.1(m, 2H), 7.4(t, As for 18 (IV) above
    1H), 7.8(m, 3H), 7.9-8.1(m, 3H), 9.5-10.0(bm, 1H)
    293 (IV) 445(M+H) 66-68 (DMSO-D6) δ 1.6-3.0(m, 7H), 2.8(m, 1H), 3.2(m, 3H), 3.3(s, 3H), Example 15
    3.4-3.7(m, 4H), 4.62(m, 1H), 5.1-5.4(m, 2H), 7.2(m, 1H), 7.8(m,
    2H), 7.95(m, 1H), 8.02(d, 1H), 8.6(m, 2H), 9.5(bs, 1H)
    339 (I) (M+H) foam (DMSO-D6) δ 1.42-1.70(m, 5H), 1.84-1.94(m, 3H), Example 2 step c
    458 2.35-2.42(m, 2H), 2.54-2.62(m, 1H), 2.73-2.87(m, 3H), 3.02-3.10(m, 1H),
    3.30-3.36(m, 1H), 4.39-4.44(m, 1H), 4.53-4.57(m, 1H),
    6.95-6.99(m, 1H), 7.24-7.25(m, 1H), 7.47-7.50(m, 1H), 7.56-7.67(m,
    2H), 7.77-7.82(m, 1H), 7.94-7.96(m, 1H)
    340 (I) (M+H) 156-157 (DMSO-D6) δ 1.40-1.99(m, 8H), 2.35-2.46(m, 2H), Example 2 step c
    484 2.54-2.62(m, 1H), 2.73-2.85(m, 3H), 3.02-3.13(m, 1H), 3.60-3.72(m, 1H),
    4.39-4.47(m, 1H), 4.51-4.64(m, 1H), 6.96-7.00(m, 1H),
    7.25-7.26(m, 1H), 7.50(d, 1H), 7.59-7.63(m, 1H), 7.74-7.78(m, 1H),
    8.06-8.09(m, 2H), 8.45-8.48(m, 1H), 8.96-8.98(m, 1H)
    341 (I) (M+H) 127-129 (DMSO-D6) δ 1.44-1.99(m, 8H), 2.40-2.48(m, 2H), Example 2 step c using
    485 2.58-2.67(m, 1H), 2.75-2.90(m, 3H), 3.04-3.16(m, 1H), 3.56-3.69(m, 1H), Quinoxaline-6-carboxylic acid
    4.40-4.49(m, 1H), 4.53-4.63(m, 1H), 6.96-7.00(m, 1H), (obtained from hydrolysis of
    7.26-7.27(m, 1H), 7.48-7.51(m, 1H), 7.85-7.88(m, 1H), 8.09-8.11(m, the commercially available
    1H), 8.16-8.19(m, 1H), 9.01(s, 2H) Quinoxaline-6-carboxylic acid
    methyl ester)
    342 (I) (M+H) foam (DMSO-D6) δ 1.36-1.44(2H, m), 1.55-1.61(2H, m), Example 2 step c using 3-
    532 1.76-1.82(2H, m), 1.89-1.96(2H, m), 2.34-2.41(3H, m), 2.72-2.80(2H, m), Amino-4-methanesulfonyl-
    2.95(2H, t), 3.21(3H, s), 4.15-4.22(2H, m), 4.38-4.46(1H, m), thiophene-2-carboxylic acid
    5.87(2H, s), 6.96-6.99(2H, m), 7.24-7.26(2H, m), 7.49(1H, d), (obtained from hydrolysis of
    8.34(1H, s) the commercially available
    3-Amino-4-methanesulfonyl-
    thiophene-2-carboxylic acid
    methyl ester)
    63 (IV) 491(M+H) 127-129 (DMSO-D6) δ 1.42-1.96(8H, m), 2.26(3H, s), 2.32-2.41(2H, m), Example 2 step c
    2.53-2.59(2H, m), 2.67-3.11(4H, m), 3.24(3H, s), 4.28-4.35(2H,
    m), 6.77-6.81(1H, m), 6.95(1H, d), 7.26(1H, dd), 7.50(1H, ddd),
    7.70(1H, d), 7.76-7.82(1H, m), 7.98(1H, ddd)
    79 (IV) 497(M+H) 168-169 (DMSO-D6) δ 1.41-1.49(2H, m), 1.53-1.60(2H, m), 1.80(2H, d), Example 2 step c
    1.92(2H, dz), 2.27(3H, s), 2.38(2H, t), 2.54-2.62(2H, m), 2.77(2H,
    t), 2.93-3.12(2H, m), 3.40(3H, s), 4.33(2H, dt), 6.80(1H, dd),
    6.95(1H, d), 7.26(1H, d), 7.49(1H, d), 7.77(1H, d)
    423 (I) (M+H) 181-183 (DMSO-D6) δ 1.44-1.63(6H, m), 1.91-1.98(3H, m), Example 2 step c
    499 2.36-2.39(2H, m), 2.53-2.62(4H, m), 2.76-2.90(2H, m), 3.03-3.11(1H, m),
    3.34-3.42(1H, m), 4.40-4.45(1H, m), 4.56-4.64(1H, m),
    6.96-6.99(1H, m), 7.24(1H, s), 7.48-7.51(1H, m), 7.61-7.65(1H, m),
    8.39-8.47(2H, m), 9.06-9.08(1H, m)
    578 (I) (M+H) 145-147 (DMSO-D6) δ 1.33-1.45(2H, m), 1.53-1.64(2H, m), Example 2 step c
    473 1.76-1.94(4H, m), 2.36-2.44(2H, m), 2.55-2.64(1H, m), 2.70-2.80(3H, m),
    3.03-3.15(1H, m), 4.35-4.44(1H, m), 4.51-4.61(1H, m),
    5.08-5.20(1H, m), 6.93-7.00(2H, m), 7.25-7.34(2H, m),
    7.45-7.50(1H, m), 7.57-7.63(1H, m), 8.33(1H, s), 8.50-8.62(1H, m)
    580 (I) (M+H) >200 (DMSO-D6) δ 1.43-1.65(4H, m), 1.85-1.96(3H, m), Example 2 step c
    500 2.32-2.41(2H, m), 2.54-2.62(2H, m), 2.73-3.14(4H, m), 3.40-3.47(1H, m),
    4.37-4.45(1H, m), 4.53-4.62(1H, m), 6.45(1H, d), 6.93-7.00(1H,
    m), 7.17-7.26(2H, m), 7.33-7.59(4H, m), 11.99(1H, s)
    419 (I) (M+H) >200 (DMSO-D6) δ 1.25-1.68(5H, m), 1.72-1.81(2H, m), Example 2 step c
    464 1.88-1.95(2H, m), 2.22(3H, s), 2.31-2.40(2H, m), 2.60-2.78(3H, m),
    2.92-3.00(1H, m), 3.44-3.52(1H, m), 4.36-4.49(2H, m), 5.92-6.11(1H,
    m), 6.91-7.06(1H, m), 7.25(1H, s), 7.30-7.41(1H, m),
    7.44-7.54(1H, m), 11.86(1H, s)
    550 (I) (M+H) 80-85 (DMSO-D6) δ 1.40-1.65(5H, m), 1.83-1.96(3H, m), Example 2 step c
    484 2.31-2.43(2H, m), 2.50-2.56(1H, m), 2.69-2.92(4H, m), 3.08-3.17(1H, m),
    4.36-4.42(1H, m), 4.65-4.73(1H, m), 6.94-7.00(1H, m),
    7.19-7.25(1H, m), 7.45-7.50(1H, m), 7.58-7.71(3H, m),
    8.00-8.05(1H, m), 8.39-8.46(1H, m), 8.91-8.96(1H, m)
    426 (I) (M+H) 158-159 (DMSO-D6) δ 1.36-1.45(2H, m), 1.53-1.61(2H, m), Example 2 step c
    464 1.72-1.79(2H, m), 1.88-1.96(2H, m), 2.35-2.43(2H, m), 2.52-2.57(1H, m),
    2.72-2.79(2H, m), 2.85-2.94(2H, m), 3.32-3.38(1H, m),
    3.49(3H, s), 3.99-4.12(1H, m), 4.34-4.51(1H, m), 6.36(1H, d),
    6.90-7.06(1H, m), 7.21-7.29(1H, m), 7.42-7.54(2H, m), 7.91-8.03(1H,
    m)
    416 (I) (M+H) 133-135 (DMSO-D6) δ 1.38-1.45(2H, m), 1.53-1.60(2H, m), Example2 stepc
    448 1.66-1.84(2H, m), 1.88-1.95(2H, m), 2.34-2.41(2H, m), 2.51-2.58(1H, m),
    2.73-2.78(3H, m), 3.01-3.10(1H, m), 3.29-3.36(3H, m),
    3.53-3.63(1H, m), 4.38-4.53(2H, m), 6.94-7.01(1H, m),
    7.21-7.28(1H, m), 7.29-7.35(1H, m), 7.47-7.52(1H, m), 7.68-7.75(1H, m),
    8.42-8.50(1H, m)
    575 (I) (M+H) 140-142 Example 2 step c
    645
    534 (I) (M+H) 189-190 Example 2 step c
    543
    294 (IV) (M+H) foam (CDCl3) δ 1.32-1.45(1H, m), 1.56-1.71(2H, m), 1.79-2.01(5H, Example 2 step c
    529 m), 2.46-2.61(3H, m), 2.79-2.87(3H, m), 2.92-3.16(4H, m),
    3.36-3.42(1H, m), 4.28-4.33(1H, m), 4.79(1H, t), 6.90(2H, dd),
    7.12(1H, dt), 7.49(1H, dd), 7.89(1H, ddd), 8.01(1H, dd)
     67 (IV) (M+H) 132-133 (CDCl3) δ 1.38-1.65(2H, m), 1.73-2.04(6H, m), 2.40-2.67(3H, Example 2 step c
    495 m), 2.72-2.89(3H, m), 2.99-3.08(1H, m), 3.23-3.28(3H, m),
    3.33-3.53(1H, m), 4.21-4.33(1H, m), 4.61-4.86(1H, m), 6.87-6.92(2H,
    m), 7.10-7.14(1H, m), 7.31-7.37(1H, m), 7.55-7.70(2H, m),
    8.07(1H, td)
     83 (IV) (M+H) foam (CDCl3) δ 1.50-1.63(2H, m), 1.85-2.00(6H, m), 2.44-2.51(2H, Example 2 step c
    501 m), 2.56-2.66(1H, m), 2.80-2.88(2H, m), 3.01(2H, s), 3.20(3H, s),
    4.27-4.51(3H, m), 6.91(2H, dd), 7.13(1H, dt), 7.23(1H, d),
    7.63(1H, d)
    295 (IV) (M+H) (CDCl3) δ 1.75-2.03(10H, m), 2.18-2.19(3H, m), 2.44-2.54(2H, Example 2 step c
    491 m), 2.77-2.89(3H, m), 3.00-3.09(1H, m), 3.23-3.28(3H, m),
    3.36-3.52(1H, m), 4.63-4.85(1H, m), 6.70-6.75(1H, m), 7.05-7.11(2H,
    m), 7.31-7.37(1H, m), 7.56-7.68(2H, m), 8.05-8.10(1H, m)
    568 (I) (M+H) (DMSO-D6) δ 1.21-1.95(8H, m), 2.35-2.42(2H, m), Example 2 step c
    558 2.57-2.66(1H, m), 2.72-2.77(2H, m), 3.08-3.17(1H, m), 4.08-4.13(1H, m),
    4.29(2H, d), 4.40-4.46(3H, m), 6.96-7.00(1H, m), 7.25-7.26(1H,
    m), 7.48-7.51(1H, m), 7.58-7.62(1H, m), 8.01-8.07(2H, m),
    8.40-8.43(1H, m), 8.75-8.78(2H, m)
    296 (IV) (M+H) (CDCl3) δ 1.58-1.68(4H, m), 1.85(2H, s), 2.00(2H, s), 2.19(3H, s), Example 2 step c
    525 2.51-2.59(3H, m), 2.80-2.92(3H, m), 2.98-3.16(4H, m),
    3.37-3.43(1H, m), 4.33(1H, s), 4.76-4.85(1H, m), 6.72-6.74(1H, m),
    7.06-7.12(2H, m), 7.45-7.53(1H, m), 7.88-7.91(1H, m),
    8.00-8.02(1H, m)
    471 (I) 472(M+H) δ 1.40(m, 2H), 1.57(m, 2H), 1.79(m, 2H), 1.90(m, 2H), 2.40(m, 2H), Example 2 step c
    2.58(m, 1H), 2.79(m, 2H), 2.87(m, 2H), 4.30(d, 2H), 4.43(m, 1H),
    6.97(dd, 1H), 7.13(m, 2H), 7.25(d, 1H), 7.43(d, 1H), 7.49(d, 1H),
    7.65(m, 2H)
    475(I) 526(M+H) (DMSO-D6) δ 1.67-1.78(m, 2H), 1.95-2.09(m, 3H), Example 2 step c
    2.18-2.27(m, 2H), 2.44(d 3H), 2.77-2.88(m, 1H), 3.08-3.19(m, 3H),
    3.33-3.52(m, 5H), 3.59-3.67(m, 1H), 4.60-4.68(m, 1H), 4.84(s, 1H),
    7.05(ddd, 1H), 7.14-7.27(m, 1H), 7.37(dd, 1H), 7.55(t, 1H),
    7.61(q, 1H), 7.70-7.71(m, 2H), 7.78-7.80(m, 1H), 7.86-7.89(m, 1H),
    569(I) 512(M+H) (DMSO-D6) δ 1.65-1.80(m, 2H), 1.99-2.09(m, 2H), Example 2 step c
    2.19-2.30(m, 3H), 2.77-2.90(m, 1H), 3.07-3.21(m, 3H), 3.30-3.37(m, 3H),
    3.47-3.57(m, 2H), 3.59-3.71(m, 1H), 4.59-4.69(m, 1H),
    4.82-4.86(m, 1H), 7.05(ddd, 1H), 7.37(dd, 1H), 7.49(s, 2H), 7.55(t, 1H),
    7.64-7.69(m, 2H), 7.84-7.86(m, 1H), 7.92(td, 1H)
    477(I) 507(M+H) (DMSO-D6) δ 1.64-1.78(m, 2H), 1.99-2.09(m, 2H), Example 2 step c
    2.17-2.29(m, 3H), 2.70-2.85(m, 1H), 3.04-3.19(m, 3H), 3.28-3.38(m, 3H),
    3.31(s, 3H), 3.46-3.55(m, 2H), 3.66(t, 2H), 4.12(t, 2H),
    4.56-4.68(m, 1H), 4.81-4.86(m, 1H), 6.94-6.97(m, 2H), 7.04(dd, 1H),
    7.05(ddd, 1H), 7.34-7.39(m, 2H), 7.55(t, 1H),
    584(I) 592(M+H) (CDCl3) δ 1.45(s, 9H), 1.48-1.67(m, 4H), 1.75-1.85(m, 2H), Example 2 step c
    1.90-2.03(m, 3H), 2.42-2.51(m, 2H), 2.56(m, 1H), 2.71-2.84(m, 3H),
    2.91-3.06(m, 1H), 3.54(q, 2H), 3.75-3.88(m, 1H), 4.03(t, 2H),
    4.27(septet, 1H), 4.68-4.82(m, 1H), 4.93-5.01(m, 1H), 6.75(dd,
    1H), 6.90-7.00(m, 3H), 7.25-7.32(m, 3H)
    325 (I) 491(M+H) (DMSO-D6) δ 1.69-1.83(2H, m), 1.98-2.11(3H, m), Example 2 step c using acid
    2.17-2.28(3H, m), 2.81-2.92(1H, m), 3.08-3.21(3H, m), 3.47-3.59(2H, m), prepared according to Journal
    3.61-3.71(1H, m), 4.61-4.73(2H, m), 4.82-4.86(1H, m), of Heterocyclic chemistry,
    7.05(1H, ddd), 7.37(1H, dd), 7.56(1H, t), 7.77(1H, ddd), 8.51(1H, s), 1972, p1149
    8.80(1H, d)
    585 (I) 507(M+H) (DMSO-D6) δ 1.70-1.78(m, 2H), 2.00-2.09(m, 2H), Example 2 step c, using 3-
    2.18-2.26(m, 2H), 3.05-3.17(m, 2H), 3.24-3.40(m, 2H), 3.97-4.06(m, 2H), tert-butoxycarbonylmethoxy-
    4.44-4.52(m, 2H), 4.59-4.70(m, 2H), 4.73(s, 2H), 4.81-4.86(m, benzoic acid, followed by the
    1H), 4.91-4.93(m, 2H), 6.90-6.93(m, 1H), 6.96-7.04(m, 1H), addition of (1M) HCl in
    7.07-7.11(m, 1H), 7.17-7.20(m, 1H), 7.34-7.43(m, 2H), ether to form final compound
    7.52-7.55(m, 1H), as hydrochloride salt. (HCl
    also cleaved tert-butyl ester to
    leave acid.)
    586 (I) 492(M+H) (DMSO-D6) δ 1.56-1.87(3H, m), 1.94-2.17(5H, m), 3.06-3.27(7H, Prepared by deprotection
    m), 3.50-3.78(3H, m), 4.19(2H, t), 4.57-4.69(1H, m), 4.80-4.85(1H, of 584(I) using trifluoroacetic
    m), 6.98-7.10(4H, m), 7.34-7.44(2H, m), 7.57(1H, dd) acid in dichloromethane
    588 (I) 551(M+H)   145 (CDCl3) δ 0.09(2H, dd), 0.44(2H, dd), 0.83-0.89(1H, m), Example 2 step c
    1.67-1.78(2H, m), 1.96-2.09(3H, m), 2.18-2.28(4H, m), 2.78-2.89(1H,
    m), 3.08-3.20(4H, m), 3.34(2H, s), 3.47-3.65(3H, m),
    4.59-4.68(1H, m), 4.84(1H, s), 7.05(1H, ddd), 7.36(1H, dd), 7.55(1H, t),
    7.73-7.81(2H, m), 7.90(1H, t), 8.00(1H, d)
     71 (IV) 497(M+H) (CDCl3) δ 1.56(2H, qd), 1.79-1.99(8H, m), 2.19(3H, s), Example 2 step c
    2.45-2.52(2H, m), 2.60(1H, tt), 2.76-2.83(2H, m), 2.91-3.11(2H, m),
    3.21(3H, s), 4.28-4.35(1H, m), 6.74(1H, d), 7.05-7.12(2H, m),
    7.24(1H, d), 7.63(1H, d)
    245 (IV) 486(M+H) 120-126 (CDCl3) δ 1.45-1.61(2H, m), 1.80-2.03(6H, m), 2.19(3H, s), Example 2 step c using 2-
    2.45-2.53(2H, m), 2.54-2.62(1H, m), 2.79-3.09(4H, m), 3.80-3.99(1H, Oxo-2,3-dihydro-
    m), 4.28-4.34(1H, m), 4.62-4.81(1H, m), 6.73(1H, d), benzothiazole-6-carboxylic
    7.05-7.12(3H, m), 7.30(1H, dd), 7.47(1H, d) acid prepared according
    to Chem. Pharm. Bull.
    1988, 36, p2253
    297 (IV) 526(M+H) 115-117 (CDCl3) δ 1.42-1.64(2H, m), 1.78-1.87(3H, m), 1.93-2.01(3H, Example 2 step c
    m), 2.19(3H, s), 2.44-2.51(2H, m), 2.57(1H, tt), 2.75-2.88(3H,
    m), 3.01-3.14(1H, m), 3.64-3.73(1H, m), 4.27-4.33(1H, m),
    4.65-4.74(1H, m), 6.73(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.52(1H, dd),
    7.58(1H, d), 8.11(1H, d)
    298 (IV) 480(M+H) 120-126 (CDCl3) δ 1.31-1.66(2H, m), 1.70-2.05(6H, m), 2.19(3H, s), Example 2 step c
    2.38-2.60(3H, m), 2.73-2.83(2H, m), 2.85-3.11(2H, m), 3.71-3.86(1H,
    m), 4.26-4.35(1H, m), 4.76-4.92(1H, m), 6.73(1H, d), 7.07(1H,
    dd), 7.11(1H, s), 7.19-7.34(1H, m), 7.57(1H, t), 7.59-7.68(1H, m),
    7.73(1H, t), 8.46(1H, d)
    214 (IV) 514(M+H)    96 (CDCl3) δ 1.42-1.62(2H, m), 1.74-2.02(6H, m), 2.19(3H, s), Example 2 step c
    2.44-2.61(3H, m), 2.75-2.85(3H, m), 2.95-3.11(1H, m), 3.42(2H, s),
    3.45(3H, s), 3.78-3.93(1H, m), 4.26-4.36(1H, m), 4.64-4.81(1H,
    m), 6.74(1H, d), 7.02-7.15(3H, m), 7.27(1H, s), 7.38(1H, d)
    589 (I) 540(M+H) (CDCl3) δ 1.52-1.62(2H, m), 1.68(1H, d), 1.84(1H, d), 1.92(2H, d), Example 2 step c
    2.35-2.42(2H, m), 2.52-2.55(1H, m), 2.63(6H, s), 2.72-2.83(3H,
    m), 2.99-3.13(2H, m), 3.46-3.56(2H, m), 4.38-4.45(1H, m),
    4.49(1H, d), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 7.73-7.75(2H, m),
    7.81-7.83(1H, m), 8.31(1H, s)
    590(I) 556(M+H) (DMSO-D6) δ 1.43-1.62(4H, m), 1.66(1H, d), 1.85(1H, d), Example 2 step c
    1.89-1.97(2H, m), 2.35-2.44(3H, m), 2.73-2.87(3H, m), 3.11(1H, t),
    3.42(3H, s), 3.52(1H, d), 4.39-4.46(1H, m), 4.50(1H, d), 6.98(1H,
    dd), 7.25(1H, d), 7.49(1H, d), 8.36(1H, t), 8.54(1H, t), 8.67(1H, t)
    591 (I) 526(M+H) (DMSO-D6) δ 1.29-1.39(2H, m), 1.90(2H, d), 2.11-2.18(1H, m), Example 2 step c
    2.39(2H, t), 3.13(2H, t), 3.44-3.52(2H, m), 3.65-3.73(2H, m),
    3.82-3.91(4H, m), 3.94-4.01(2H, m), 4.47-4.57(1H, m),
    6.15(1H, d), 6.88-6.93(1H, m), 6.95(1H, dd), 7.03(1H, d), 7.31(1H, t),
    7.62-7.65(1H, m), 8.32-8.51(2H, m), 8.95(1H, t)
    593 (I) 536(M+H) (DMSO-D6) δ 1.42-1.63(4H, m), 1.66(1H, d), 1.84(1H, d), Example 2 step c
    1.89-1.97(2H, m), 2.32-2.45(1H, m), 2.50-2.61(2H, m), 2.72-2.87(3H,
    m), 3.08(1H, t), 3.37(3H, s), 3.48(1H, d), 4.37-4.46(1H, m),
    4.46-4.55(1H, m), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 8.21(1H, t),
    8.30(1H, t), 8.48(1H, t)
    594 (I) 550(M+H) (DMSO-D6) δ 1.38-1.52(2H, m), 1.53-1.64(2H, m), 1.84(2H, d), Example 2 step c
    1.88-1.98(2H, m), 2.37-2.45(4H, m), 2.58-2.68(1H, m),
    2.74-2.82(3H, m), 3.17(3H, s), 4.37-4.50(2H, m), 6.99(1H, dd),
    7.00-7.02(1H, m), 7.26(1H, d), 7.49(1H, d), 7.61(1H, d), 7.70(1H, dd),
    8.23(1H, d)
    299 (IV) 525(M+H) (DMSO-D6) δ 1.38-1.5(2H, m), 1.60-1.70(2H, m), Example 12
    1.81-2.00(2H, m), 2.40(3H, s), 2.41-3.31(9H, m), 3.35(3H, s),
    3.41-3.58(1H, m), 4.4-4.55(2H, m), 7.09(1H, d), 7.34(1H, d), 7.71(2H, m),
    7.90(1H, s), 8.0(1H, m)
    300 (IV) 489(M+H) (DMSO-D6) δ 1.10(3H, t), 1.35-1.50(2H, m), 1.58-1.70(2H, m), Example 12
    1.81-1.97(2H, m), 2.25-3.20(11H, m), 3.32(3H, s), 3.4-3.6(1H,
    m), 4.25-4.6(2H, m), 6.85-7.00(3H, m), 7.63-7.78(2H, m),
    7.90(1H, s), 7.98-8.02(1H, m)
    143 (IV) 465(M+H) (CDCl3) δ 1.63-1.74(2H, m), 1.78-1.88(3H, m), 1.92-2.04(3H, Example 2 step c
    m), 2.19(3H, s), 2.43-2.55(2H, m), 2.64(1H, tt), 2.76-2.94(3H,
    m), 3.13-3.27(1H, m), 4.25-4.35(2H, m), 4.82-4.90(1H, m),
    6.74(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.56(1H, dd), 7.85(1H, d),
    8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd)
    301 (IV) 530(M+H) (CDCl3) δ 1.57-1.71(2H, m), 1.80-1.91(3H, m), 1.95-2.06(3H, Example 2 step c
    m), 2.20(3H, s), 2.47-2.55(2H, m), 2.61-2.72(1H, m),
    2.79-2.86(2H, m), 2.91-3.35(2H, m), 3.08(3H, s), 4.28-4.37(1H, m),
    4.69-4.80(2H, m), 6.74(1H, d), 6.90(1H, d), 7.07(1H, dd), 7.12(1H, d),
    7.57(1H, d), 7.79(1H, dd), 8.32(1H, d)
    572 (I) 500(M+H) (CDCl3) δ 1.37-1.66(2H, m), 1.73-1.88(3H, m), 1.93-2.05(3H, Example 2 step c
    m), 2.41-2.51(2H, m), 2.52-2.63(1H, m), 2.75-2.86(2H, m),
    2.86-3.09(2H, m), 3.71-3.90(1H, m), 4.23-4.32(1H, m), 4.77-4.93(1H,
    m), 6.75(1H, dd), 6.99(1H, d), 7.27-7.32(3H, m), 7.54-7.67(1H,
    m), 7.57(1H, t), 7.74(1H, t), 8.46(1H, d)
    120 (IV) 480(M+H) (CDCl3) δ 1.46-1.66(2H, m), 1.79-2.01(6H, m), 2.19(3H, s), Example 2 step c using acid
    2.45-2.52(2H, m), 2.59(1H, tt), 2.75-2.84(2H, m), 2.92-3.20(2H, m), available from Bionet
    3.74-4.00(1H, m), 4.27-4.35(1H, m), 4.55-4.90(1H, m), Research Ltd., Highfield
    6.49(1H, dd), 6.74(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.76(1H, d), Industrial Estate,
    7.88(1H, dd), 8.03(1H, d), 8.48(1H, d), 8.57(1H, d) Camelford, Cornwall,
    PL32 9QZ, United Kingdom
    145 (IV) 538(M+H) (CDCl3) δ 1.35-1.73(2H, m), 1.77-1.89(3H, m), 1.92-2.06(3H, Example 2 step c using acid
    m), 2.19(3H, s), 2.43-2.64(3H, m), 2.74-2.83(2H, m), available from Peakdale Inc.
    2.83-2.94(1H, m), 3.00-3.12(1H, m), 3.38-3.54(1H, m), 4.26-4.35(1H, m), 109 East Scotland Drive
    4.76-4.92(1H, m), 6.73(1H, d), 7.07(1H, dd), 7.11(1H, d), Bear, DE, 19701-1756
    7.70(1H, d), 7.98(1H, dd), 8.19(1H, d) USA
    240 (IV) 465(M+H) (CDCl3) δ 1.62-1.74(2H, m), 1.77-1.86(3H, m), 1.93-2.03(3H, Example 2 step c
    m), 2.33(3H, s), 2.41-2.54(2H, m), 2.65(1H, tt), 2.78-2.86(1H,
    m), 2.89(2H, td), 3.21(1H, td), 4.21-4.35(2H, m), 4.81-4.90(1H,
    m), 6.67(1H, dd), 6.78(1H, d), 7.20(1H, d), 7.57(1H, dd), 7.85(1H,
    d), 8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd)
    267 (IV) 453(M+H) (CDCl3) δ 1.62(2H, qd), 1.79-2.01(6H, m), 2.19(3H, s), Example 2 step c
    2.43-2.52(2H, m), 2.64(1H, tt), 2.74-2.85(2H, m), 3.12-3.22(1H, m),
    4.26-4.32(1H, m), 4.77-4.86(1H, m), 5.24-5.33(1H, m), 6.74(1H, d),
    6.84(1H, td), 7.07(1H, dd), 7.11(1H, d), 7.21(1H, dd), 7.23(1H, dd),
    7.60(1H, dd), 8.06(1H, d), 8.13(1H, dt)
    199 (IV) 470(M+H) (CDCl3) δ 1.57-1.67(2H, m), 1.81-1.88(2H, m), 1.93-2.01(4H, Example 2 step c
    m), 2.20(3H, s), 2.50(2H, td), 2.65(1H, tt), 2.82(2H, td),
    2.96-3.20(2H, m), 4.28-4.35(1H, m), 4.74(2H, d), 6.73-6.75(2H, m),
    7.01-7.12(3H, m), 7.28(1H, d), 7.35(1H, dd), 9.35(1H, s)
    181 (IV) 538(M+H) (CDCl3) δ 1.50-1.65(2H, m), 1.70-1.83(3H, m), 1.93-2.04(3H, Example 2 step c
    m), 2.32(3H, s), 2.40-2.50(2H, m), 2.52-2.62(1H, m),
    2.76-2.92(3H, m), 3.01-3.10(1H, m), 3.38-3.52(1H, m), 4.22-4.30(1H, m),
    4.77-4.90(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d),
    7.70(1H, d), 7.98(1H, dd), 8.19(1H, d)
    216 (IV) 526(M+H) (CDCl3) δ 1.47-1.66(2H, m), 1.79-1.88(3H, m), 1.95-2.04(3H, Example 2 step c
    m), 2.32(3H, s), 2.53-2.61(2H, m), 2.70(1H, tt), 2.76-2.89(3H,
    m), 2.99-3.13(1H, m), 3.63-3.74(1H, m), 4.27-4.33(1H, m),
    4.63-4.77(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d), 7.50(1H, dd),
    7.56(1H, d), 8.09(1H, d)
    266 (IV) 480(M+H) (CDCl3) δ 1.37-1.67(2H, m), 1.76-1.85(3H, m), 1.93-2.01(3H, Example 2 step c
    m), 2.32(3H, s), 2.41-2.48(2H, m), 2.50-2.60(1H, m),
    2.77-2.85(2H, m), 2.86-3.10(2H, m), 3.73-3.85(1H, m), 4.23-4.29(1H, m),
    4.77-4.92(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d),
    7.21-7.31(1H, m), 7.54-7.68(1H, m), 7.56(2H, t), 7.73(1H, t), 8.46(1H,
    d)
    540 (I) 485(M+H) (CDCl3) δ 1.69-1.84(4H, m), 1.95-2.02(4H, m), 2.43-2.53(2H, Example 2 step c
    m), 2.65(1H, tt), 2.79-2.93(3H, m), 3.18-3.25(1H, m),
    4.23-4.35(2H, m), 4.82-4.90(1H, m), 6.75(1H, dd), 7.00(1H, d), 7.31(1H, d),
    7.57(1H, dd), 7.86(1H, d), 8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd)
    204 (IV) 470(M+H) (CDCl3) δ 1.57-1.67(2H, m), 1.77-1.85(2H, m), 1.94-2.02(4H, Example 2 step c
    m), 2.33(3H, s), 2.45-2.52(2H, m), 2.61-2.69(1H, m),
    2.81-2.86(2H, m), 2.97-3.18(2H, m), 4.24-4.30(1H, m), 4.74(2H, d),
    6.68(1H, dd), 6.73(1H, d), 6.78(1H, d), 7.04(1H, td), 7.20(1H, d),
    7.28(1H, d), 7.35(1H, dd), 9.34(1H, s).
    104 (IV) 480(M+H) (CDCl3) δ 1.49-1.63(2H, m), 1.76-2.00(6H, m), 2.33(3H, s), Example 2 step c
    2.43-2.49(2H, m), 2.59(1H, tt), 2.79-2.85(3H, m), 3.00-3.18(1H, m),
    3.81-3.96(1H, m), 4.24-4.29(1H, m), 4.67-4.83(1H, m),
    6.49(1H, dd), 6.67(1H, dd), 6.78(1H, d), 7.20(1H, d), 7.76(1H, d),
    7.88(1H, dd), 8.03(1H, d), 8.48(1H, d), 8.57(1H, d)
    243 (IV) 486(M+H) (DMSO-D6/CDCl3) δ 1.43-1.59(2H, m), 1.73-1.98(6H, m), Example 2 step c
    2.32(3H, s), 2.43-2.48(2H, m), 2.79-2.87(2H, m), 2.91-3.40(5H, m),
    4.23-4.30(1H, m), 6.68(1H, dd), 6.78(1H, d), 7.14(1H, d),
    7.19(1H, d), 7.26(1H, dd), 7.43(1H, d), 7.51(1H, s).
    191 (IV) 514(M+H) (CDCl3) δ 1.46-1.59(2H, m), 1.76-2.00(6H, m), 2.32(3H, s), Example 2 step c
    2.44-2.48(2H, m), 2.54-2.59(1H, m), 2.78-2.85(3H, m), 3.42(3H, s),
    3.45(3H, s), 3.79-3.92(1H, m), 4.23-4.30(1H, m), 4.67-4.79(1H,
    m), 6.67(1H, dd), 6.77(1H, d), 7.02(1H, d), 7.15(1H, s), 7.20(1H, d),
    7.37(1H, d)
    519 (I) 490(M+H) (CDCl3) δ 1.61(2H, qd), 1.77-1.85(2H, m), 1.94-2.02(4H, m), Example 2 step c
    2.38-2.51(2H, m), 2.65(1H, tt), 2.80-2.85(2H, m), 2.95-3.14(2H, m),
    4.25-4.30(1H, m), 4.73-4.77(2H, m), 6.73(1H, d), 6.75(1H, dd),
    7.00(1H, d), 7.03(1H, td), 7.27(1H, dd), 7.31(1H, d), 7.35(1H, dd),
    9.49(1H, s)
    494 (I) 558(M+H) (CDCl3) δ 1.48-1.71(2H, m), 1.74-1.83(3H, m), 1.93-2.03(3H, Example 2 step c
    m), 2.42-2.50(2H, m), 2.55-2.62(18, m), 2.76-2.93(3H, m),
    3.01-3.10(1H, m), 3.40-3.50(1H, m), 4.22-4.31(1H, m), 4.77-4.90(1H,
    m), 6.75(1H, dd), 6.98(1H, d), 7.30(1H, d), 7.67(1H, d), 7.98(1H,
    dd), 8.19(1H, d)
    238 (IV) 511(M+H) 172-173 (CDCl3) δ 1.53-1.63(2H, m), 1.82-1.89(3H, m), 2.00-2.05(3H, Example 21
    m), 2.05-2.61(3H, m), 2.80-2.84(3H, m), 2.98-3.09(1H, m),
    3.03(3H, s), 3.77(1H, br s), 4.41-4.45(1H, m), 4.70(1H, br s), 6.99(2H,
    d), 7.21-7.26(1H, m), 7.44-7.54(2H, m), 7.86(2H, d)
    496 (I) 500(M+H) (DMSO-D6) δ 1.46(2H, qd), 1.54-1.61(2H, m), 1.65-1.88(3H, m), Example 2 step c
    1.89-1.97(2H, m), 2.37-2.42(2H, m), 2.54-2.61(1H, m),
    2.73-2.83(2H, m), 3.04-3.17(1H, m), 3.61-3.72(1H, m), 4.39-4.56(2H,
    m), 6.62(1H, dd), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 7.87(1H,
    dd), 7.97(1H, dd), 8.04(1H, dd), 8.52(1H, dd), 8.65(1H, dd)
    483 (I) 506(M+H) (DMSO-D6) δ 1.41(2H, qd), 1.53-1.62(2H, m), 1.68-1.82(2H, m), Example 2 step c
    1.89-1.96(2H, m), 2.36-2.43(3H, m), 2.53-2.59(3H, m),
    2.74-2.80(3H, m), 4.39-4.45(1H, m), 6.97(1H, dd), 7.13(1H, d),
    7.25(1H, d), 7.30(1H, dd), 7.49(1H, d), 7.66(1H, d)
    302 (IV) 498(M+H) (CDCl3) δ 1.40-1.74(2H, m), 1.79-2.02(6H, m), 2.20(3H, s), Example 2 step c
    2.42-2.61(3H, m), 2.67(1H, td), 2.74-2.84(2H, m), 3.16(1H, t),
    3.91-4.00(1H, m), 4.26-4.36(1H, m), 4.58-4.78(5H, m), 6.74(1H, d),
    6.76-6.79(1H, m), 6.98-7.02(3H, m), 7.07(1H, dd), 7.12(1H, d)
    303 (IV) 498(M+H) (CDCl3) δ 1.42-1.61(2H, m), 1.77-1.90(3H, m), 1.93-2.03(3H, Example 2 step c
    m), 2.33(3H, s), 2.41-2.49(2H, m), 2.57(1H, tt), 2.67(1H, t),
    2.77-2.84(2H, m), 3.16(1H, t), 3.95(1H, d), 4.24-4.29(1H, m),
    4.59-4.77(5H, m), 6.68(1H, dd), 6.75-6.79(2H, m), 6.97-7.00(3H, m),
    7.21(1H, d)
    596 (I) 518(M+H) (CDCl3) δ 1.43-1.64(2H, m), 1.77-1.89(3H, m), 1.94-2.01(3H, Example 2 step c
    m), 2.41-2.50(2H, m), 2.57(1H, tt), 2.68(1H, t), 2.76-2.83(2H, m),
    3.16(1H, t), 3.94-3.97(1H, m), 4.24-4.30(1H, m), 4.58-4.63(1H,
    m), 4.68(2H, s), 4.76(2H, d), 6.76-6.78(2H, m), 6.98-7.00(3H, m),
    7.26(1H, s), 7.31(1H, d)
    467 (I) 534(M+H) (DMSO-D6) δ 1.35-1.50(2H, m), 1.52-1.65(3H, m), Example 2 step c
    1.68-1.84(2H, m), 1.88-1.98(2H, m), 2.35-2.44(2H, m), 2.54-2.61(1H, m),
    2.73-2.82(3H, m), 3.37(3H, s), 3.57(2H, s), 3.60-3.71(1H, m),
    4.38-4.56(2H, m), 6.98(1H, dd), 7.07(1H, dd), 7.24(1H, d),
    7.26(1H, d), 7.47(1H, d), 7.50(1H, d)
    269 (IV) 453(M+H) (CDCl3) δ 1.55-1.68(4H, m), 1.75-2.01(4H, m), 2.33(3H, s), Example 2 step c
    2.41-2.51(2H, m), 2.64(1H, tt), 2.78-2.87(3H, m), 3.12-3.24(1H, m),
    4.21-4.29(1H, m), 4.76-4.88(1H, m), 5.23-5.34(1H, m),
    6.67(1H, dd), 6.78(1H, d), 6.84(1H, t), 7.19-7.26(2H, m), 7.60(1H, d),
    8.06(1H, s), 8.13(1H, dd)
    597 (I) 546(M+H) (CDCl3) δ 1.39-1.66(2H, m), 1.73-1.86(4H, m), 1.92-2.03(2H, Example 2 step c
    m), 2.41-2.50(2H, m), 2.53-2.63(1H, m), 2.76-2.88(2H, m),
    2.98-3.12(1H, m), 3.62-3.77(1H, m), 4.24-4.29(1H, m), 4.62-4.78(1H,
    m), 6.75(1H, dd), 6.99(1H, d), 7.31(2H, d), 7.53(1H, dd), 7.57(1H,
    t), 8.12(1H, d)
    598 (I) 474(M+H) (CDCl3) δ 1.58-1.75(2H, m), 1.80-1.88(2H, m), 1.91-2.05(4H, Example 2 step c
    m), 2.53-2.61(2H, m), 2.71-2.90(4H, m), 3.18-3.22(1H, m),
    4.27-4.33(1H, m), 4.84(1H, d), 5.55(1H, d), 6.75(1H, dd), 6.95(1H, dd),
    7.00(1H, d), 7.31(1H, d), 8.09(1H, s), 8.46(1H, dd), 8.62(1H, dd)
    579 (I) 491(M+H) (CDCl3) δ 1.61(1H, qd), 1.75-2.02(7H, m), 2.42-2.51(2H, m), Example 2 step c
    2.59-2.67(1H, m), 2.75-2.86(3H, m), 3.12-3.21(1H, m),
    4.23-4.29(1H, m), 4.76-4.85(1H, m), 5.23-5.32(1H, m), 6.75(1H, dd),
    6.99(1H, d), 7.16(1H, ddd), 7.30(1H, d), 7.58(1H, dd), 8.07(2H, s)
    599 (I) 487(M+H) (CDCl3) δ 1.58-1.67(1H, m), 1.75-2.02(7H, m), 2.43-2.51(3H, Example 2 step c
    m), 2.59-2.68(1H, m), 2.61(3H, s), 2.76-2.85(3H, m),
    3.12-3.23(1H, m), 4.23-4.28(1H, m), 4.78-4.87(1H, m), 5.30-5.38(1H, m),
    6.67(1H, d), 6.75(1H, dd), 7.20(1H, dd), 7.30(1H, d), 7.51(1H, d),
    8.01(1H, s)
    600 (I) 507(M+H) (CDCl3) δ 1.61(1H, qd), 1.70-2.04(7H, m), 2.41-2.53(2H, m), Example 2 step c
    2.63(1H, t), 2.73-2.88(3H, m), 3.09-3.23(1H, m), 4.21-4.31(1H, m),
    4.74-4.86(1H, m), 5.20-5.30(1H, m), 6.75(1H, dd), 6.99(1H, d),
    7.19(1H, d), 7.30(1H, d), 7.55(1H, d), 8.04(1H, s), 8.19(1H, s)
    304 (IV) 505(M+H) (CDCl3) δ 1.57-1.68(2H, m), 1.82-2.01(6H, m), 2.46-2.54(2H, Example 2 step c
    m), 2.46(3H, s), 2.59-2.69(1H, m), 2.73-2.90(3H, m),
    3.10-3.23(1H, m), 4.32-4.39(1H, m), 4.76-4.85(1H, m), 5.22-5.32(1H, m),
    6.75(1H, d), 7.14-7.27(2H, m), 7.58(1H, dd), 8.07(2H, s)
    601 (I) 487(M+H) (CDCl3) δ 1.55-1.65(1H, m), 1.75-2.01(7H, m), 2.40(3H, s), Example 2 step c
    2.44-2.50(2H, m), 2.63(1H, qt), 2.73-2.86(3H, m), 3.10-3.22(1H, m),
    4.22-4.28(1H, m), 4.75-4.86(1H, m), 5.22-5.34(1H, m),
    6.66(1H, dd), 6.75(1H, dd), 6.99(1H, d), 7.30(1H, d), 7.34(1H, s),
    7.97(1H, s), 7.99(1H, d)
    343 (I) 566(M+H) (CDCl3) δ 1.39-1.65(1H, m), 1.77-1.89(4H, m), 1.94-2.03(3H, Example 2 step c
    m), 2.43-2.50(2H, m), 2.54-2.62(1H, m), 2.77-2.90(3H, m),
    3.03-3.13(1H, m), 3.53(3H, s), 3.65-3.74(1H, m), 4.26-4.31(1H, m),
    4.26(2H, s), 4.69-4.79(1H, m), 6.75(1H, dd), 6.99(1H, d),
    7.26-7.35(3H, m), 8.00(1H, d)
    603 (I) 526(M+H) (CDCl3) δ 1.49-1.58(2H, m), 1.76-1.84(3H, m), 1.90-2.01(4H, Example 2 step c
    m), 2.44-2.48(2H, m), 2.53-2.59(1H, m), 2.78-2.82(2H, m),
    2.78-3.00(5H, m), 3.15-3.19(1H, m), 4.24-4.29(1H, m), 4.96(2H, s),
    6.74-6.80(2H, m), 6.99(1H, d), 7.31(1H, d), 7.66-7.70(2H, m)
    534 (I) 543(M+H) (CDCl3) δ 1.49(3H, t), 1.57-2.00(6H, m), 2.43-2.52(2H, m), Example 2 step c
    2.56-2.62(3H, m), 2.67(3H, s), 2.78-2.84(3H, m), 3.10-3.19(1H, m),
    3.74(1H, d), 4.25(1H, dquintet), 4.42-4.49(2H, m), 4.76(1H, d),
    6.75(1H, dd), 6.99(1H, d), 7.23(1H, d), 7.30(1H, d), 8.09(1H, s),
    8.60(1H, d)
     5 (II) 474(M+H) Example 2 step c
     6 (II) 468(M+H) (DMSO-D6) δ 1.39-1.45(1H, m), 1.54-1.93(6H, m), Example 2 step c
    2.32-2.39(2H, m), 2.49-2.53(2H, m), 2.72-3.02(4H, m), 3.29-3.32(2H, m),
    4.31-4.34(1H, m), 6.75-6.79(1H, m), 7.08(1H, ddd), 7.30(2H, dt),
    7.49-7.56(2H, m), 7.76(1H, t), 8.24(1H, dd)
     7 (II) 453(M+H) (DMSO-D6) δ 1.45-1.69(5H, m), 1.84-1.99(3H, m), 2.40(2H, t), Example 2 step c
    2.59-2.66(1H, m), 2.73-2.92(3H, m), 3.03-3.14(1H, m),
    3.69-3.76(1H, m), 4.31-4.37(1H, m), 4.55-4.61(1H, m), 6.78(1H, dd),
    7.09(1H, ddd), 7.31(1H, dt), 7.69-7.78(2H, m), 8.49-8.65(2H, m),
    9.15(1H, dd)
     8 (II) 441(M+H) (DMSO-D6) δ 1.34-1.45(2H, m), 1.52-1.61(2H, m), Example 2 step c
    1.76-1.86(2H, m), 1.87-1.96(2H, m), 2.33-2.44(2H, m), 2.56-2.63(1H, m),
    2.72-2.81(3H, m), 3.05-3.14(1H, m), 4.29-4.38(1H, m),
    4.51-4.61(1H, m), 5.09-5.19(1H, m), 6.73-6.79(1H, m),
    6.94-6.99(1H, m), 7.04-7.12(1H, m), 7.28-7.34(2H, m), 7.61(1H, dd),
    8.30(1H, s), 8.56(1H, dt)
    305 (IV) 514(M+H) (DMSO-D6) δ 1.42-1.51(2H, m), 1.60-1.93(6H, m), Example 2 step c
    2.41-2.47(2H, m), 2.41(3H, s), 2.54-2.60(1H, m), 2.72-2.80(2H, m),
    3.05-3.15(1H, m), 3.29-3.35(1H, m), 3.60-3.71(1H, m), 4.44-4.54(2H,
    m), 6.59-6.64(1H, m), 7.07-7.13(1H, m), 7.31-7.38(1H, m),
    7.86-7.89(1H, m), 7.95-7.99(1H, m), 8.01-8.07(1H, m), 8.50-8.54(1H,
    m), 8.63-8.67(1H, m)
    306 (IV) 531(M+H) (DMSO-D6) δ 1.39-1.95(8H, m), 2.40(3H, s), 2.42-2.47(2H, m), Example 2 step c
    2.55-2.63(2H, m), 2.72-2.81(2H, m), 2.94-3.09(2H, m), 3.42(3H,
    s), 4.14-4.32(1H, m), 4.46-4.54(1H, m), 7.10(1H, d), 7.36(1H, d),
    7.49(1H, d), 7.78(1H, d)
    307 (IV) 525(M+H) (DMSO-D6) δ 1.39-1.95(9H, m), 2.42(3H, s), 2.44-2.48(1H, m), Example 2 step c
    2.55-2.61(1H, m), 2.70-2.83(2H, m), 2.99-3.10(1H, m),
    3.29(3H, s), 3.41-3.52(2H, m), 4.46-4.58(2H, m), 7.11(1H, d),
    7.36(1H, d), 7.66(2H, dd), 7.99(2H, dd)
    308 (IV) 512(M+H) (DMSO-D6) δ 1.60-4.25(18H, m), 4.55-4.80(1H, m), 5.22-5.45(1H, Prepared in a similar manner
    m), 7.05(1H, t), 7.75-7.82(2H, m), 7.85(1H, s), 8.00-8.18(2H, m), to Example 15 and isolated
    8.60(1H, s), 9.63(1H, br s) as the trifluoroacetate salt
     1 (V) 509(M+H) 87-88 (DMSO-D6) δ 1.11-1.18(2H, m), 1.36-1.53(4H, m), Example 2 step c
    1.63-1.78(2H, m), 2.07(2H, t), 2.48-2.52(2H, m), 2.81-2.84(4H, m),
    3.01-3.04(2H, m), 3.27-3.27(3H, m), 3.49-3.50(1H, m), 4.44-4.53(1H,
    m), 7.15-7.18(1H, m), 7.44-7.45(1H, m), 7.50-7.53(1H, m),
    7.69-7.76(2H, m), 7.90(1H, t), 7.98-8.02(1H, m)
     2 (V) 510(M+H) (CDCl3) δ 1.38-1.48(3H, m), 1.59(1H, br s), 1.81-2.07(4H, m), Example 12
    2.34(2H, t), 2.55-2.60(1H, m), 2.84-2.92(3H, m), 3.07(4H, s),
    3.21(1H, br s), 3.60(1H, d), 3.68(1H, br s), 4.74(1H, br s), 6.41(1H, dd),
    6.64(1H, d), 7.16(1H, d), 7.62-7.70(2H, m), 7.97-8.02(2H, m)
     3 (V) 523(M+H) (DMSO-D6) δ 1.42-1.56(4H, m), 1.64-1.86(4H, m), 2.33(2H, t), Prepared in a similar maner to
    2.54-2.61(1H, m), 2.76-2.85(1H, m), 2.87-2.93(2H, m), Example 12 using (3,4-
    3.04-3.12(1H, m), 3.28(3H, s), 3.36-3.44(1H, m), 3.48-3.57(1H, m), Dichloro-phenyl)-piperidin-
    4.47-4.55(1H, m), 7.70-7.77(2H, m), 7.80(1H, d), 7.91-7.95(2H, 4-yl-methanone hydrochloride
    m), 8.00(1H, dt), 8.14-8.16(1H, m) (free base was made
    insitu using triethylamine
    310 (IV) 478(M+H) 169-170 (DMSO-D6) δ 1.29-1.40(2H, m), 1.53-1.62(2H, m), Example 26 using 4-
    1.71-1.77(2H, m), 1.89-1.96(2H, m), 2.35-2.42(2H, m), 2.45-2.49(1H, m), Methoxyphenylisocyanate
    2.68-2.79(4H, m), 3.70(3H, s), 4.10-4.17(2H, m), 4.38-4.45(1H,
    m), 6.78-6.82(2H, m), 6.98(1H, dd), 7.25(1H, d), 7.30-7.34(2H,
    m), 7.49(1H, d), 8.30(1H, s)
    311 (IV) 466(M+H)   217 (DMSO-D6) δ 1.29-1.40(2H, m), 1.53-1.62(2H, m), Example 26 using 4-
    1.72-1.78(2H, m), 1.89-1.96(2H, m), 2.36-2.42(2H, m), 2.44-2.49(1H, m), Fluorophenylisocyanate
    2.71-2.79(4H, m), 4.11-4.17(2H, m), 4.38-4.45(1H, m),
    6.98(1H, dd), 7.05(2H, t), 7.25(1H, d), 7.45(2H, tt), 7.49(1H, d), 8.50(1H, s)
    312 (IV) 494(M+H) 170-172 (DMSO-D6) δ 1.29-1.40(2H, m), 1.52-1.62(2H, m), Example 26 using 3-
    1.72-1.78(2H, m), 1.89-1.96(2H, m), 2.36-2.42(2H, m), 2.43(3H, s), (Methylthio)phenylisocyanate
    2.44-2.48(1H, m), 2.71-2.79(4H, m), 4.15(2H, d), 4.38-4.45(1H, m),
    6.81(1H, d), 6.98(1H, dd), 7.15(1H, t), 7.24-7.27(2H, m), 7.43(1H,
    t), 7.49(1H, d), 8.48(1H, s)
    313 (IV) 462(M+H) 178-179 (DMSO-D6) δ 1.22-1.34(2H, m), 1.52-1.61(2H, m), Example 26 using
    1.65-1.72(2H, m), 1.88-1.95(2H, m), 2.33-2.46(3H, m), 2.61-2.76(4H, m), Benzylisocyanate
    3.99-4.05(2H, m), 4.22(2H, d), 4.37-4.44(1H, m), 6.97(1H, dd),
    7.04(1H, t), 7.18-7.31(6H, m), 7.49(1H, d)
    314 (IV) 492(M+H) 166-167 (DMSO-D6) δ 1.21-1.32(2H, m), 1.51-1.61(2H, m), Example 26 using 4-
    1.64-1.71(2H, m), 1.88-1.95(2H, m), 2.32-2.46(3H, m), 2.59-2.67(2H, m), Methoxybenzylisocyanate
    2.69-2.76(2H, m), 3.71(3H, s), 4.01(2H, d), 4.14(2H, d),
    4.37-4.44(1H, m), 6.83-6.87(2H, m), 6.94-6.99(2H, m), 7.14-7.18(2H, m),
    7.25(1H, d), 7.49(1H, d)
    315 (IV) 480(M+H) 209-210 (DMSO-D6) δ 1.21-1.32(2H, m), 1.52-1.61(2H, m), Example 26 using 4-
    1.65-1.71(2H, m), 1.88-1.95(2H, m), 2.32-2.46(3H, m), 2.60-2.68(2H, m), Fluorobenzylisocyanate
    2.70-2.76(2H, m), 4.01(2H, d), 4.19(2H, d), 4.38-4.44(1H, m),
    6.97(1H, dd), 7.05(1H, t), 7.11(2H, t), 7.24-7.29(3H, m), 7.49(1H, d)

    MS = Mass Spectrum has been obtained using either APCI+ or ES+ or ES−
  • The preparations of certain intermediates are now presented.
    • Method A 1-(3-Methoxy-4-nitro-benzoyl)-piperidin-4-one
  • CDI (9 g) added to a solution of 3-methoxy-4-nitrobenzoic acid (10 g) stirring in THF (200 ml) at RT. After 1 hour, 4-piperidone hydrochloride (6.9 g) and triethylamine (7.8 ml) were added and the mixture stirred overnight. The mixture was diluted with ethyl acetate, washed with 2N HCl (100 ml) then saturated NaHCO3 solution (200 ml) then saturated brine (200 ml). The organic layer was dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography (silica, mixtures of MeOH in dichloromethane) to give the product as a yellow solid (8.5 g; MS: APCI+ (M+H) 279).
    • Method B 1-(3-Methanesulfonyl-benzoyl)-piperidin-4-one
  • PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonyl benzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base (25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture was stirred overnight then washed with saturated NaHCO3 solution (200 ml) and then with saturated brine (200 ml). The organic layer was evaporated and the resulting residue purified by column chromatography (silica, 1:1 ethyl acetate: dichloromethane) to give the product as a thick oil (9.6 g; MS: APCI+ (M+H) 282).
    • Method C 1-(Benzo[1,2,3]thiadiazole-5-carbonyl)-piperidin-4-one
  • CDI (4.5 g) added to a solution of the benzo[1,2,3]thiadiazole-5-carboxylic acid (5 g) stirring in THF (100 ml) at RT. After 1 hour 4-piperidone hydrochloride (3.7 g) and triethylamine (4.3 ml) were added and the mixture stirred overnight. The resulting mixture was diluted with ethyl acetate, washed with 2M HCl (100 ml), saturated NaHCO3 solution (200 ml ) and then with saturated brine (200 ml). The organic layer was dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography (silica, eluting with mixtures of ethyl acetate in dichloromethane) to give the product as a yellow oil (2.1 g; MS: APCI+ (M+H) 262).
    • Method D [1,4′]Bipiperidinyl-4-ol
  • 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and 4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200 ml) with acetic acid (4 ml) at RT for 30 minutes. Sodium triacetoxyborohydride (23 g) was then added and the mixture stirred at RT overnight. The mixture was evaporated to dryness and the residue taken into water, extracted with diethyl ether (3×200 ml), the aqueous was basified to pH 9-10 and extracted with dichloromethane (3×200 ml). The dichloromethane extracts were combined, dried (MgSO4) and evaporated to leave an oil (19 g; same compound as Example 9 step 1). The oil was dissolved in methanol (300 ml ) and treated with concentrated hydrochloric acid (5 ml). The mixture was stirred overnight and then evaporated to dryness to leave the title compound as the hydrochloride salt (15 g).
  • 1H NMR (400 MHz, DMSO-D6) δ 1.6-2.4 (m, 9H), 2.8-3.5 (m, 8H), 3.62 (m, 1H), 3.95 (s, 1H), 9.29 and 9.059 (bs, 2H), 10.9 and 11.09 (bs, 1H).
    • Method E (4-Hydroxy-[1,4′]bipiperidinyl-1 ′-yl)-(3-methanesulfonyl-phenyl)-methanone
  • PyBrOP™ (25.3 g) was added to a stirred solution of 3-methanesulphonyl benzoic acid (10 g), [1,4′]bipiperidinyl-4-ol dihydrochloride (13 g, see Method D) and Hunig's base (34 ml) in dichloromethane (500 ml). The resulting mixture was stirred at RT overnight, then washed with saturated NaHCO3 solution (300 ml) followed by saturated brine (300 ml). The organic layer was dried (MgSO4) and evaporated to leave an oily residue. Column chromatography (silica, 20% methanol in DCM) gave the product as a white solid (16 g; MS: APCI+ (M+H) 367).
    • Method F 4-(3-Chloro-4-fluoro-phenoxy)-piperidine
  • DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g), 3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture was stirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixture stirred at RT overnight. The mixture was then evaporated to dryness and triethylamine (5 ml) was added. The mixture was evaporated and the residue was dissolved in methanol (10 ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge available from International Sorbent Technology Isolute® Flash SCX-2) and eluted: first with methanol then with 10% NH3 in methanol. The basic fractions were combined and evaporated to give the product as an oil (0.6 g).
  • 1H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.46 (2H, m), 1.83-1.91 (2H, m), 2.53-2.59 (2H, m), 2.87-2.96 (2H, m), 3.22-3.39 (1H, m), 4.39 (1H, septet), 6.92-6.98 (1H, m), 7.17-7.20 (1H, m), 7.30 (1H, t).
  • The following intermediates were prepared in similar manner to Method F:
    MS: (M + H)
    4-(4-chloro-2-methyl-phenoxy)-piperidine 226
    4-(4-chloro-3-fluoro-phenoxy)-piperidine 230
    4-(4-chloro-2-methoxy-phenoxy)-piperidine 242
    4-(4-fluoro-2-methoxy-phenoxy)-piperidine 226
    4-(4-methoxy-phenoxy)-piperidine 208
    4-p-tolyloxy-piperidine 192
    4-(4-chloro-3-methyl-phenoxy)-piperidine 226
    4-(4-chloro-phenoxy)-piperidine 212
    4-(4-fluoro-phenoxy)-piperidine 196
    4-(2,4-dichloro-phenoxy)-piperidine 246
    4-(2-chloro-4-fluoro-phenoxy)-piperidine 230
    4-(2,4-difluoro-phenoxy)-piperidine 214
    4-(4-chloro-2-fluoro-phenoxy)-piperidine 230
    4-(4-fluoro-2-methyl-phenoxy)-piperidine 210
    4-(4-chloro-2,6-dimethyl-phenoxy)-piperidine 240
    4-(2,3-dichloro-phenoxy)-piperidine 246
    4-(2,5-dichloro-phenoxy)-piperidine 246
    4-(2-chloro-4-methyl-phenoxy)-piperidine 226
    4-(2-chloro-5-methyl-phenoxy)-piperidine 226
    1-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-ethanone 234
    4-(2-chloro-6-methyl-phenoxy)-piperidine 226
    4-[2-(piperidin-4-yloxy)-phenyl]-morpholine 263
    4-(4-chloro-2-ethyl-phenoxy)-piperidine 240
    7-(piperidin-4-yloxy)-quinoline 229
    4-(2-tert-butyl-phenoxy)-piperidine 234
    4-(indan-5-yloxy)-piperidine 218
    4-(4-chloro-2-cyclohexyl-phenoxy)-piperidine 294
    5-chloro-2-(piperidin-4-yloxy)-benamide 255
    4-(4-chloro-2-isoxazol-5-yl-phenoxy)-piperidine 279
    4-(5-chloro-2-methyl-phenoxy)-piperidine 226
    4-phenoxy-piperidine 178
    4-(2,4-dichloro-6-methyl-phenoxy)-piperidine 260
    4-(3-chloro-4-methyl-phenoxy)-piperidine 226
    5-chloro-2-(piperidin-4-yloxy)-benzonitrile 237
    4-(2,4-dichloro-3-methyl-phenoxy)-piperidine 260
    4-(2-ethyl-4-fluoro-phenoxy)-piperidine 224
    4-(4-methanesulfonyl-phenoxy)-piperidine 297
    • Method G 4-Amino-3-ethoxy-benzoic acid
  • Potassium hydroxide (0.278 g) was added to a solution of 3-fluoro-4-nitrobenzoic acid (0.4 g) in ethanol (7 ml) and the reaction treated with microwaves (300W, 100° C.) for 5 minutes. The reaction mixture was acidified using 2N HCl and extracted with ethyl acetate. The extracts were combined, washed with water, dried (MgSO4) and evaporated to give 3-ethoxy-4-nitro-benzoic acid (0.325 g).
  • 3-Ethoxy-4-nitrobenzoic acid (0.31 g) was treated with 5% palladium on charcoal under an atmosphere of hydrogen (1 bar) for 3 hours. The reaction mixture was filtered and the filtrate was evaporated to leave the product as a beige solid (0.245 g; MS: ES31 (M−H) 180).
    • Method H 3,4-bis-Methanesulfonyl-benzoic acid
  • To 3-fluoro-4-nitro-benzoic acid tert-butyl ester (0.5 g) in DMSO was added NaSO2Me. The reaction mixture was heated to 100° C. for 24 hours. A mixture of water, diethyl ether and ethyl acetate (1:1:1) was added and the resulting mixture was extracted with diethyl ether/ethyl acetate (1:1). The organic extracts were combined, dried with MgSO4 and concentrated to leave a residue which was purified by chromatography (using 80% ethyl acetate/20% hexane) to give 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (366mg). 1H NMR (399.98 MHz, DMSO-D6) 1.59 (9H, s), 3.50 (3H, s) 3.52 (3H, s), 8.37-8.65 (3H, m).
  • To 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (0.366 g) in dichloromethane was added trifluoroacetic acid and the reaction mixture was stirred for 3 hours. The mixture was evaporated and trituration of the residue with diethyl ether gave the title compound (0.29 g; MS: APCI+ (M+H) 279).
    • Method I 4-Carbamoyl-5-methanesulfonyl-thiophene-2-carboxylic acid
  • To 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid methyl ester (0.5 g) in THF/H2O (3:1; 16 ml) was added LiOH (0.102 g). Hydrochloric acid (2M) was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined and the solvent evaporated to leave a mixture of 4-cyano-5-methanesulfonyl-thibphene-2-carboxylic acid and the title compound. This mixture was used without further purification. 1H NMR (299.944 MHz, DMSO-D6) δ 3.62 (3H, s), 7.99 (1H, s).
    • Method J 3-(2-Methyl-propane-1-sulfonyl)-benzoic acid
  • To a suspension of 3-sulfo-benzoic acid (1 g) and potassium carbonate (1.2 g) in dimethylacetamide (10 ml) was added iso-butyl iodide (0.65 ml). The mixture was heated by microwaves (600W) at 150° C. for 15 minutes. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the aqueous layer was separated, acidified to pH 1 with HCl (2N) and extracted with ethyl acetate (100 ml). The extract was evaporated to leave a residue which was purified by flash chromatography (Biotage 12S eluting with ethyl acetate: hexane: acetic acid, 29:70:1) to give the title product as a white solid (0.34 g). 1H NMR: (399.98 MHz, DMSO-D6) δ 0.98 (6H, d), 2.03 (1H, septet), 3.29 (2H, d), 7.81 (1H, t), 8.16 (1H, ddd), 8.27 (1H, dt), 8.38 (1H, t).
  • 3-Cyclopropylmethanesulfonyl-benzoic acid was prepared in a similar manner to that described in Method J. MS: (M−H) 239; 1H NMR: (DMSO-d6) δ0.06-0.10 (2H, m), 0.40-0.45 (2H, m), 0.82-0.89 (1H, m), 3.34 (2H, d), 7.80 (1H, t), 8.14 (1H, d), 8.28 (1H, d), 8.39 (1H, s).
    • Method K 3-(2-Methoxy-ethoxy)-benzoic acid methyl ester
  • To a solution of methyl 3-hydroxybenzoate (5.7 g) and 2-bromoethylmethyl ether (5.2 g) in dimethylformamide (100 ml) was added caesium carbonate (24.3 g). The reaction mixture was stirred for 12 hours. The mixture was then patitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (Biotage 12M, eluting iso-hexane then MeOH:dichloromethane 2:98 ) to give the product as a colourless oil (5.3 g).
  • 1H NMR: (CDCl3) δ 3.44 (3H, s), 3.75 (2H, t), 3.89 (3H, s), 4.15 (2H, t), 7.13 (1H, ddd), 7.32 (1H, t), 7.57 (1H, dd), 7.62 (1H, dt).
  • 3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester can be prepared in a similar manner to that described in Method K: 1H NMR: (299.944 MHz CDCl3) 1.49 (9H, s), 3.91 (3H, s), 4.56 (2H, s), 7.13-7.68 (4H, m).
    • Method L 3-(2-Methoxy-ethoxy)-benzoic acid
  • To a suspention of 3-(2-methoxy-ethoxy)-benzoic acid methyl ester (5.3 g) in tetrahydrofuran (200 ml) was added lithium hydroxide monohydrate (5.3 g) followed by water until an homogeneous solution was obtained. The reaction mixture was stirred for 12 hours, acidified and partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to yield a colourless solid (3.6 g).
  • 1H NMR: (DMSO-D6) δ 3.31 (3H, s), 3.67 (2H, t), 4.14 (2H, t), 7.20 (1H, ddd), 7.41 (1H, t), 7.44 (1H, dd), 7.53 (1H, dt)
  • 3-(2-tert-Butoxycarbonylamino-ethoxy)-benzoic acid can be prepared in a similar manner to that described in Method L.
  • 3-tert-Butoxycarbonylmethoxy-benzoic acid can be prepared in a similar manner to that described in Method L: 1H NMR (299.944 MHz, DMSO-D6) δ 2.51 (9H, s), 4.74 (2H, s), 7.18 (1H, dq), 7.38 (1H, m), 7.41 (1H, m), 7.55 (1H, dt), 13.03 (1H, s).
    • Method M 4-(2-Carboxy-2-phenyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
  • Piperazine-1-carboxylic acid tert-butyl ester (17.43 g) and 2-phenylacrylic acid (18 g) in iso-propanol (500 ml) was heated at reflux for four days. The resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give the title compound as a white solid (17 g; MS: APCI+ (M+H) 335).
    • Method N 5-Methanesulfonyl-1H-indole-2-carboxylic acid
  • To a solution of the 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester (0.49 g) in THF (12 mL) and water (4 ml) was added LiOH (0.098 g). The reaction mixture as left to stir for 2 hours. Acetic acid was added and the product extracted with dichloromethane. The organic extracts were combined, dried with magnesium sulfate, filtered and the filtrate evaporated to give the title compound as a solid (0.110 g).
  • 1H NMR (299.946 MHz, DMSO-D6) δ 3.18 (3H, s), 7.32-7.33 (1H, m), 7.61-7.64 (1H, m), 7.73-7.77 (1H, m), 8.30-8.31 (1H, m).
    • Method O
  • 5-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid was prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (see Example 25) using the commercially available 5-methyl-1,8a-dihydro-imidazo[ 1,2-a]pyridine-2-carboxylic acid ethyl ester. 6-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid and 6-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester were prepared in a similar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid and its ester above.
    • Method P Preparation of 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1,1,6-benzo[ 1,4]thiazine-6-carboxylic acid Step 1: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1,1,6-benzo[1,4]thiazine-6-carboxylic acid methyl ester
  • Figure US20070179297A1-20070802-C00095
  • To a solution of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g) in dichloromethane (25 ml) was added 32% peracetic acid dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 48 hours and then diluted with dichloromethane. The organic phase was washed once with water, twice with aqueous sodium sulfite solution, and once with saturated aqueous sodium bicarbonate.
  • The organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated to give the sub-title compound as a solid (1.012 g).
  • 1H NMR (399.978 MHz, CDCl3) δ 3.58 (3H, s), 4.00 (3H, s), 4.27 (2H, s), 7.96 -7.99 (2H, m), 8.04-8.06 (1H, m).
    • Step 2: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1,1,6-benzo[1,4]thiazine-6-carboxylic acid
  • To a solution of 4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-116-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g, from step 1) in MeOH (7 ml) was added dropwise a solution of sodium hydroxide (0.6 g) in water (5 ml). The reaction mixture was stirred at room temperature for 1 hour, diluted with water, cooled in an ice/water bath. Slow acidification with HCl (1N) to pH 2 yielded a precipitate which was isolated by filtration to give the title compound (0.595 g) as a solid.
  • 1H NMR (399.978MHz, DMSO-D6) δ 3.49 (3H,s), 4.91 (2H,s), 7.90-8.03 (3H, m).
    • Method Q Preparation of 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl Step a: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester
  • To a solution of 4-(4-methanesulfonyl-phenoxy)-piperidine (0.7 g) dissolved in THF (5 ml) and 1,2-dichloroethane (loml) with 1-Boc4-piperidone (0.71 g) was added NaBH(OAc)3 (0.926 g) and acetic acid (0.18 g). After 16 hours at RT aqueous NaOH (1M) solution and dichloromethane were added and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, dried with magnesium sulfate and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol 90:10) to give the sub-title product (1.1 g; MS: APCI+ (M+H) 439).
    • Step b: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl
  • The product of step a was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (5 ml) was added. After 16 hours at room temperature the solution was evaporated to leave the title compound as a TFA salt. The free base (0.7 g; oil; MS: APCI+ (M+H) 339) was liberated by addition of aqueous NaOH (1M) and extraction with dichloromethane followed by evaporation of the solvent.
  • 3-Methanesulfonyl-5-nitro-benzoic acid and 3-cyano-5-methanesulfonyl-benzoic acid can be prepared according to a method described in EP-A1-556674.
  • 2-amino-5-MeSO2-benzoic acid can be prepared according to a method described in J. Org. Chem. (1953) 18 1380.
  • 3-Ethanesulfonyl-benzoic acid can be prepared according to a method described in J. Chem. Soc. 1946, 763.
  • 3-Methylsulfamoyl-benzoic acid and 3-dimethylsulfamoyl-benzoic acid can be repared according to a method described in DE2133038. 3-Methylsulfamoyl-benzoic acid 1H NMR: (399.98 MHz, DMSO-D6) δ 7.42 (3H, d), 7.63 (1H, q), 7.76 (1H, t), 8.01 (1H, m), 8.18 (1H, dt), 8.31 (1H, t), 13.48 (1H, s).
  • Other intermediates can be prepared by literature methods, by adaptation of literature methods or are available commercially. For example:
      • (2-methyl-4-nitro-2H-pyrazol-3-yl)methanecarboxylic acid, 2- {1-[sulfonyl chloride]-ethyl}-isoindole-1,3-dione and (1,3-dimethyl-3,7-dihydro-purine-2,6-dion-8-yl)methanecarboxylic acid are available from Salor (Aldrich Chemical Company Inc 1001 West Saint Paul Avenue Milwaukee, Wis. 53233 USA);
      • [4-amino-5-(iso-propyl-sulfonyl)-thiophen-3-yl]carboxylic acid, [3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-isoxazol-4-yl]carboxylic acid, 3-cyano-4-(pyrrol-1-yl)-thiophen-5-yl)carboxylic acid, 4-isopropylsulfanyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and 1-cyclopropyl-5-methoxy-2-methyl-2,3-dihydro-1H-indole-3-carboxylic acid, (5-(isoxazol-3-yl)-thiophen-2-yl)sulfonyl chloride, 4-bromo-1-methyl-1H-pyrazol-3-ylmethanal, 4-chloro-1H-pyrazol-3-ylmethanal and 1-(4-chloro-benzyl)-1H-pyrazol-3-ylmethanal are available from Maybridge Chemical Company Ltd.; Trevillett, Tintagel, Cornwall PL34 OHW, UK;
      • (5-methanesulfonyl-1H-indol-2-yl)carboxylic acid is available by hydrolysis of an ester available from Maybridge Chemical Company Ltd., details above;
      • (4-chloro-5-methyl-3-nitro-pyrazol-1-yl)methanecarboxylic acid, (5-methyl-3,4-dinitro-pyrazol-1-yl)methanecarboxylic acid and (2,4-dinitro-imidazol-1-yl)methanecarboxylic acid are available from ASINEX Ltd., 6 Schukinskaya ulitsa, Moscow 123182, Russia;
      • (6-(imidazol-1-yl)-pyridin-3-yl)carboxylic acid and 2-methyl-2-([1,2,4]triazol-1-yl)-propanoic acid are available from Bionet Research Ltd, 3 Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ, UK; and,
      • (2-methyl-[1,8]naphthyridin-3-yl)carboxylic acid, (2-methyl-[1,6]naphthyridin-3-yl)carboxylic acid and (5-trifluoromethyl-thieno[3,2-b]pyridin-6-yl)-methanecarboxylic acid are available from Peakdale Fine Chemicals Ltd., 7 Brookfield Industrial Estate, Glossop, Derbyshire, SK13 6LQ, UK.
    EXAMPLE 28 Pharmacological Analysis: Calcium Flux [Ca2+]i Assay
  • Human Eosinophils
  • Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J Immunol. Methods, 1991, 145, 105-110). The cells were resuspended (5×106 ml−1) and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μ/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118 mM, MgSO4 0.8 mM, glucose 5.5 mM, Na2CO3 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl2 1.8 mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 2.5×106 ml−1. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 μM fibronectin for two hours) at 25 μ/well. The plate was centrifuged at 200 g for 5 min and the cells were washed twice with LKS (2001 μl; room temperature).
  • A compound of the Examples was pre-dissolved in DMSO and added to a final concentration of 0.1%(v/v) DMSO. Assays were initiated by the addition of an A50 concentration of eotaxin and the transient increase in fluo-3 fluorescence (IEX=490 nm and lEm=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).
    • Human Eosinophil Chemotaxis
  • Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended at 10×106 ml−1 in RPMI containing 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.
  • Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μl of either vehicle or compound (100× required final concentration in 10% DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loaded by adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate. The filter was then placed over the wells and 25 μl of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C. in a humidified incubator with a 95% air/5% CO2 atmosphere to allow chemotaxis.
  • The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300×g for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysed by the addition of 28 μl of PBS containing 0.5% Triton x100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al., J Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.
  • Compounds of the Examples were found to be antagonists of the eotaxin mediated human eosinophil chemotaxis.
    • EXAMPLE 29
  • Guinea-Pig Isolated Trachea
  • (See for example, Harrison, R. W. S., Carswell, H. & Young, J. M. (1984) European J. Pharmacol., 106, 405-409.)
  • Male albino Dunkin-Hartley guinea-pigs (250 g) were killed by cervical dislocation and the whole trachea removed. After clearing the adherent connective tissue, the trachea was cut into six ring segments each three cartilage bands wide and then suspended in 20 ml organ baths containing Krebs-Henseleit solution of the following composition (mM): NaCl 117.6, NaH2PO4 0.9, NaHCO3 25.0, MgSO4 1.2, KCl 5.4, CaCl2 2.6 and glucose 11.1. The buffer was maintained at 37° C. and gassed with 5% CO2 in oxygen. Indomethacin (2.8 μM) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo-oxygenase products. The tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders.
  • Experimental Protocols
  • At the beginning of each experiment a force of 1 g was applied to the tissues and this was reinstated over a 60 minute equilibration period until a steady resting tone was achieved. Subsequently, a cumulative histamine concentration effect (E/[A]) curve was constructed at 0.5 log10 unit increments, in each tissue. The tissues were then washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added. Following an incubation period of 60 minutes a second E/[A] curve was performed to histamine.
  • Contraction responses were recorded as a percentage of the first curve maximum.
  • Data Analysis
  • Experimental E/[A] curve data were analysed for the purposes of estimating the potencies (p[A50] values) of histamine in the absence and presence of the test compound. Affinity (pA2) values of test compounds were subsequently calculated using the following equation:
    log(r−1)=log[B]+pA 2
    where r=[A]50 in presence of test compound/[A]50 in absence of-antagonist and [B] is the concentration of test compound. Compounds of the Examples were found to be H1 antagonists.

Claims (8)

1-26. (canceled)
27. A compound of the following formula:
Figure US20070179297A1-20070802-C00096
wherein:
X is CH2,
R1 is phenyl substituted with one or more of fluorine, chlorine, or C1-4 alkyl;
R3 is heterocyclyl optionally substituted by: halogen, OH, SH, NO2, oxo, C1-6 alkyl {said alkyl being optionally substituted by halogen, OC(O)C1-6 alkyl, S(O)2R48, phenyl (said phenyl being optionally substituted by halogen), C1-6 alkyl, S(O)2R38 or C(O)NR39R40), naphthyloxy (itself optionally substituted by halo or C2-6 alkenyl), C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo) or NR41C(O)OCH2(fluoren-9-yl)}, NR41C(O)OCH2(fluoren-9-yl), C1-6 alkoxy {said alkoxy being optionally substituted by halogen, C1-6 alkoxy, NHCO2(C1-6 alkyl), CO2R4, NR5R6 or phenyl (said phenyl being optionally substituted by halogen or NO2)}, C1-6 alkylthio, C1-6 haloalkylthio, C3-10 cycloalkyl, NR7R8, NR9C(O)R10, CO2R11, C(O)NR12R13, C(O)R14, S(O)dR15, S(O)2NR42R43, NR44S(O)2R45, phenyl {said phenyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy (said alkoxy being optionally substituted by halogen, OH or pyridinyl), phenyl (said phenyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy or heterocyclyl (said heterocyclyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, heterocyclyl {said heterocyclcyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (said phenyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)or heterocyclyl (said heterocyclyl being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, phenoxy {said phenoxy being optionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy, C1-6 haloalkoxy, phenyl (said phenyl being optionally substitued by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy) or heterocyclyl (said pheterocyclcyloptionally substituted by halogen, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, C1-6 alkoxy or C1-6 haloalkoxy)}, SCN, CN, SO3H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;
or a pharmaceutically acceptable salt thereof; or a solvate thereof.
28. The compound of claim 27, wherein the heterpcyclyl is furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl, indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl, thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan, quinoxalinyl, dihydro-1-benzopyryliumyl, 3,4-dihydro-1H-2,1-benzothi-azinyl, a pyrazolopyridine, a purine, quinolinyl, isoquinolinyl, a naphthyridinyl, a benzothiazinyl, benzo[d]imidazo[2,1-b]thiazol-2-yl, or dibenzothiophenyl.
29. The compound of claim 27, wherein R1 is aryl or substituted aryl.
30. The compound of claim 28, wherein R1 is aryl or substituted aryl.
31. The compound of claim 27, wherein R1 is phenyl substituted with one or more of fluorine, chlorine, C1-4 alkyl or C1-4 alkoxy.
32. The compound of claim 28, wherein R1 is phenyl substituted with one or more of fluorine, chlorine, C1-4 alkyl or C1-4 alkoxy.
33. A method of treating CCR3 meidated disease comprising administering to a subject in need thereof an effective amount of the compound of claim 1.
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AR033517A1 (en) * 2000-04-08 2003-12-26 Astrazeneca Ab PIPERIDINE DERIVATIVES, PROCESS FOR THE PREPARATION AND USE OF THESE DERIVATIVES IN THE MANUFACTURE OF MEDICINES
ES2258642T3 (en) * 2001-07-02 2006-09-01 Astrazeneca Ab USEFUL PIPERIDINE DERIVATIVES AS MODULATORS OF THE ACTIVITY OF THE CHEMIOKIN RECEPTOR.
GB0120461D0 (en) 2001-08-22 2001-10-17 Astrazeneca Ab Novel compounds
AR036366A1 (en) 2001-08-29 2004-09-01 Schering Corp USEFUL PIPERIDINE DERIVATIVES AS CCR5 ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS, THE USE OF SUCH DERIVATIVES FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND A KIT
GB0122503D0 (en) 2001-09-18 2001-11-07 Astrazeneca Ab Chemical compounds
GB0124020D0 (en) * 2001-10-05 2001-11-28 Astrazeneca Ab Chemical compounds
WO2003031432A1 (en) * 2001-10-12 2003-04-17 Novo Nordisk A/S Substituted piperidines and their use for the treatment of diseases related to the histamine h3 receptor
WO2003037271A2 (en) * 2001-10-30 2003-05-08 Millennium Pharmaceuticals,Inc. Compounds, pharmaceutical compositions and methods of use therefor
TW200303304A (en) 2002-02-18 2003-09-01 Astrazeneca Ab Chemical compounds
US7183276B2 (en) 2002-02-28 2007-02-27 Takeda Pharmaceutical Company Limited Azole compounds
WO2004052862A1 (en) * 2002-12-10 2004-06-24 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic compounds and medicinal use thereof
BRPI0406778A (en) 2003-01-17 2006-01-17 Warner Lambert Co Androgen Receptor Antagonists
US20040192738A1 (en) * 2003-03-18 2004-09-30 Aventis Pharma Deutschland Gmbh 2-(Butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl] benzamide, its use as a medicament, and pharmaceutical preparations comprising it
US20070043079A1 (en) * 2003-04-18 2007-02-22 Hiromu Habashita Heterocyclic compound containing nitrogen atom and use thereof
SE0301368D0 (en) * 2003-05-09 2003-05-09 Astrazeneca Ab Chemical compounds
US20050020605A1 (en) * 2003-06-13 2005-01-27 Schering Aktiengesellschaft Quinolyl amide derivatives as CCR-5 antagonists
US20070021404A1 (en) * 2003-06-24 2007-01-25 Dan Peters Novel aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
CN1812981A (en) * 2003-06-27 2006-08-02 万有制药株式会社 Heteroaryloxy nitrogenous saturated heterocyclic derivative
CA2532800C (en) 2003-07-23 2013-06-18 Exelixis, Inc. Anaplastic lymphoma kinase modulators and methods of use
GB0325956D0 (en) 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
SE0302956D0 (en) * 2003-11-07 2003-11-07 Astrazeneca Ab Chemical compounds
SE0400208D0 (en) 2004-02-02 2004-02-02 Astrazeneca Ab Chemical compounds
ES2324224T3 (en) * 2004-02-05 2009-08-03 Schering Corporation PIPERIDINE DERIVATIVES THAT CAN BE USED AS CCR3 ANTAGONISTS.
EP1753421B1 (en) 2004-04-20 2012-08-01 Amgen Inc. Arylsulfonamides and uses as hydroxysteroid dehydrogenase
TWI396686B (en) 2004-05-21 2013-05-21 Takeda Pharmaceutical Cyclic guanamine derivatives, as well as their products and usage
KR100896546B1 (en) * 2004-08-10 2009-05-07 노파르티스 아게 Piperazine Derivatives Having CRC3 Inhibitory Activity
GB0417804D0 (en) * 2004-08-10 2004-09-15 Novartis Ag Organic compounds
GB0510143D0 (en) * 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds A1
BRPI0519288A2 (en) * 2004-12-24 2009-01-06 Astrazeneca Ab heterocyclic compounds as ccr2b antagonists
MX2007009947A (en) * 2005-02-16 2007-09-26 Schering Corp Pyrazinyl substituted piperazine-piperidines with cxcr3 antagonist activity.
CA2598651A1 (en) * 2005-02-23 2006-08-31 Schering Corporation Piperidinyl piperazine derivatives useful as inhibitors of chemokine receptors
WO2006091534A1 (en) * 2005-02-23 2006-08-31 Schering Corporation Piperidinyl piperidine derivatives useful as inhibitors of chemokine receptors
GB0510141D0 (en) * 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B3
DE602006008945D1 (en) 2005-06-28 2009-10-15 Sanofi Aventis ISOCHINOLINE DERIVATIVES AS INHIBITORS OF RHO-KINASE
ES2372067T3 (en) 2005-07-26 2012-01-13 Sanofi ISOQUINOLONE CYCLHEXYLAMINE DERIVATIVES AS INHIBITORS OF RHO-QUINASA.
BRPI0613861B8 (en) 2005-07-26 2021-05-25 Sanofi Aventis piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors
SI1934174T1 (en) 2005-10-07 2011-08-31 Exelixis Inc Azetidines as mek inhibitors for the treatment of proliferative diseases
US7576218B2 (en) 2005-10-11 2009-08-18 Chemocentryx, Inc. 4-phenylpiperdine-pyrazole CCR1 antagonists
WO2007076318A2 (en) * 2005-12-21 2007-07-05 Smithkline Beecham Corporation Camphor-derived cxcr3 antagonists
EP1979335A2 (en) 2006-01-18 2008-10-15 F.Hoffmann-La Roche Ag Thiazoles as 11 beta-hsd1 inhibitors
EP2059515A2 (en) * 2006-04-12 2009-05-20 Pfizer Limited Pyrrolidine derivatives as modulators of chemokine ccr5 receptors
US8649933B2 (en) 2006-11-07 2014-02-11 Smartdrive Systems Inc. Power management systems for automotive video event recorders
MX2009005252A (en) * 2006-11-17 2009-05-28 Abbott Lab Aminopyrrolidines as chemokine receptor antagonists.
TR201900306T4 (en) 2006-12-14 2019-02-21 Exelixis Inc Methods of using Mek inhibitors.
RS51655B (en) 2006-12-27 2011-10-31 Sanofi-Aventis Isoquinoline derivatives and isoquinolinone derivatives substituted by cycloalkylamine
CN101573353B (en) 2006-12-27 2014-08-06 塞诺菲-安万特股份有限公司 Substituted isoquinoline and isoquinolinone derivatives
JP5313919B2 (en) 2006-12-27 2013-10-09 サノフイ Novel substituted isoquinoline and isoquinolinone derivatives
MY151953A (en) 2006-12-27 2014-07-31 Sanofi Aventis Cycloalkylamine substituted isoquinoline derivatives
JP5405314B2 (en) 2006-12-27 2014-02-05 サノフイ Cycloalkylamine substituted isoquinolone derivatives
KR101517154B1 (en) 2006-12-27 2015-04-30 사노피 Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase
WO2008108309A1 (en) * 2007-03-02 2008-09-12 Kyowa Hakko Kirin Co., Ltd. Fused pyridine derivative
CA2685029A1 (en) * 2007-04-26 2008-11-06 Avalon Pharmaceuticals Multi-ring compounds and uses thereof
BRPI0814403A2 (en) * 2007-07-02 2015-01-27 Hoffmann La Roche Devoid of Imidazole as CCR2 Receptor Antagonists
BRPI0817935A2 (en) 2007-10-01 2015-04-07 Hoffmann La Roche BIARILLE DERIVATIVES
HRP20131040T1 (en) 2008-06-24 2013-12-06 Sanofi BI- AND POLYCYCLIC SUBSTITUTED ISOQINOLINE AND ISOQINOLINE DERIVATIVES AS RHO-KINASE INHIBITORS
AU2009262516B8 (en) 2008-06-24 2014-01-30 Sanofi 6-substituted isoquinolines and isoquinolinones
KR101638326B1 (en) 2008-06-24 2016-07-12 사노피 Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors
HUP0800478A2 (en) * 2008-07-31 2010-03-01 Sanofi Aventis Substituted pyrrolidinyl-[1,3]thiazolo[4,5-b]pyridin derivatives as ccr3 receptor ligands
EP2623101B1 (en) * 2009-04-02 2021-04-21 Merck Patent GmbH Piperidine and piperazine derivatives as autotaxin inhibitors
US8278302B2 (en) * 2009-04-08 2012-10-02 Boehringer Ingelheim International Gmbh Substituted piperidines as CCR3 antagonists
JP5649644B2 (en) 2009-04-22 2015-01-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ Azetidinyl diamide as a monoacylglycerol lipase inhibitor
US8435977B2 (en) 2009-04-22 2013-05-07 Janssen Pharmaceutica, Nv Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration
UY32940A (en) 2009-10-27 2011-05-31 Bayer Cropscience Ag AMIDAS REPLACED WITH HALOGENO RENT AS INSECTICIDES AND ACARICIDES
US8356975B2 (en) * 2010-03-23 2013-01-22 United Technologies Corporation Gas turbine engine with non-axisymmetric surface contoured vane platform
BR112013005141A2 (en) 2010-09-03 2016-05-10 Janssen Pharmaceutica Nv diazetidinyl diamide as monoacylglycerol lipase inhibitors
US8637498B2 (en) 2010-09-27 2014-01-28 Janssen Pharmaceutica, Nv Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors
US8513423B2 (en) 2010-10-22 2013-08-20 Janssen Pharmaceutica, Nv Piperidin-4-yl-azetidine diamides as monoacylglycerol lipase inhibitors
JP2013540160A (en) 2010-10-22 2013-10-31 ヤンセン ファーマシューティカ エヌ．ベー． Amino-pyrrolidine-azetidine diamide as monoacylglycerol lipase inhibitor
BR112015008113B1 (en) 2012-10-12 2022-05-24 Exelixis, Inc. New process to prepare compounds for use in cancer treatment
RU2727516C2 (en) * 2013-09-10 2020-07-22 Борд Оф Риджентс Оф Дзе Юниверсити Оф Техас Систем Therapeutic agents aimed at shortened proteins of adenomatous polyposis coli (apc)
WO2018112843A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
WO2021151014A1 (en) * 2020-01-23 2021-07-29 Myoforte Therapeutics, Inc. Pgdh inhibitors and methods of making and using
US12221463B2 (en) 2020-08-07 2025-02-11 The Board Of Regents Of The University Of Oklahoma Method of promoting wound healing by inhibiting CCR3
US20250042873A1 (en) * 2021-08-24 2025-02-06 The Johns Hopkins University Compositions and methods for treating proteotoxicity-associated diseases

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4505915A (en) * 1979-05-29 1985-03-19 Merck & Co., Inc. 6-N-Heterocyclyl penicillins
US4588722A (en) * 1984-01-09 1986-05-13 Janssen Pharmaceutica N.V. N-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives
US4695575A (en) * 1984-11-13 1987-09-22 Janssen Pharmaceutica, N.V. 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines
US5883096A (en) * 1995-02-23 1999-03-16 Schering Corporation Muscarinic antagonists
US5889006A (en) * 1995-02-23 1999-03-30 Schering Corporation Muscarinic antagonists
US5952349A (en) * 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
US5977138A (en) * 1996-08-15 1999-11-02 Schering Corporation Ether muscarinic antagonists
US6066636A (en) * 1998-06-30 2000-05-23 Schering Corporation Muscarinic antagonists
US6294554B1 (en) * 1999-09-22 2001-09-25 Schering Corporation Muscarinic antagonists
US6387930B1 (en) * 1999-05-04 2002-05-14 Schering Corporation Piperidine derivatives useful as CCR5 antagonists
US6440440B1 (en) * 1998-02-04 2002-08-27 Lieven Meerpoel Biocidal benzylbiphenyl derivatives
US6525070B2 (en) * 2000-04-08 2003-02-25 Astrazeneca Ab Bipiperidine derivatives as modulators of CCR3 activity and as H1 antagonists
US6759411B2 (en) * 1998-12-18 2004-07-06 Bristol-Myers Squibb Pharma Company Heterocyclic piperidines as modulators of chemokine receptor activity
US20050176708A1 (en) * 2002-03-19 2005-08-11 Christopher Luckhurst Piperidine derivatives useful as modulators of chemokine receptor activity
US20050182094A1 (en) * 2002-03-19 2005-08-18 Hitesh Sanganee Piperidine derivatives useful as modulators of chemokine receptor activity
US20060040984A1 (en) * 2002-09-24 2006-02-23 Christopher Luckhurst Novel piperidine derivatives for use in the treatment of chemokine medicated disease states
US20060264463A1 (en) * 2003-05-09 2006-11-23 Christopher Luckhurst Chemical compounds
US20060281726A1 (en) * 2003-03-25 2006-12-14 Christopher Luckhurst Piperidine derivatives for the treatment of chemokine or h1 mediated disease state
US20070032523A1 (en) * 2003-04-01 2007-02-08 Moya Caffrey Chemical compounds
US7186718B2 (en) * 2001-08-22 2007-03-06 Astrazeneca Ab Piperidinyl-morpholinyl derivatives as modulators of chemokine receptor activity
US7238691B2 (en) * 2001-09-18 2007-07-03 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine (especially CCR3) activity
US7265227B2 (en) * 2001-07-23 2007-09-04 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7307090B2 (en) * 2001-07-02 2007-12-11 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7517013B1 (en) * 2008-01-31 2009-04-14 Dd&G Holdings 1, Llc Combination cooling pad for a vehicle seat and cooled, dual-configuration bag

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4556660A (en) * 1982-07-12 1985-12-03 Janssen Pharmaceutica N.V. N-(Bicyclic heterocyclyl)-4-piperidinamines
US4634704A (en) * 1983-10-06 1987-01-06 Janssen Pharmaceutica, N.V. Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines
PH23995A (en) * 1984-01-09 1990-02-09 Janssen Pharmaceutica Nv 4((bicycle heterocyclyl)-methyl and hetero)piperidines
US5696267A (en) * 1995-05-02 1997-12-09 Schering Corporation Substituted oximes, hydrazones and olefins as neurokinin antagonists
PT912515E (en) 1996-07-10 2003-03-31 Schering Corp 1,4-DI-SUBSTITUTED PIPERIDINES AS MUSCLEAN ANTAGONISTS
EP0821954A1 (en) * 1996-08-01 1998-02-04 Eli Lilly And Company Method for treating mental retardation
HUP9904363A3 (en) * 1996-08-15 2000-12-28 Schering Corp Piperidine ether muscarinic antagonists and pharmaceutical compositions containing them
SK285631B6 (en) * 1996-09-10 2007-05-03 Dr. Karl Thomae Gmbh Modified amino acids, pharmaceutical composition comprising its and its use
WO1999004794A1 (en) 1997-07-25 1999-02-04 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
WO2000000488A1 (en) 1998-06-30 2000-01-06 Schering Corporation Muscarinic antagonists
SK286968B6 (en) 1999-05-04 2009-08-06 Schering Corporation Piperidine-piperidinyl derivatives useful as CCR5 antagonists, pharmaceutical composition comprising them and the use of them

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4505915A (en) * 1979-05-29 1985-03-19 Merck & Co., Inc. 6-N-Heterocyclyl penicillins
US4588722A (en) * 1984-01-09 1986-05-13 Janssen Pharmaceutica N.V. N-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives
US4695575A (en) * 1984-11-13 1987-09-22 Janssen Pharmaceutica, N.V. 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines
US5883096A (en) * 1995-02-23 1999-03-16 Schering Corporation Muscarinic antagonists
US5889006A (en) * 1995-02-23 1999-03-30 Schering Corporation Muscarinic antagonists
US5952349A (en) * 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
US5977138A (en) * 1996-08-15 1999-11-02 Schering Corporation Ether muscarinic antagonists
US6440440B1 (en) * 1998-02-04 2002-08-27 Lieven Meerpoel Biocidal benzylbiphenyl derivatives
US6066636A (en) * 1998-06-30 2000-05-23 Schering Corporation Muscarinic antagonists
US6759411B2 (en) * 1998-12-18 2004-07-06 Bristol-Myers Squibb Pharma Company Heterocyclic piperidines as modulators of chemokine receptor activity
US6387930B1 (en) * 1999-05-04 2002-05-14 Schering Corporation Piperidine derivatives useful as CCR5 antagonists
US6294554B1 (en) * 1999-09-22 2001-09-25 Schering Corporation Muscarinic antagonists
US6525070B2 (en) * 2000-04-08 2003-02-25 Astrazeneca Ab Bipiperidine derivatives as modulators of CCR3 activity and as H1 antagonists
US7179922B2 (en) * 2000-04-08 2007-02-20 Astrazeneca Ab Chemical compounds
US6903115B2 (en) * 2000-04-08 2005-06-07 Astrazeneca Ab Bipiperidine compounds
US7238811B2 (en) * 2000-04-08 2007-07-03 Astrazeneca Ab Chemical compounds
US7307090B2 (en) * 2001-07-02 2007-12-11 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7265227B2 (en) * 2001-07-23 2007-09-04 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7186718B2 (en) * 2001-08-22 2007-03-06 Astrazeneca Ab Piperidinyl-morpholinyl derivatives as modulators of chemokine receptor activity
US7238691B2 (en) * 2001-09-18 2007-07-03 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine (especially CCR3) activity
US20050182094A1 (en) * 2002-03-19 2005-08-18 Hitesh Sanganee Piperidine derivatives useful as modulators of chemokine receptor activity
US20050176708A1 (en) * 2002-03-19 2005-08-11 Christopher Luckhurst Piperidine derivatives useful as modulators of chemokine receptor activity
US7517989B2 (en) * 2002-03-19 2009-04-14 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US20060040984A1 (en) * 2002-09-24 2006-02-23 Christopher Luckhurst Novel piperidine derivatives for use in the treatment of chemokine medicated disease states
US20060281726A1 (en) * 2003-03-25 2006-12-14 Christopher Luckhurst Piperidine derivatives for the treatment of chemokine or h1 mediated disease state
US20070032523A1 (en) * 2003-04-01 2007-02-08 Moya Caffrey Chemical compounds
US7495013B2 (en) * 2003-04-01 2009-02-24 Astrazeneca Ab Chemical compounds
US20060264463A1 (en) * 2003-05-09 2006-11-23 Christopher Luckhurst Chemical compounds
US7517013B1 (en) * 2008-01-31 2009-04-14 Dd&G Holdings 1, Llc Combination cooling pad for a vehicle seat and cooled, dual-configuration bag

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050276857A1 (en) * 2002-01-10 2005-12-15 University Of Washington Hydrogels formed by non-covalent linkages
US20050182094A1 (en) * 2002-03-19 2005-08-18 Hitesh Sanganee Piperidine derivatives useful as modulators of chemokine receptor activity
US20050176708A1 (en) * 2002-03-19 2005-08-11 Christopher Luckhurst Piperidine derivatives useful as modulators of chemokine receptor activity
US7517989B2 (en) 2002-03-19 2009-04-14 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7482363B2 (en) 2002-03-19 2009-01-27 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US20060040984A1 (en) * 2002-09-24 2006-02-23 Christopher Luckhurst Novel piperidine derivatives for use in the treatment of chemokine medicated disease states
US20060281726A1 (en) * 2003-03-25 2006-12-14 Christopher Luckhurst Piperidine derivatives for the treatment of chemokine or h1 mediated disease state
US7495013B2 (en) 2003-04-01 2009-02-24 Astrazeneca Ab Chemical compounds
US20070032523A1 (en) * 2003-04-01 2007-02-08 Moya Caffrey Chemical compounds
US20090118513A1 (en) * 2003-04-01 2009-05-07 Astrazeneca Ab Chemical Compounds
US20080262037A1 (en) * 2004-04-06 2008-10-23 Astrazeneca Ab Piperidine Derivatives for the Treatment of Chemokine Mediated Disease
US20080200505A1 (en) * 2005-05-27 2008-08-21 Astrazeneca Ab Piperidines for the Treatment of Chemokine Mediated Diseases
US20080275084A1 (en) * 2005-05-27 2008-11-06 Astrazeneca Ab Piperidines for the Treatment of Chemokine Mediated Diseases
US20080207688A1 (en) * 2005-07-21 2008-08-28 Astrazeneca Ab Novel Piperidine Derivatives
US8314127B2 (en) 2005-07-21 2012-11-20 Astrazeneca Ab Piperidine derivatives

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