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WO2001044223A1 - Inhibitors of interleukin 5 gene expression - Google Patents

Inhibitors of interleukin 5 gene expression Download PDF

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Publication number
WO2001044223A1
WO2001044223A1 PCT/US2000/034229 US0034229W WO0144223A1 WO 2001044223 A1 WO2001044223 A1 WO 2001044223A1 US 0034229 W US0034229 W US 0034229W WO 0144223 A1 WO0144223 A1 WO 0144223A1
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WIPO (PCT)
Prior art keywords
methyl
fluoro
phenyl
phenoxy
pyran
Prior art date
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PCT/US2000/034229
Other languages
French (fr)
Inventor
Fatima Z. Basha
Mira M. Hinman
Hana A. Kopecka
Xenia B. Searle
Thomas J. Sowin
Dariusz Wodka
Carol Surowy
Connie R. Faltynek
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Abbott Laboratories
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to AU22717/01A priority Critical patent/AU2271701A/en
Priority to EP00986489A priority patent/EP1250332A1/en
Priority to JP2001544713A priority patent/JP2003523956A/en
Priority to BR0012502-4A priority patent/BR0012502A/en
Priority to MXPA02005982A priority patent/MXPA02005982A/en
Priority to CA002393027A priority patent/CA2393027A1/en
Publication of WO2001044223A1 publication Critical patent/WO2001044223A1/en
Priority to HK03101827.4A priority patent/HK1051033A1/en

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel organic compounds that inhibit interleukin 5 (IL-5) gene expression in mammals, to pharmaceutical compositions comprising these compounds, and to a method of treating asthma.
  • IL-5 interleukin 5
  • Asthma is a chronic inflammatory disease characterized by substantial inflammation of the airways. Although inflammatory responses in general are protective mechanisms for the host, excessive or inappropriate inflammatory responses occur in certain diseases such as asthma. Common allergens such as pollen, molds, cockroaches, animal dander, and dust-mite feces contain potent antigens that can give rise to allergic responses and inflammation characteristic of asthma.
  • the Expert Panel Report issued in 1997 by the National Asthma Education and Prevention Program and the NIH emphasizes the critical role that inflammation plays in asthma (S. Murphy, et al., Expert Panel Report 2. NIH Publication No. 97-4051 (1997)). There is evidence that early intervention with anti-inflammatory therapy modifies the disease process and that persistent asthma is most effectively controlled with daily anti-inflammatory medications (S. Murphy, et al., Expert Panel Report 2. NIH Publication No. 97-4051 (1997)).
  • asthma is an inflammatory disease
  • inhaled steroids and other anti-inflammatory agents are not ideal, since most have significant side-effects and/or are not amenable to oral administration.
  • anti-inflammatory agents are not ideal, since most have significant side-effects and/or are not amenable to oral administration.
  • the key unmet medical needs in the treatment of asthma include the development of more specific, safer, orally active anti-inflammatory agents.
  • Agents targeted specifically to critical events in the pathogenesis of asthma are expected to be efficacious and to have fewer side effects than most current agents.
  • Eosinophils and mast cells infiltrating the asthmatic airways play critical roles in the airway inflammation that occurs in asthma (G. Vogel, Science 276, 1643-1646 (1997)). In the 1980's, attention was focused on mast cells, since these cells release a variety of inflammatory mediators upon activation by antigen. However, more recent information indicates that eosinophils also play a major role in the bronchial hyperreactivity and inflammation that are characteristic of asthma. Infiltration and activation of eosinophils in the bronchial mucosa is considered to be a central event in the pathogenesis of asthma (A.J. Wardlaw, R. Moqbel, A.B. Kay, Adv. Immunol. 60, 151-266 (1995)).
  • T lymphocytes The activation of both eosinophils and mast cells is orchestrated by T lymphocytes, in particular by a subset of T helper cells designated Th2 cells (A.K., Abbas, K.M., Murphy, A. Sher, Nature 383, 787-793 (1996)).
  • Th2 cells are central regulators of the immune system and the integrated inflammatory response to antigens.
  • Th2 cells When activated by antigen, Th2 cells synthesize specific cytokines, including interleukins 4 and 5 (IL-4 and IL-5). Interleukin 4 is required both for differentiation and expansion of Th2 cells, as well as for synthesis of IgE by B lymphocytes.
  • Interleukin 5 is a critical cytokine that regulates both the differentiation and activation of eosinophils (C. J. Sanderson, Blood 79, 3101-3109 (1992); CJ. Bagley, A.F., Lopez, M.A. Vadas, J. Allergy Clin. Immunol. 99, 725-728 (1997)).
  • IL-5 selectively inhibitors of IL-5 are expected to have highly specific effects in allergic diseases such as asthma, with few mechanism based side effects.
  • eosinophils and basophils are known to be affected by IL-5.
  • the role for eosinophils in allergic late-phase bronchoconstriction is well established.
  • basophils have also been found to participate in the pathogenesis of allergic late-phase reactions.
  • Asthmatic patients have elevated numbers of activated T cells expressing IL-5 mRNA, which further increase following allergen challenge (D. Robinson et al. J. Allergy Clin. Immunol 92, 313- 324 (1993)).
  • mice in which the IL-5 gene was ablated had significantly reduced numbers of eosinophils as well as significantly less severe airway hyperreactivity and lung damage than the IL-5 gene-containing litter mates (P.S. Foster, J. Exp. Med. 183, 195- 201 (1996)).
  • anti-IL-5 antibodies administered to a variety of experimental animals decreased the airway hyperreactivity that occurred following antigen challenge of sensitized animals (R.W. Egan, In: Therapeutic Modulation of Cytokines. CRC Press (1996)).
  • Broad spectrum immunosuppressants such as cyclosporin A, as well as glucocorticoids inhibit expression of multiple cytokines and exhibit unacceptable toxicities for chronic systemic use in treatment of asthma.
  • the present invention describes the identification of compounds which are potent inhibitors of IL-5 gene expression. Such compounds may have therapeutic potential for the treatment of asthma as well as other allergic diseases such as chronic rhinitis/sinusitis.
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of one or more compounds selected from the group consisting of formula I
  • R is selected from hydrogen and lower alkyl.
  • R is methyl.
  • R 2 is selected from hydrogen and lower alkyl.
  • R 2 is methyl.
  • R 3 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR 5 R 6 wherein R 5 and Rg are each independently selected from hydrogen and alkyl.
  • R 3 is selected from hydrogen and halogen.
  • a preferred halogen substituent is fluorine.
  • R 4 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR J R J; wherein R 5 and Rg are as defined above.
  • R 4 is selected from hydrogen and halogen.
  • a preferred halogen substituent is chlorine.
  • A is selected from alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR 7 R g wherein R 7 and R 8 are independently selected from the group consisting of alkenyl, alkoxy alkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl.
  • A is selected from alkyl, alkoxy, cycloalkyl, heterocycles selected from azepanyl, azetidinyl, azocanyl, furyl, piperdinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, tetrahydropyridyl, thiazolidinyl, and thiomorpholinyl, and NR 7 R 8 wherein R 7 and R 8 are independently selected from alkenyl, alkoxyalkyl, alkyl, alkynyl, alkoxyalkyl, alkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (l,3-dioxolan-2-yl)alkyl, tetrahydro-2-furanylmethyl, hydroxyalkoxyalkyl, and hydroxyalkyl.
  • B is selected from heterocycle and NRgR 10 wherein R, and R, 0 are independently selected from alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl.
  • B is selected from a heterocycle selected from morpholinyl, piperazinyl, piperdinyl, pyrrolidinyl, tetrahydro-2H- pyranyl, and thiomorpholinyl, and NR_,R I0 wherein R, and R, 0 are independently selected from alkoxyalkyl, alkyl, and cycloalkyl.
  • X is selected from CH 2 , and O.
  • Y is selected from CH and N.
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of one or more compounds selected from formula I
  • R is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is selected from azepinyl, azetidinyl, azocanyl, furyl, piperdinyl, pyrrolyl, pyrrolidinyl, 2,5-dihydrolH-pyrrolyl, tetrahydropyridyl, thiazolidinyl, and thiomorpholinyl; B is selected from morpholinyl, piperazinyl, piperdinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, and thiomorpholinyl; X is selected from CH 2 and O; and Y is selected from CH and N.
  • Examples of compounds of this embodiment include, but are not limited to: ethyl 4- ⁇ 3-fluoro-5-[(4- ⁇ methyl[(2-methyl-l - pyrrolidinyl)carbonyl]amino ⁇ benzyl)oxy]phenyl ⁇ - 1 -piperazinecarboxylate,
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or pharmaceutically acceptable salts thereof wherein, R, is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is NR 7 R 8 wherein R 7 and R 8 are indpendently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (l,3-dioxolan-2-yl)alkyl, tetrahydro-2- furanylalkyl, hydroxyalkoxyalkyl, and hydroxyalkyl; B is selected from cyclohexyl, morpholinyl, piperazinyl, piper
  • Examples of compounds of this embodiment include, but are not limited to: ethyl 4-[3-( ⁇ 4-[[(diethylamino)carbonyl](methyl)amino]benzyl ⁇ oxy)-5-fluorophenyl]-
  • N,N-diethyl-N'-(4- ⁇ [3-fluoro-5-(4-morpholinyl)phenoxy]methyl ⁇ phenyl)-N'- methylurea and N,N-diethyl-N'-[4-( ⁇ [6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2- pyridinyl]oxy ⁇ methyl)phenyl]-N'-methylurea.
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or pharmaceutically acceptable salts thereof wherein, R, is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is pyrrolidinyl; B is NR ⁇ R,,, wherein R ⁇ , and R 10 are independently selected from hydrogen, alkoxyalkyl, and alkyl; X is selected from CH 2 and O; and Y is selected from CH and N.
  • Examples of compounds of this embodiment include, but are not limited to: N-[4-( ⁇ 3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy ⁇ methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide and
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or a pharmaceutically acceptable salt thereof wherein, R, is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is NR 7 R 8 wherein R 7 and R 8 are independently selected from hydrogen and alkyl; B is NI ⁇ R ⁇ wherein , and R 10 are independently selected from hydrogen, alkoxyalkyl, alkyl, and cycloalkyl; X is selected from CH 2 and O; and Y is selected from CH and N.
  • Examples of compounds of this embodiment include, but are not limited to:
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or a pharmaceutically acceptable salt thereof wherein, R, is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is selected from alkoxy, alkyl, and cycloalkyl; B is tetrahydro-2H-pyranyl; X is selected from CH 2 and O; and Y is selected from CH and N.
  • R is methyl
  • R 3 is selected from hydrogen and fluorine
  • R 4 is selected from hydrogen and chlorine
  • A is selected from alkoxy, alkyl, and cycloalkyl
  • B is tetrahydro-2H-pyranyl
  • X is selected from CH 2 and O
  • Y is selected from CH and N.
  • Examples of compounds of this embodiment include, but are not limited to: N-(4- ⁇ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl ⁇ phenyl)- N,3,3-trimethylbutanamide,
  • the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula II
  • R is methyl; R 2 is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; B is selected from cyclohexyl, piperdinyl, and tetrahydro-2H-pyranyl; X is selected from CH 2 and O; and Y is selected from CH and N.
  • Examples of compounds of this embodiment include, but are not limited to:
  • compositions comprising a therapeutically effective amount of a compound of formula I-II or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method of treating allergic diseases comprising administering a therapeutically effective amount of a compound of formula I-II or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention relates to a method of treating asthma comprising administering a therapeutically effective amount of a compound of formula I-II or a pharmaceutically acceptable salt thereof.
  • R is selected from hydrogen and lower alkyl
  • R 2 is selected from hydrogen and lower alkyl
  • R 3 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR 5 R ⁇ ; wherein R 5 and R f , are independently selected from hydrogen and alkyl;
  • R 4 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and wherein R 5 and Rg are independently selected from hydrogen and alkyl;
  • A is selected from the group consisting of alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR 7 R g wherein R 7 and R 8 are independently selected from alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl;
  • B is selected from the group consisting of heterocycle and NR
  • R is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is selected from azetidinyl, azepanyl, azocanyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, thiazolidinyl, and tetrahydropyridyl; B is selected from the group consisting of morpholinyl, piperazinyl, piperdinyl, tetrahydro-2H-pyranyl, pyrrolidinyl, thiomorpholinyl, and NR ⁇ R ⁇ wherein R, and R 10 are independently selected from alkoxyalkyl and alkyl; X is selected from CH 2 and O; and Y is CH.
  • Examples of compounds of this embodiment include, but are not limited to: ethyl 4- ⁇ 3-fluoro-5-[(4- ⁇ methyl[(2-methyl- 1 - pyrrolidinyl)carbonyl] amino ⁇ benzyl)oxy]phenyl ⁇ - 1 -piperazinecarboxylate,
  • R [ is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is NR 7 R 8 wherein R 7 and R 8 are independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, (1,3- dioxolan-2-yl)alkyl, tetrahydro-2-furanylalkyl, hydroxyalkoxyalkyl, and phenylalkyl; B is selected from tetrahydro-2H-pyranyl and cyclohexyl; X is selected from CH 2 and O; and Y is
  • Examples of compounds of this embodiment include, but are not limited to: N-allyl-N'-(4- ⁇ [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl ⁇ phenyl)-N,N'-dimethylurea, N-(3-chloro-4- ⁇ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl ⁇ phenyl)-N,N',N'-trimethylurea,
  • R is methyl; R 3 is selected from hydrogen and fluorine; R 4 is selected from hydrogen and chlorine; A is NR 7 R 8 wherein R 4 and R 5 are independently selected from hydrogen and alkyl; B is selected from mo ⁇ holinyl, piperazinyl, piperdinyl, pyrrolidinyl, thiomo ⁇ holinyl, and wherein R, and R 10 are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, and cycloalkyl; X is selected from CH 2 and O; and Y is CH.
  • Examples of compounds of this embodiment include, but are not limited to: ethyl 4-[3-( ⁇ 4-[ [(diethy lamino)carbony 1 ] (methy l)amino] benzyl ⁇ oxy )-5 -fluorophenyl] - 1 -piperazinecarboxylate,
  • N,N-diethyl-N'-(4- ⁇ [3-fluoro-5-(4-mo ⁇ holinyl)phenoxy]methyl ⁇ phenyl)-N'- methylurea In another embodiment of the present invention are disclosed compounds of formula I wherein, R, is methyl; R 3 is selected from hydrogen and fluorine; R 4 is chlorine; A is NR 7 R 8 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; B is tetrahydro-2H-pyranyl; X is O; and Y is CH.
  • An Example of compounds of this embodiment include, but are not limited to:
  • R is methyl; R 3 is hydrogen; R 4 is hydrogen; A is selected from the group consisting of pyrrolidinyl and NR 7 R 8 wherein R 7 and R 8 are independently selected from hydrogen and alkyl; B is tetrahydro-2H-pyranyl; X is O; and Y is N.
  • Examples of compounds of this embodiment include, but are not limited to:
  • R is methyl; R 3 is selected from hydrogen and halogen; R 4 is selected from hydrogen and halogen; A is selected from the group consisting of alkoxy, alkyl, and cycloalkyl; B is tetrahydro-2H-pyranyl; X is O; and Y is CH.
  • Examples of compounds of this embodiment include, but are not limited to: N-(4- ⁇ [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl ⁇ pheny 1)- N, 3 , 3 -trimethy lbutanamide,
  • R is methyl; R 2 is methyl; R 3 is halogen; R, is selected from hydrogen and halogen; B is selected from cyclohexyl, piperdinyl, and tetrahydro-2H-pyranyl; X is O; and Y is CH.
  • Examples of compounds of this embodiment include, but are not limited to:
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl and the like.
  • alkenyloxy refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • alkenyloxy include, but are not limited to, 2-propenyloxy (allyloxy), 2-butenyloxy, 3-butenyloxy, and the like.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • alkoxyalkoxy refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
  • alkoxyalkoxyalkyl refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert- butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy )methyl, 2-(2- methoxyethoxy)ethyl, and the like.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl,'2-methoxyethyl, methoxymethyl, and the like.
  • alkoxy carbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxy carbonyl, and the like.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2-ethylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
  • alkylcarbonyloxy refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.
  • alkylene denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • alkylene examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and the like.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • alkynyloxy refers to an alkynyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkynyloxy include, but are not limited to, 2-propynyloxy, 2- butynyloxy, 3-butynyloxy, and the like.
  • aryl refers to a monocyclic-ring system, or a bicyclic- fused ring system wherein one or both of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, dihydronaphthyl, tetrahydronaphthyl, and the like.
  • the aryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxy carbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, alkynyloxy, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, carboxy, cyano, ethylenedioxy, formyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NR ⁇ R,,, and (NR 92 R_ 93 )carbony 1.
  • substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxy carbonyl, alkyl, alkylcarbonyl, al
  • arylalkoxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of arylalkoxy include, but are not limited to, benzyloxy, 2- phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
  • arylalkoxyalkyl refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkoxyalkyl include, but are not limited to, benzyloxymethyl, 2-phenylethoxymethyl, 3-naphth-2-ylpropoxymethyl, 5-phenylpentyloxymethyl, and the like.
  • arylalkoxycarbonyl refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 2- (4-hydroxyphenyl)ethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylcarbonyl include, but are not limited to, benzoyl, naphthoyl, and the like.
  • carbonyl refers to a -C(O)- group.
  • carboxy refers to a -CO 2 H group.
  • carboxyalkyl refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxy ethyl, 3-carboxypropyl, and the like.
  • cyano refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, 3-cyanopropyl, and the like.
  • cycloalkyl refers to a monocychc, bicyclic, or tricyclic ring system. Monocychc ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.
  • monocychc ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • Bicyclic ring systems are exemplified by a bridged monocychc ring system in which two non-adjacent carbon atoms of the monocychc ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, and the like.
  • Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3,7 ]nonane, tricyclo[3.3.1.1 3 ' 7 ]decane (adamantane), and the like.
  • the cycloalkyl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, alkynyloxy, aryl, arylalkoxycarbonyl, carboxy, cyano, ethylenedioxy, formyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, oxo, -NR ⁇ R ⁇ , and (NR 92 R 93 )carbonyl.
  • cycloalkylalkyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like.
  • ethylenedioxy refers to a -O(CH 2 ) 2 O- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring.
  • formyl refers to a -C(O)H group.
  • halo refers to -CI, -Br, -I or -F.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group of one to four carbons, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, bromomethoxy, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group of one to four carbons, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, bromomethyl, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, and the like.
  • heterocycle refers to a monocychc ring system.
  • Monocychc ring systems are exemplified by any 3 or 4 membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5, 6, 7, or 8 membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds.
  • monocychc ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, azocanyl, diazepinyl, 2,5-dihydro-lH-pyrrolyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, mo ⁇ holinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl,
  • heterocycles of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, alkynyloxy, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, arylcarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR ⁇ R,,, and (NR 92 R 93 )carbonyl.
  • substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxy
  • heterocycles substituted with 1, 2, or 3 substituents include, but are not limited to, 1,4-dioxa- 8-azaspiro[4.5]decane, 2-methylpyrrolidinyl, 4-hydroxy-4-phenyl-l -piperdinyl, 2- hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 2 -hydroxy ethyl- 1 -piperazinyl, and the like.
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, 2-(l,3-dioxolan-2-yl)ethyl, tetrahydro-2-furanylmethyl, and the like.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, and the like.
  • lower alkyl refers to a straight or branched chain hydrocarbon group containing from l-to-4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
  • -NR ⁇ R ⁇ refers to two groups, R,,, and R ⁇ , which are appended to the parent molecular moiety through a nitrogen atom.
  • R ⁇ and Rg are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl.
  • Representative examples of -NR ⁇ R ⁇ include, but are not limited to, amino, benzylamino, methylamino, acetylamino, acetylmethylamino, phenylamino, and the like.
  • Rg 2 and Rg 3 are independently selected from hydrogen, alkyl, aryl, and arylalkyl.
  • Representative examples of -NR ⁇ R ⁇ include, but are not limited to, amino, benzylamino, methylamino, dimethylamino, ethylamino, phenylamino, and the like.
  • (NR 92 R 93 )carbonyl refers to a -NR ⁇ R ⁇ group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR 92 R 93 )carbonyl include, but are not limited to, aminocarbonyl, benzylaminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, and the like.
  • the term “oxo,” as used herein, refers to a O moiety.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • salts refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p- toluenesulfonate and undecano
  • the basic nitrogen-containing groups can be quateraized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil- soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as dec
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Stereoisomers can exist as stereoisomers, wherein asymmetric or chiral centers are present.
  • Stereoisomers are designated “R” or “S,” depending on the configuration of substituents around the chiral carbon atom.
  • R and S used herein are configurations as defined in (IUPAC 1974 Recommendations for Section E,
  • Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • the present invention contemplates pharmaceutically active metabolites formed by in vivo biotransformation of compounds of formula I-II.
  • pharmaceutically active metabolite refers to a compound formed by the in vivo biotransformation of compounds of formula I-II.
  • the present invention contemplates compounds of formula I-II and metabolites thereof. A thorough discussion of biotransformation is provided in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition).
  • Compounds of the present invention were evaluated as inhibitors of interleukin 5 gene expression in an assay involving stimulated human T lymphocytes.
  • HUT 78 Cells of the human cutaneous T cell lymphoma cell line, HUT 78 (ATCC, Rockville, MD) were cultured in RPMI 1640 medium containing 10% (v/v) fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin (100 units/mL and 100 ⁇ g/mL final concentration, respectively) (Life Technologies, Gaithersburg, MD). Three days prior to stimulation, the HUT 78 cells were seeded at a density of 2 x 10 5 cells/mL.
  • cells (at ⁇ 1 x lOVmL) were centrifuged at 1200 ⁇ m for 10 minutes at room temperature, and resuspended in fresh growth medium at a density of lxl 0 6 cells/mL.
  • Cells were then pretreated with compounds of the present invention, followed by stimulation with anti-CD3 (clone X-35, Coulter-Immunotech, Miami, FL) and phorbol 12-myristate 13-acetate (PMA) (Sigma, St. Louis, MO) as follows.
  • anti-CD3 clone X-35, Coulter-Immunotech, Miami, FL
  • PMA phorbol 12-myristate 13-acetate
  • IL-5 ELISA assay 100 ⁇ L of HUT 78 cell supernatants were added to wells of an Immulon 4 HBX plate (Dynex, Chantilly, VA) that had been pre-coated with 100 ⁇ L of a 1 ⁇ g/mL solution of rat anti-human IL-5 antibody (clone TRFK5, Pharmingen, San Diego, CA). After incubation for 2 hours at room temperature, the plate was washed and each well was subsequently incubated for 1 -2 hours at room temperature with 100 ⁇ L of a 1 ⁇ g/mL solution of biotinylated rat anti -human IL-5 antibody (clone JES1-5A10, Pharmingen).
  • the plate was then washed again, and each well was incubated with 100 ⁇ L of a 1 ⁇ g/mL solution of streptavidin-horseradish peroxidase conjugate (Pierce, Rockford, IL) for 1 hour, followed by incubation with 100 ⁇ L substrate [0.3 g/L 2,2'-azino-di-(3-ethylbenzthiazoline-6- sulfonate); ABTS] (Kirkegaard & Perry Laboratories, Gaithersburg, MD) for 15-30 minutes. After addition of 100 ⁇ L of ABTS stop solution (Kirkegaard & Perry Laboratories, Gaithersburg, MD), the plate was read at an O.D. of 405 nm.
  • Human IL-5 used in the standard curve was from R&D Systems, Inc., Minneapolis, MN.
  • the percent inhibition of IL-5 expression produced by each concentration of compounds of the present invention was calculated relative to IL-5 levels produced by the stimulated control cells.
  • the IC 50 values, shown in Table 1 were graphically determined from 8-point dose response curves generated for each compound. IL-5 protein levels in the supernatant from stimulated HUT 78 cells were approximately 1500 pg/mL, whereas no IL-5 was detectable from unstimulated cells.
  • Table 1 demonstrates that compounds of the present invention are potent inhibitors of interleukin 5 gene expression and therefore may have utility in the treatment of allergic diseases, in particular, asthma, chronic sinusitus, and chronic rhinitis.
  • compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen
  • the present invention provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula I-II prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions.
  • the pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • the abso ⁇ tion of the drug in order to prolong the effect of a drug, it is often desirable to slow the abso ⁇ tion of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material with poor water solubility. The rate of abso ⁇ tion of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed abso ⁇ tion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Suspensions in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof. If desired, and for more effective distribution, the compounds of the present invention can be inco ⁇ orated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • the compounds of the present invention can be inco ⁇ orated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres
  • sterile solid compositions may be sterilized, for example, by filtration through a bacteria-retaining filter or by inco ⁇ oration of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomesror microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) abso ⁇ tion accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i)
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Compounds of the present invention may also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
  • the compounds of the present invention inhibit interleukin 5 gene expression.
  • the compounds of the present invention may be useful for the treatment and prevention of allergic diseases such as asthma, chronic sinusitis, and chronic rhinitis.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.003 to about 50 mg/kg/day.
  • more preferable doses can be in the range of from about 0.01 to about 5 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for pu ⁇ oses of administration, e.g. two to four separate doses per day.
  • N- protected benzoic acids can then be treated with a reducing agent, such as borane tetrahydrofuran complex or borane diethyl ether complex, to provide benzylic alcohols of general formula (2), wherein P is a nitrogen protecting group.
  • a reducing agent such as borane tetrahydrofuran complex or borane diethyl ether complex
  • Benzylic alcohols of general formula (2) can be treated with benzene compounds of general formula (3), prepared as described in Scheme 4, and sodium hydride to provide ethers of general formula (4).
  • Ethers of general formula (4) can be deprotected by standard chemistry known to those of ordinary skill in the art to provide anilines of general formula (5).
  • Anilines of general formula (5) can be treated with acid chlorides, chloroformates, or isocyanates under standard conditions known to those of ordinary skill in the art to provide amides, carbamates, or ureas of general formula (6).
  • A is selected from NR 7 R 8 or nitrogen containing heterocycles such as azetidine, azocane, azepane, mo ⁇ holine, piperdine, piperazine, pyrrole, pyrroline, pyrrolidine, thiazolidine, tetrahydropiperdine, and thiomo ⁇ hoine
  • B is selected from cyclohexyl or heterocycle
  • R 4 , R 7 , and R 8 are as defined in formula I, can be prepared as described in Scheme 2.
  • Anilines of general formula (5), from Scheme 1 can be treated with phosgene in toluene at 0 °C to provide carbamoyl chlorides of general formula (7).
  • Carbamoyl chlorides of general formula (7) can be treated with amines or nitrogen containing heterocycles to provide compounds of general formula (6) wherein A is an amine or nitrogen containing heterocycle and B is cyclohexyl or a heterocycle.
  • Isocyanates of general formula (9) can be treated with amines or nitrogen containing heterocycles to provide compounds of general formula (10) wherein R is alkyl.
  • Compounds of general formula (10) can be treated with sodium hydride and iodomethane in DMF to provide compounds of general formula (11).
  • Compounds of general formula (11) can be treated with reducing agents, such as lithium borohydride and methanol in THF, to provide alcohols of general formula (12).
  • Alcohols of general formula (12) can be treated with l-bromo-3,5- difluorobenzene to provide ethers of general formula (13).
  • Ethers of general formula (13) can be treated with a palladium catalyst such as Pd(dba) 2 , BI AP, and sodium tert-butoxide in toluene in the presence of an amine or nitrogen containing heterocycle to provide compounds of general formula (6) wherein A is an amine or nitrogen containing heterocycle and B is an amine or nitrogen containing heterocycle.
  • a palladium catalyst such as Pd(dba) 2 , BI AP, and sodium tert-butoxide in toluene in the presence of an amine or nitrogen containing heterocycle to provide compounds of general formula (6) wherein A is an amine or nitrogen containing heterocycle and B is an amine or nitrogen containing heterocycle.
  • Cyclohexanones or heterocycles containing an oxo moiety such as tetrahydro-4H-pyran-4-one
  • the alcohols can be treated with sodium hydride, iodomethane, and a catalytic amount of 15-crown-5 to provide l-substituted-3,5-difluorobenzenes of general formula (3) such as 4-(3,5- difluorophenyl)-4-methoxytetrahydro-2H-pyran, (16).
  • Method B demonstrates the replacement of bromine with amines and N-containing heterocycles using conditions as described in Scheme 3 or conditions described in (Wagaw, S. and Buchwald, S., J. Org. Chem. 61 (1996) 7240-7241; Harris, M.C. et al., J. Org. Chem. 64 (1999) 6019-6022).
  • Method C demonstrates the replacement of bromine with aryl groups or heterocycles using well known Heck, Suzuki, or Stille chemistry as described in (Sha ⁇ , M.J. and Snieckus, V., Tet. Lett. 26 (1985) 5997; Syn. Commun., 11 (1981) 513; J. Org. Chem., 49 (1984) 5237; Tet. Lett., 28 (1987) 5093; Tet. Lett., 28 (1987) 5097; Bailey, T.R., Tet. Lett., 27 (1986) 4407; and Tet. Lett. 28 (1987) 2645).
  • Alcohols of general formula (12), from Scheme 3, can be treated with phenols of general formula (18), from Scheme 7, azo compounds such as DEAD, DBAD, and DIAD, and PPh 3 in a solvent such as THF to provide compounds of general formula (6).
  • Scheme 6
  • Analogous chloromethyl compounds can also be prepared by treating alcohols of general formula (12) with phosphorous trichloride. Bromomethyl compounds of general formula (20) or the analogous chloromethyl compounds can be treated with phenols of general formula (18), from Scheme 7, and sodium hydride in DMF to provide compounds of general formula (6).
  • Phenols of general formula (18), wherein B is as defined in formula I, can be prepared as described in Scheme 7.
  • l-Bromo-3,5-difluorobenzene can be treated with benzyl alcohol and sodium hydride in DMF to provide l-(benzyloxy)-3-bromo-5-fluorobenzene.
  • 1- (Benzyloxy)-3-bromo-5-fluorobenzene can be processed as described in Scheme 4 to provide compounds of general formula (22).
  • Compounds of general formula (22) can be treated with a palladium catalyst such as 10% palladium on carbon under 1 atmosphere of hydrogen gas to provide phenols of general formula (18).
  • Alcohols of general formula (27) can be processed with benzenes of general formula (3), from Scheme 4, as described in Scheme 1 to provide compounds of general formula (28).
  • alcohols of general formula (27) can be processed with phenols of general formula (18), from Scheme 7, using methodology described in Scheme 5 to provide compounds of general formula (28).
  • additionaly alcohols of general formula (27) can be processed as described in Scheme 6 to provide bromides or chlorides of general formula (29).
  • Bromomethyl compounds of general formula (29) or the analogous chloromethyl can be processed with phenols of general formula (18), from Scheme 7, using methodology described in Scheme 6 to provide compounds of general formula (28).
  • Triflates of general formula (31) can be treated with a palladium catalyst such as palladium(II) acetate, dppf, trioctylsilane, a base such as triethylamine under an atmosphere of carbon monoxide to provide benzaldehydes of general formula (32).
  • Phosphonium salts of general formula (30) can be treated with sodium methoxide and benzaldehydes of general formula (32) to provide alkenes of general formula (33).
  • Alkenes of general formula (33) can be treated with a palladium catalyst such as 10% palladium on carbon under 1 atmosphere of hydrogen gas to provide compounds of general formula (34).
  • Example 1A ethyl 4-isocvanatobenzoate The title compound was purchased from Acros Organics.
  • Example 15 A The product from Example 1 A and diethylamine were processed as described in Example 15 A to provide the title compound.
  • Example IB The product from Example IB was processed as described in Example 133B to provide the title compound.
  • Example IE N- ⁇ 4-r(3-bromo-5-fluorophenoxy)methyllphenyl)-N',N'-diethyl-N-methylurea
  • the product from Example ID and l-bromo-3,5difluorobenzene were processed as described in Example 15D to provide the title compound.
  • Example IF ethyl 4-[3-( ⁇ 4-[ " [(diethylamino ⁇ carbonvn(methyl)amino]benzyl ⁇ oxy)-5-fluorophenyl1-l- piperazinecarboxylate The product from Example IE (49 mg, 0.12 mmol) in 2.2 mL of dry degassed toluene was treated with ethyl 1 -piperazinecarboxylate (2 equivalents), Pd(dba) 2 (7 mg, 0.01 mmol), BINAP (23 mg, 0.037 mmol), and sodium tert-butoxide (41 mg, 0.43 mmol). The mixture was kept at 80 °C for 15 hours and then allowed to cool to ambient temperature.
  • the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, and filtered through a silica gel sep-pak cartridge (Alltech 209150). The resulting solution was concentrated in vacuo to provide crude material. The crude residue was purified by preparative HPLC (Waters Nova-Pak ® HR C18 6 ⁇ m 60 D 25x100 mm, 50- 95% MeCN/10 mM NH 4 OAc over 10 min at 40 mL/min) to provide 34.7 mg (59%) of the title compound as a light yellow oil.
  • Example IE The product from Example IE and N,N-bis(2-methoxyethyl)amine were processed as described in Example IF to provide the title compound as a light yellow oil.
  • Example 3 N-(4- ⁇ r3-(2,6-dimethyl-4-mo ⁇ holinyl)-5-fluorophenoxylmethyl ⁇ phenyl -N',N'-diethyl-N- methylurea
  • the product from Example IE and 2,6-dimethylmo ⁇ holine were processed as described in Example IF to provide a cis:trans (4:1) mixture of the title compound as a light yellow oil.
  • Example 4 N,N-diethyl-N'-( " 4-(r3-fluoro-5- 4-thiomo ⁇ holinyl phenoxylmethyl
  • the product from Example IE and thiomo ⁇ holine were processed as described in Example 1 to provide the title compound as a light yellow oil.
  • Example IE N,N-diethyl-N'-(4- ⁇ [3-fluoro-5-( ' 4-hvdroxy-l-piperidinyl)phenoxylmethyl ⁇ phenyl)-N'- methylurea
  • the product from Example IE and 4-hydroxypiperdine were processed as described in Example IF to provide the title compound as a yellow oil.
  • Example IE The product from Example IE and piperdine were processed as described in Example IF to provide the title compound as a yellow oil.
  • Example 8 N-(4-
  • the product from Example IE and cyclopentylamine were processed as described in Example IF to provide the title compound as a light yellow-green oil.
  • Example 9 N-(4- ⁇ [3-(cvclohexylamino)-5-fluorophenoxy]methyl)phenyl)-N',N'-diethyl-N-methylurea
  • the product from Example IE and cyclohexylamine were processed as described in Example IF to provide the title compound as a light yellow-green oil.
  • Example IE and 4-methylpiperdine were processed as described in Example IF to provide the title compound as a light yellow oil.
  • H NMR 500 MHz, CD 3 OD
  • Example 12 N,N-diethyl-N'-r4-( ⁇ 3-rethyl(2-methoxyethyl)aminol-5-fluorophenoxy
  • the product from Example IE and ethyl(2-methoxyethyl)amine were processed as described in Example IF to provide the title compound as a light yellow oil.
  • Example IE N,N-diethyl-N'-(4- ⁇ [3-fluoro-5-(l-pyrrolidinyl)phenoxylmethv phenyl)-N'-methylurea
  • the product from Example IE and pyrrolidine were processed as described in Example IF to provide the title compound as a light yellow oil.
  • Example IE The product from Example IE and 3-methyl-2-piperazinone were processed as described in Example IF to provide the title compound as a light yellow oil.
  • Example 15 ethyl 4- ⁇ 3-fluoro-5-r(4- ⁇ methvir(2-methyl-l- pyrrolidinvDcarbonyll amino ⁇ benzyl)oxylphenyl ) - 1 -piperazinecarboxylate
  • Example 15A ethyl 4- ⁇ r(2-methyl-l -pyrrolidinvDcarbonyllaminolbenzoate
  • the product from Example 1 A (3 g, 15.7 mmol) was treated with 1 -methylpyrrolidine (1.34 g, 15.7 mmol) in lmL of THF at 0 °C. After consumption of starting material was determined via TLC, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to provide 4.1 grams (95%) of the title compound as a white solid.
  • Example 15B ethyl 4- (methyl
  • the product from Example 15A was processed as described in Example 133B to provide the title compound.
  • the mixture was quenched with 5% aqueous NH 4 C1 and extracted with ethyl acetate.
  • the organic extracts were washed with 5% aqueous NH 4 C1, saturated aqueous NaHCO 3 , water, brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to provide an oily yellow residue which was kept under vacuum at ambient temperature for 48 hours.
  • the residue was dissolved in ethyl acetate and filtered through a silica gel sep-pak cartridge (Alltech 239310). The solution was concentrated in vacuo to provide 1.26 grams (92%) of the title compound as a light yellow oil.
  • Example 15D The product from Example 15D (50 mg, 0.12 mmol), Pd(dba) 2 (7 mg, 0.01 mmol), BINAP (23 mg, 0.037 mmol), ethyl 1 -piperazinecarboxylate (2 equivalents), and sodium tert- butoxide (40 mg, 0.42 mmol) were processed as described in Example IF. The resulting residue was dissolved in ethyl acetate and filtered through a silica gel sep-pak cartridge (Alltech 209150).
  • Example 16 N- 4-f ( 3 - [bis(2-methoxyethyl)amino1-5-fluorophenoxy ⁇ methvDphenyl] -N,2-dimethyl- 1 - pyrrolidinecarboxamide
  • the product from Example 15D and N,N-bis(2-methoxyethyl)amine were processed as described in Example 15E to provide the title compound as a colorless oil.
  • Example 17 N-(4- ⁇ f3-( " 2.6-dimethyl-4-mo ⁇ holinyl)-5-fluorophenoxy1methyl
  • the product from Example 15D and 2,6-dimethylmo ⁇ holine were processed as described in Example 15E to provide a (4:1) cis:trans mixture of the title compound as a light yellow oil.
  • Example 18 N-(4- ⁇ [3 -fluoro-5-(4-thiomo ⁇ holinyl)phenoxy1methy 11 phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide
  • the product from Example 15D and thiomo ⁇ holine were processed as described in Example 15E to provide the title compound as a light yellow oil.
  • Example 19 N-(4- ⁇
  • the product from Example 15D and 4-hydroxypiperdine were processed as described in Example 15E to provide the title compound as a light yellow solid.
  • Example 20 N-(4- ⁇ [3-(4-acetyl- 1 -piperazinyl)-5-fluorophenoxy]methyl ⁇ phenvIVN_ -dimethyl- 1 - pyrrolidinecarboxamide
  • the product from Example 15D and 1 -acetylpiperazine were processed as described in Example 15E to provide the title compound as a light yellow oil.
  • Example 21 N-(4- ⁇ [3 -fluoro-5-( 1 -piperidinyDphenoxylmethyl ⁇ phenyl VN.2-dimethyl- 1 - pyrrolidinecarboxamide
  • the product from Example 15D and piperdine were processed as described in
  • Example 15E to provide the title compound as a yellow oil.
  • Example 23 N-(4- ⁇ 3-fluoro-5-(4-methyl-l-piperidinyl ' )phenoxylmethyl)phenyl N )-N.2-dimethyl-l- pyrrolidinecarboxamide
  • the product from Example 15D and 4-methylpiperdine were processed as described in Example 15E to provide the title compound as a yellow oil.
  • Example 24 N-
  • the product from Example 15D and ethyl(2-methoxyethyl)amine were processed as described in Example 15E to provide the title compound as a light yellow oil.
  • Example 15D N-(4-( 3-fluoro-5-fl-pyrrolidinyl)phenoxy1methyl ⁇ phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide
  • Example 15E N-(4-( 3-fluoro-5-fl-pyrrolidinyl)phenoxy1methyl ⁇ phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide
  • Example 28 N-(4- ⁇ [3-fluoro-5-f3-hvdroxy-l -pyrrolidinvDphenoxylmethv pheny l)-N.2-dimethyl-l - pyrrolidinecarboxamide
  • the product from Example 15D and 3-hydroxypyrrolidine were processed as described in Example 15E to provide the title compound as a yellow oil.
  • Example 15E The product from Example 15D and 1 -(2-methoxyethyl)piperazine were processed as described in Example 15E to provide the title compound as a yellow oil.
  • Example 30A azocane hydrochloride Azocane was purchased from Aldrich Chemical Co.
  • reaction mixture was concentrated in vacuo to half of the initial volume to provide a clear yellow solution.
  • the solution was basified to pH 12 with IM NaOH, washed with ethyl acetate, acidified to pH 2-3 with 10% aqueous KHSO 4 , and extracted with ethyl acetate. The extracts were washed with 10% aqueous KHSO 4 and brine and evaporated to dryness to provide 5.60 grams (86%) of the title compound as a white solid.
  • Example 3 PC tert-butyl 4-(hvdroxymethyl)phenyl(methyl)carbamate
  • a solution of the product from Example 30B (2.80 g, 11.1 mmol) in 45 mL of dry THF at 0°C was treated dropwise with a 1.0 M solution of borane diethyl etherate in THF (45.0 mL, 45.0 mmol). After stirring at 0°C for 10 minutes, the reaction mixture was allowed to warm up slowly to ambient temperature. After stirring at ambient temperature for 3 hours, the reaction mixture was cooled in an ice bath and quenched with THF: water (1 :1) and then water.
  • the reaction mixture was quenched with 150 mL of aqueous NH 4 C1 and extracted with diethyl ether (150 mL, 3X). The combined extracts were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the crude material was purified by column chromatography (0 to 2.5% CH 3 OH in CH 2 C1 2 ) to provide 3.74 grams (67%) of the title compound as a white solid.
  • Example 30D The product from Example 30D (3.00 g, 14.0 mmol) and 10 drops of 15-crown-5 in 20 mL of DMF was treated with sodium hydride (1.96 g, 49.0 mmol) 60% dispersion in mineral oil prewashed with hexanes (20 mL, 4X). After stirring for 45 minutes at ambient temperature, the reaction mixture was treated with methyl iodide (3.5 mL, 56.0 mmol) resulting in the formation of a white precipitate. An additional 10 mL of DMF was added and the reaction mixture was allowed to stir overnight.
  • Example 3 OF tert-butyl 4- ⁇ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- vDphenoxylmethyl ⁇ phenvKmethvDcarbamate
  • the product from Example 30C (2.16 g, 9.10 mmol) in 10 mL of DMF was treated with sodium hydride (764 mg, 19.1 mmol), 60% in mineral oil, in portions. After stirring at ambient temperature for 45 minutes, the solution turned bright yellow. The bright yellow solution was treated with the product from Example 30E (1.09 g, 4.77 mmol) in 2.5 mL of DMF via cannula under positive N 2 pressure.
  • reaction mixture was heated to 90 °C for 3 hours, allowed to cool to ambient temperature, and then carefully quenched with water.
  • the mixture was extracted with diethyl ether (75 mL, 3X) and the combined extracts were washed with water, brine, dried over Na 2 SO 4 , and concentrated in vacuo.
  • Example 30G 4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl ' )phenoxylmethyl
  • the product from Example 30F (659 mg, 1.48 mmol) in 5 mL of dry dioxane was treated with 4M HC1 in dioxane (15 mL). The mixture was stirred for 1 hour at ambient temperature. The solvent was removed in vacuo and the resultant oily yelllow residue was dried under vacuum at ambient temperature for 16 hours. The crude hydrochloride salt was used without further purification.
  • Example 3 4-r3-( ⁇ 4-r(chlorocarbonyl)(methyl)aminolbenzyl ⁇ oxy)-5-fluorophenyll-4- methoxytetrahvdro-2H-pyran
  • the crude product from Example 30G suspended in 8 mL of dry toluene, was treated with triethylamine (0.740 mL, 5.31 mmol), stirred for 30 minutes at ambient temperature, and filtered.
  • a vigorously stirred solution of phosgene (3.65 mL, 6.90 mmol) in 3 mL of toluene at 0 °C was slowly treated with the above filtrate via an addition funnel.
  • reaction mixture was stirred at 0 °C for 30 minutes and then allowed to warm up to ambient temperature.
  • the solvent was removed in vacuo and the resultant yellow solid was suspended in 10 mL of THF and filtered to provide a solution of the title compound which was used immediately in preceding steps.
  • N-methyl- 1 -pyrrolidinecarboxamide The product from Example 30H and 3-hydroxypyrrolidine were processed as described in Example 301 to provide 22.2 mg (35%) of the title compound as a colorless oil.
  • Example 32 N-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl phenoxylmethyl
  • the product from Example 30H and 2-methylpyrrolidine were processed as described in Example 301 to provide 35.0 mg (57%) of an oily, white solid.
  • Example 35 N-(4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyllphenv ⁇ -N.N'- dimethyl-N'-propylurea
  • the product from Example 3 OH and N-methyl-N-propylamine were processed as described in Example 301 to provide 31.0 mg (52%) of the title compound as a yellow oily solid.
  • Example 36 A 4- ⁇ methyl[(methylamino ' )carbonyllamino ⁇ benzoic acid
  • a suspension of 4-(methylamino)benzoic acid (756 mg, 5.0 mmol), purchased from Aldrich Chemical Co., in toluene (20 mL) was treated with a four-fold excess of methyl isocyanate (1.2 mL, 20.0 mmol) at ambient temperature under a N 2 atmosphere.
  • the mixture was heated to near reflux temperature ( ⁇ 100 °C).
  • the reaction mixture was insoluble, anhydrous THF (5 mL) was added, and the mixture was heated to reflux for an additional 1 hour. After TLC showed no starting material remaining, the mixture was allowed to cool to ambient temperature and stirred overnight.
  • Example 36A The product from Example 36A (948 mg, 4.55 mmol) and N-methylmo ⁇ holine (0.6 mL, 5.4 mmol) in anhydrous dimethoxyethane (10 mL) and anhydrous DMF (3.0 mL) was cooled in ice water and treated with isobutyl chloroformate (0.7 mL, 5.4 mmol). The mixture was stirred at 0 °C for 35 minutes and then allowed to warm to ambient temperature and stirred an additional 40 minutes. The mixture was filtered and the filtrate treated with sodium borohydride (800 mg, 21.0 mmol) and then poured over a mixture of ethyl acetate/saturated NH 4 C1.
  • sodium borohydride 800 mg, 21.0 mmol
  • Example 36C N-[4-(chloromethyl)phenyll-N,N'-dimethylurea
  • Example 36D 3-fluoro-5-( ' 4-methoxytetrahvdro-2H-pyran-4-yl)phenol The title compound was prepared as described in WO 95/26346.
  • Example 36E N-(4- ⁇ [ -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy1methyl IphenvP-N.N'- dimethylurea
  • a suspension of NaH (80% suspension in mineral oil, 35 mg, 1.2 mmol) in DMF (2 mL) was treated with the product from Example 36D (226 mg, 1.0 mmol) in dry DMF (2 mL) at ambient temperature. After stirring at ambient temperature for 1 hour, the reaction mixture was treated with the product from Example 36C in dry DMF (1 mL). The mixture was diluted with a saturated NH 4 C1 solution and extracted with a hexane: diethyl ether mixture (1 :1).
  • Example 38 N-(4- ⁇ r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyllphenv ⁇ -N,2.5- trimethyl- 1 -pyrrolidinecarboxamide
  • the product from Example 3 OH and 2,6-dimethylpyrrolidine were processed as described in Example 301 to provide 36.0 mg (57%) of the title compound as a yellow solid.
  • Example 3 The product from Example 3 OH and 2-(methylamino)ethanol were processed as described in Example 301 to provide 12.0 mg (25%) of the title compound as a light yellow oil.
  • Example 40A The product from Example 40A (1.25 g, 6.26 mmol) and methyl isocyanate (1.5 mL, 25.0 mmol) in toluene (25 mL) were heated at 100 °C for 2 hours. The reaction mixture was treated with additional methyl isocyanate (0.5 mL) and heated at 100 °C overnight. The mixture was cooled in an ice bath and filtered. The filter cake was washed with diethyl ether and dried in vacuo to provide (0.66 g) of the title compound as a solid, mp 146-148 °C; MS (DCI/NH 3 ) m/z 274 (M+NH 4 ) + .
  • Example 40C ethyl 2-chloro-4-
  • the product from Example 40B (1.85 g, 7.20 mmol) in DMF was treated with 80% sodium hydride in mineral oil (540 mg, 18.0 mmol) at 0 °C.
  • the mixture was allowed to warm to ambient temperature and stir for 30 minutes.
  • the mixture was then recooled to 0 °C and treated with iodomethane (4.62 g, 30.0 mmol) and then allowed to warm to ambient temperature and stirred overnight.
  • a solution of saturated NH 4 C1 was added and the mixture was extracted with diethyl ether :hexanes (1 :1).
  • the organic phase was dried (MgSO 4 ) and concentrated in vacuo to provide (1.89 g) of the title compound.
  • Example 40D N-[3-chloro-4-(hvdroxymethyl)phenyl -N,N',N'-trimethylurea
  • the product from Example 40C was processed as described in Example ID to provide the title compound.
  • Example 40E N-
  • the product from Example 40D (512 mg, 2.11 mmol) in anhydrous methylene chloride (12 mL) was treated with phosphorous trichloride (320 mg, 2.33 mmol) at -40 °C. The temperature was allowed to slowly rise to -20 °C. After stirring at -20 °C for 3 hours, saturated NaHCO 3 solution and ethyl acetate were added and the layers separated. The organic layer was washed with water, brine, dried over MgSO 4 and concentrated in vacuo to provide the title compound (416 mg) as a yellow oil.
  • Example 40E The product from Example 40E (416 mg, 1.59 mmol), the product from Example 36D (386 mg, 1.71 mmol), and 80% sodium hydride in mineral oil (59 mg, 1.95 mmol) were processed as described in Example 36E to provide crude product. The residue was purified by flash chromatography (silica gel, CH 2 C1 2 to 25% ethyl acetate in CH 2 C1 2 ) to provide the title compound (425 mg) as a pale yellow oil.
  • Example 41 (3RVN-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenyl)-3- hydroxy-N-methyl- 1 -pyrrolidinecarboxamide
  • the product from Example 30H and (3R)-3-pyrrolidinol were processed as described in Example 301 to provide 28.8 mg (45%) of the title compound as a white oily solid. ⁇
  • Example 30H N,2,4-trimethyl- 1 -pyrrolidinecarboxamide
  • 3-ethyl-2,4-dimethylpyrrolidine were processed as described in Example 301 to provide 32.6 mg (47%) of the title compound as a mixture of isomers as a yellow oil.
  • Example 30H The product from Example 30H and 2,5-dimethyl-2,5-dihydro-lH-pyrrole were processed as described in Example 301 to provide 29.2 mg (45%) of the title compound as a yellowish solid.
  • Example 3 The product from Example 3 OH and N-(cyclopropylmethyl)-N-propylamine were processed as described in Example 301 to provide 29.0 mg (56%) of the title compound as an off white solid.
  • Example 46 N-(4- ⁇ r3-fluoro-5-( , 4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethv phenyl)-N.N'- dimethyl-N'-(2-propynyl)urea
  • the product from Example 30H and N-methyl-N-(2-propynyl)amine were processed as described in Example 301 to provide 27.0 mg (58%) of the title compound as a white solid.
  • Example 47A N-r4-(bromomethyl)phenyl]-N,2-dimethyl-l-pyrrolidinecarboxamide
  • the product from Example 15C was processed as described in Example 133D to provide the title compound.
  • Example 47B (A- (methyl[(2 -methyl- 1 -pyrrolidinvDcarbonyllamino I benzylXtriphenyDphosphonium bromide
  • the product from Example 47A (0.225 g, 0.73 mmol) and triphenylphosphine (0.190 g, 0.73 mmol) in 15 mL of xylene were heated to reflux for 3 hours. The precipitate was filtered and washed with hexanes to provide 0.23 g (56%) of the title compound.
  • Example 47C 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenyl trifluoromethanesulfonate 3-Fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenol (0.630 g. 2.77 mmol), prepared as described in WO 95/26346, in anhydrous pyridine (10 ml) was treated with trifluoromethanesulfonic anhydride (0.56 mL, ⁇ 1.2 eq) at 0 °C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was partitioned between IN HCl and ethyl acetate.
  • Example 47D 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)benzaldehyde
  • the product from Example 47C (0.46 g. 1.27 mmol), Pd(OAc) 2 (0.006 g, 2 mol %), and dppf (0.011 g, 2 mol %), in DMF (10 mL) was heated at 70 °C for 20 minutes and then treated with triethylamine (0.42 mL, ⁇ 2.5 eq) dropwise followed with trioctylsilane (1.15 mL, ⁇ 2 eq). The reaction was stirred under an atmosphere of carbon monoxide for 2 hours.
  • Example 47E N-(4- ⁇ -2- 1 ⁇ 3 -fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenyl] ethenyl ⁇ phenylVN.2- dimethyl- 1 -pyrrolidinecarboxamide
  • the product from Example 47B (0.18 g, 0.31 mmol) in 3 mL of dry MeOH was treated with sodium methoxide (0.094 mL 30 wt% in methanol) at ambient temperature. After stirring for 30 minutes, the product from Example 47D (0.075 g, 0.31 mmol) in 1 mL of MeOH was added dropwise.
  • Example 47F N-(4-(2-r3-fluoro-5-(4-methoxytetrahvdro-2H- ⁇ yran-4-yDphenyllethyl
  • EtOH 2 mL
  • Pd/C 10%, 0.008 g
  • the mixture was then filtered through celite and silica gel and evaporated to provide 0.025 g (81%) of the desired compound.
  • Example 51 N-allyl-N-ethyl-N'-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy "
  • the product from Example 30H and N-allyl-N-ethylamine were processed as described in Example 301 to provide the title compound as a white solid.
  • Example 52 N- ⁇ -ieS-fluoro-S- ⁇ -methoxytetrahvdro ⁇ H-pyran ⁇ -vDphenoxylmethvUphenv ⁇ -S- fhydroxymethylVN-methyl- 1 -piperidinecarboxamide
  • the product from Example 3 OH and 3-hydroxymethylpiperdine were processed as described in Example 301 to provide the title compound as a white oily solid.
  • Example 54 N-(4- ⁇ [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl ⁇ phenyl)-N'-f 2- methoxyethyl)-N,N'-dimethylurea
  • the product from Example 3 OH and N-(2-methoxyethyl)-N-methylamine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 55 N-(4- ⁇
  • the product from Example 3 OH and 4-hydroxymethylpiperdine were processed as described in Example 301 to provide the title compound as a white oily solid.
  • Example 3 The product from Example 3 OH and N-isopentyl-N-methylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 59 N-(4- ⁇ 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-
  • N-methyl- 1 -piperidinecarboxamide The product from Example 3 OH and 4-hydroxypiperdine were processed as described in Example 301 to provide the title compound as a white solid.
  • Example 61 N-r2-d.3-dioxolan-2-vnethyll-N'-( , 4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxylmethyl)phenyl)-N,N'-dimethylurea
  • the product from Example 30H and N-[2-(l,3-dioxolan-2-yl)ethyl]-N-methylamine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 62 N-(4- ⁇ [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl phenoxy1methyl ⁇ phenyl)-N,2- dimethyl- 1 -piperidinecarboxamide
  • the product from Example 3 OH and 2-methylpiperdine were processed as described in Example 301 to provide the title compound as a white solid.
  • Example 67 N-(4- ⁇ [3 -fluoro-5 -( " 4-methoxytetrahvdro-2H-pyran-4-vf)phenoxylmethyl ⁇ phenyl)-4-(2- hydroxyethvD-N-methyl- 1 -piperidinecarboxamide
  • the product from Example 3 OH and 2-(4-piperidinyl)ethanol were processed as described in Example 301 to provide the title compound as a light yellow solid.
  • Example 68 N,N-diallyl-N'-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy ⁇
  • the product from Example 3 OH and N,N-diallylamine were processed as described in Example 301 to provide the title compound as a bright yellow solid.
  • N'.N'-dipropylurea The product from Example 3 OH and N,N-dipropylamine were processed as described in Example 301 to provide the title compound as a yellow oily solid.
  • 'H NMR 400 MHz, CD 3 OD
  • Example 70 N-butyl-N-ethyl-N'-r4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl ⁇ phenvD-N'-methylurea
  • the product from Example 30H and N-butyl-N-ethylamine were processed as described in Example 301 to provide the title compound as a yellow solid.
  • N'-methyl-N-propylurea The product from Example 3 OH and N-ethyl-N-propylamine were processed as described in Example 301 to provide the title compound as a bright yellow solid.
  • Example 72 N-(4- ⁇ 3-fluoro-5-( ' 4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl ⁇ phenyl)-N'- isopropyl-N.N'-dimethylurea
  • the product from Example 3 OH and N-isopropyl-N-methylamine were processed as described in Example 301 to provide the title compound as a bright yellow solid.
  • Example 74 N'-cvclobuty l-N-(4- ⁇ [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl ⁇ phenyl)-N-methylurea
  • the product from Example 3 OH and cyclobutylamine were processed as described in Example 301 to provide the title compound as an off white solid.
  • Example 76 N-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methvUpheny ⁇ -N'-(2- methoxyethvD-N-methylurea
  • the product from Example 3 OH and 2-methoxyethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 3 The product from Example 3 OH and 2-amino-l-propanol were processed as described in Example 301 to provide the title compound as an off white oily solid.
  • Example 79 N'-( ' l-ethylpropylVN-( , 4- ⁇ r3-fluoro-5-( ' 4-methoxytetrahvdro-2H- ⁇ yran-4- vPphenoxylmethyl ) phenyl)-N-methylurea
  • the product from Example 3 OH and 1-ethylpropylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • N'-neopentylurea The product from Example 30H and 2,2-dimethyl-l-propylamine were processed as described in Example 301 to provide the title compound as a light yellow solid.
  • Example 82 N-(4- 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-v ⁇ phenoxylmethyl)phenylVN'- isobutyl-N-methylurea
  • the product from Example 3 OH and 2-mefhyl-l-propylamine were processed as described in Example 301 to provide .the title compound as a light yellow oil.
  • Example 84 N'-(2-ethylhexy ⁇ -N-(4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl I phenylVN -methy lurea
  • the product from Example 3 OH and 2-ethylhexylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 86 N-(4- ⁇ r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl ⁇ phenylVN'-(2- hydroxybutvD-N-methylurea
  • the product from Example 30H and l-amino-2-butanol were processed as described in Example 301 to provide the title compound as a light yellow solid.
  • Example 30H The product from Example 30H and 3-amino-2,2-dimethyl-l-propanol were processed as described in Example 301 to provide the title compound as a white solid.
  • Example 89 N'-allyl-N-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl ⁇ phenylVN- methylurea
  • the product from Example 3 OH and allylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 90 N-(4- ⁇ r3-fluoro-5-f4-methoxytetrahydro-2H-pyran-4-yl)phenoxylmethv phenyl)-N'-(2- methoxy- 1 -methylethvD-N-methylurea
  • the product from Example 3 OH and 2-methoxy-l-methylethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 91 N'-( ' cvanomethyl)-N-(4- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxylmethyl I phenyl)-N-methylurea
  • the product from Example 3 OH and aminoacetonitrile were processed as described in Example 301 to provide the title compound as an off white solid.
  • Example 92 N'-cyclopropyl-N-(4-l[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yDphenoxy] methyl I phenvD-N-methylurea
  • the product from Example 3 OH and cyclopropylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • N'-(2-methyl-2-propenyl)urea The product from Example 3 OH and 2-methyl-2-propenylamine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 101 N'- -ethylbutylVN-( ' 4- ⁇ r3-fluoro-5-C4-methoxytetrahvdro-2H-pyran-4- yf)phenoxy]mefhyl ⁇ phenvD-N-methylurea
  • the product from Example 3 OH and 2-ethylbutylamine were processed as described in Example 301 to provide the title compound as an off white solid.
  • Example 104 N'-(l,2-dimethylpropyl)-N-( ' 4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vOphenoxylmethyl ⁇ phenvD-N-methylurea
  • the product from Example 3 OH and 1 ,2-dimethylpropylamine were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 105 N'-sec-butyl-N-(4- ⁇
  • the product from Example 3 OH and sec-butylamine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 107 N-(4- ⁇ 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxylmethv phenyl)-N'-[2-(4- hvdroxyphenyl)ethyl]-N-methylurea
  • the product from Example 30H and 4-(2-aminoethyl)phenol were processed as described in Example 301 to provide the title compound as a yellow oil.
  • Example 108 N'-(2-cvanoethyl)-N-( ' 4- ⁇ r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxyl methyl IphenylVN-methy lurea
  • the product from Example 3 OH and 3-aminopropanenitrile were processed as described in Example 301 to provide the title compound as a light yellow oil.
  • Example 110 N-(4- ⁇ T3 -fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl ) phenvD-N'- f 1 - (hydroxymethyl)cvclopentyl]-N-methylurea
  • the product from Example 3 OH and (l-aminocyclopentyl)methanol were processed as described in Example 301 to provide the title compound as a tan solid.
  • Example 112 N-(4- ⁇ 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-v ⁇ phenoxy]methyl ⁇ phenyl)-N'- isopropyl-N-methylurea
  • the product from Example 3 OH and isopropylamine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 113 N.N-diethyl-N'-(4- ⁇
  • the product from Example 3 OH and diethylamine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • N-(2-methoxyethyl)-N'-rnethylurea The product from Example 3 OH and N-ethyl-N-(2-methoxyethyl)amine were processed as described in Example 301 to provide the title compound as a light yellow solid.
  • Example 116 N ' -(A- ⁇ [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl > )phenoxy1methyl ) phenyl)-N' - methyl- 1 ,3-piperidinedicarboxamide
  • the product from Example 3 OH and 3 -piperidinecarboxamide were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 118 N-(4- ⁇
  • the product from Example 30H and N-isopropyl-N-(2-methoxyethyl)amine were processed as described in Example 301 to provide the title compound as a colorless oil.
  • Example 119 N,N-diethyl-N'-f4- ( r3-fluoro-5-(4-hvdroxytetrahvdro-2H-pyran-4- yllphenoxylmethyl ⁇ phenyl)-N'-methy lurea
  • the product from Example ID (248 mg, 1.05 mmol) in 2 mL of DMF at 0 °C was treated with sodium hydride (76 mg, 3.17 mmol).
  • the cooling bath was removed and the reaction mixture was treated with the product from Example 30D (214 mg, 1.0 mmol) in 1 mL of DMF. After 3 hours at ambient temperature, the mixture was warmed to 65 °C for 4 days and then 90 °C for 16 hours.
  • Example 121 A N-[4-(hvdroxymethyl)phenyl]-N,N',N'-trimefhylurea The title compound was prepared using dimethylamine and the procedure(s) described in Example 1A through Example ID.
  • Example 12 IB N-(4- ⁇ r3-fluoro-5-(4-hvdroxytetrahydro-2H-pyran-4-yl)phenoxylmethyl)phenylVN.N'.N'- trimethylurea
  • the product from Example 121 A and the product from Example 30D were processed as described in Example 119 to provide the title compound.
  • N.N',N'-trimethylurea The product from Example 12 IB, propargyl bromide, and sodium hydride were processed as described in Example 119 to provide the title compound.
  • reaction mixture was stirred overnight and the resultant precipitate was filtered, washed with diethyl ether, and chromatographed on silica gel (90:10 hexanes: acetone) to provide 0.025 grams (25%) of the title compound as a glassy solid.
  • Example 123C 3-(4-ethyltetrahvdro-2H-pyran-4-yl)phenol
  • EtOH 2 mL
  • Pd/C 10% Pd/C (0.03 g)
  • the mixture was then filtered through Celite and a 0.2 micron filter and evaporated in vacuo to provide 0.025 grams (75%) of the title compound as a white solid.
  • Example 124 A ethyl 4-r3-(benzyloxy)phenylltetrahvdro-2H-pyran-4-carboxylate The title compound was prepared according to the procedure described in EP 0 462 830 A2.
  • Example 124B ethyl 4-(3 -hvdroxyphenyl ' )tetrahvdro-2H-pyran-4-carboxylate
  • EtOH 2 mL
  • Pd/C 0.34 g
  • the mixture was filtered through celite and a 0.2 micron filter and evaporated in vacuo to provide 0.49 grams (90%) of the title compound as a white solid.
  • Example 124C ethyl 4-[3-( " (4-[ " [(diethylamino)carbonyll(methyl ' )amino]benzyl ⁇ oxy ' )phenyl]tetrahvdro-2H- pyran-4-carboxylate
  • the product from Example 124B (0.078 g, 0.26 mmol) in lmL of DMF was treated with solid sodium hydride (0.007g, 0.28 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was treated with the product from Example 123D (0.06 g, 0.24 mmol) in 0.5 mL. The mixture was stirred overnight.
  • Example 125 A l-F3-(benzyloxy)-5-fluorophenyllcyclohexanol
  • the product from Example 128 A and cyclohexanone were processed as described in Example 128B to provide the title compound.
  • Example 125B 3-fluoro-5-(T-hvdroxycyclohexyl)phenol The product from Example 125 A was processed as described in Example 126C to provide the title compound.
  • Example 125C N.N-diethyl-N'-(4- ⁇ [3-fluoro-5-( 1 -hydroxycvclohexyDphenoxylmethyl ⁇ phenyl)-N'- methylurea
  • the product from Example 125B (0.17 g, 0.81 mmol) in 3 mL of DMF was treated with solid sodium hydride (0.048 g, 2.0 mmol) at ambient temperature. After stirring for 20 minutes, the reaction mixture was treated with the product from Example 123D (0.22 g, 1.05 mmol) in 2 mL of DMF and allowed to stir overnight.
  • Example 126 A 4-r3-( " benzyloxy)-5-fluorop_henylltetrahvdro-2H-pyran-4-ol
  • the product from Example 128 A and tetrahydro-4H-pyran-4-one were processed as described in Example 128B to provide the title compound.
  • Example 126B 4- f 3 -(benzyloxy -5 -fluorophenvntetrahydro-2H-pyran
  • the product from Example 126A 250 mg, 0.83 mmol) in 5 mL of trifluoroacetic acid and 1 mL of CH 2 C1 2 was treated with triethylsilane (5 mL). After 10 hours, the mixture was concentrated in vacuo and the crude material was purified by column chromatography (CHC1 3 ) to provide 102 mg (43%) of a colorless oil.
  • Example 126C 3-fluoro-5-tetrahvdro-2H-pyran-4-ylphenol
  • the product from Example 126B (100 mg) in 10 mL of ethanol was treated with 10% Pd/C under an atmosphere of hydrogen for 5 hours. The mixture was filtered through a plug of celite and concentrated in vacuo to provide the title compound.
  • Example 126D N- ⁇ 4-r(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyllphenyl ⁇ -N,2-dimethyl-l- pyrrolidinecarboxamide
  • the product from Example 126C (34 mg, 0.17 mmol) and the product from Example
  • Example 123D The product from Example 123D (78 mg, 0.26 mmol) and the product from Example 126C (38 mg, 0.19 mmol) were processed as described in Example 126D.
  • the resultant crude material was purified by column chromatography (200:1 CHCl 3 :MeOH) to afford 38 mg (48%) of the title compound.
  • Example 128 A l-(benzyloxy)-3-bromo-5-fluorobenzene Benzyl alcohol and l-bromo-3,5-difluorobenzene were processed as described in Example 15D to provide the title compound.
  • Example 128B tert-butyl 4-[3-(benzyloxy)-5-fluorophenyll-4-hvdroxy-l-piperidinecarboxylate
  • the Grignard reagent prepared from magnesium turnings (0.75 g, 28.5 mmol), a few drops of 1 ,2-dibromoethane, a crystal of iodine, and the product from Example 128 A (8 g, 28.5 mmol) in dry diethyl ether (50 mL) was treated with tert-butyl 4-oxo-l- piperidinecarboxylate (6.25 g, 31.4 mmol) in diethyl ether (100 mL) dropwise.
  • Example 128C tert-butyl 4-(3-fluoro-5-hvdroxyphenyl)-4-hydroxy- 1 -piperidinecarboxylate
  • the product from Example 128B was processed as described in Example 126C to provide the title compound.
  • Example 128D tert-butyl 4-[3-( " ⁇ 4-[[(diethylamino)carbonyll(methyl)amino]benzylloxy)-5-fluorophenyll-4- hydroxy-1 -piperidinecarboxylate
  • the product from Example 128C (0.9 g, 3.81 mmol) in 6 mL of DMF was treated with solid sodium hydride (0.2 g, 8.33 mmol) at ambient temperature. After 30 minutes of stirring, the reaction mixture was treated with the product from Example 123D (1.3 g, 4.15 mmol) in 2 mL of DMF. The mixture was heated at 75 °C overnight.
  • Example 129 A methyl 2-oxo-23-dihvdro-lH-benzimidazole-5-carboxylate Methyl 3,4-diaminobenzoate (1.8 g, 10.85 mmol) in 20 mL of THF:DMF (1 :1) was treated with l,l'-carbonyldiimidazole (1.95 g, 11.95 mmol). A pale white solid slowly precipitated during overnight stirring. The solid was filtered, washed with a small amount of THF, and dried in vacuo to provide 1.75 g (84%) of the title compound.
  • Example 129B methyl 1.3-dimethyl-2-oxo-2.3-dihvdro-lH-benzimidazole-5-carboxylate
  • the product from Example 129A (10.2 g, 53.13 mmol) in 300 mL of THF:DMF (1 :3) was treated with sodium hydride (2.8 g, 117 mmol). After 20 minutes, the suspension was treated with methyl iodide (8 mL) via syringe and the reaction monitored by TLC
  • Example 129C 5-(hydroxymethyl)- 1.3 -dimethyl- 1 ,3 -dihydro-2H-benzimidazol-2-one
  • the product from Example 129B (10 g, 45.5 mmol) in 350 mL of THF and 2 mL of MeOH was treated with lithium borohydride (5 g, 229 mmol) and then refluxed for 3 hours. After cooling on ice, the mixture was slowly quenched by the addition of saturated aqueous NH 4 C1 followed by addition of water.
  • Example 129D 1 -benzyl-4-(3 ,5-difluorophenyl " )-4-piperidinol
  • a solution of the Grignard reagent prepared from l-bromo-3,5-difluorobenzene (10 g, 51.8 mmol), three drops of 1 ,2-dibromoethane, one crystal of iodine, and magnesium turnings (1.35 g, 56.25 mmol) in dry diethyl ether (60 mL), was treated with a solution of l-benzyl-4- piperidinone (10.1 g, 53.5 mmol) in diethyl ether (60 mL) dropwise at ambient temperature.
  • Example 129E 5- [3 -( 1 -benzyl-4-hvdroxy-4-piperidinyl)-5-fluorophenoxylmethyl 1-1.3 -dimethyl- 1,3- dihydro-2H-benzimidazol-2-one
  • the product from Example 129C (0.5 g, 2.6 mmol) in 5 mL of DMF was treated with sodium hydride (0.190 g, 7.9 mmol) at ambient temperature. The resulting mixture was stirred for 30 minutes and then treated with a solution of the product from Example 129D (0.91 g, 3 mmol) in 3 mL of DMF. The mixture was heated at 60 °C overnight.
  • Example 131 A 8-(3.5-difluorophenviyi.4-dioxaspiror4.5]decan-8-ol
  • the Grignard reagent prepared from magnesium turnings (1.3 g, 53.5 mmol), 1- bromo-3,5-difluorobenzene (10 g, 51.8 mmol), and several drops of 1 ,2-dibromoethane in 100 mL of diethyl ether was treated with l,4-dioxaspiro[4.5]decan-8-one (8.2 g, 52.6 mmol) in 100 mL of diethyl ether over 1 hour dropwise.
  • Example 132 5- ⁇ [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl ⁇ - 1 ,3-dimethyl- 1.3- dihydro-2H-benzimidazol-2-one
  • the product from Example 129C (0.2 g, 1.05 mmol) in 5 mL of DMF was treated with solid sodium hydride (0.075 g, 3.1 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was treated with the product from Example 131 A (0.3 g, 1.1 mmol) in 1.5 mL of DMF and then heated at 60 °C overnight.
  • Example 133 A methyl 4- ( [(allylamino)carbonyllamino ⁇ benzoate Methyl 4-aminobenzoate (19.7 g, 130 mmol) in 100 mL of THF was treated with allylisocyanate (18 mL, 204 mmol), refluxed for 16 hours, and then concentrated in vacuo. The crude material was crystallized from 500 mL of hot ethyl acetate to afford 23.9 g (79%) of the title compound as a white solid.
  • Example 133B methyl 4- ⁇ rallvKmethyllaminolcarbonyl) (methyOamino]benzoate
  • the product from Example 133A (1.08 g, 4.62 mmol) in 15 mL of DMF was treated with CsCO 3 (4.4 g, 13.5 mmol) and methyl iodide (1 mL, 16.1 mmol).
  • CsCO 3 4.4 g, 13.5 mmol
  • methyl iodide 1 mL, 16.1 mmol
  • Example 133C N-allyl-N'-[4-(hvdroxymethyl)phenyl]-N,N'-dimethylurea
  • the product from Example 133B (3.75 g, 14.3 mmol) in 50 mL of diethyl ether was cooled to 0 °C and treated with lithium aluminum hydride (595 mg, 15.7 mmol). After 3 hours at 0 °C, the cooling bath was removed and stirring continued for an additional 2 hours.
  • reaction mixture was quenched by the successive addition of 0.6 mL of water, 0.6 mL of 2N NaOH, and 1.8 mL of water
  • the mixture was partitioned between IN HCl and diethyl ether and the phases were separated.
  • the organic phase was washed with water and concentrated in vacuo to give 1.6 g (48%) of the title compound, which was used without further purification.
  • Example 133D N-allyl-N'-[4-(bromomethyl)phenvH-N,N'-dimethylurea
  • the product from Example 133C (647 mg, 2.76 mmol) in 30 mL of CC1 4 was cooled to 0 °C and treated with pyridine (110 ⁇ L, 1.36 mmol) and then PBr 3 (520 ⁇ L, 5.53 mmol). After 20 minutes, the cooling bath was removed and the reaction mixture was allowed to stir for 10 minutes at ambient temperature. The white mixture was partitioned between methylene chloride and water and the phases were separated. The organic phase was washed with water and concentrated in vacuo to provide 800 mg of the title compound as a colorless oil, which was used without further purification.
  • Example 133D After stirring for 2 hours at ambient temperature, the product from Example 133D (57 mg, 0.19 mmol) in 1 mL of DMF was added to the reaction mixture. After 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water and the phases separated. The organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (99:1 CHCl 3 :MeOH) to provide 61 mg (68%) of the title compound as a clear oil.
  • Example 133E The product from Example 133E (90 mg, 0.35 mmol) in 1 mL of DMF was treated with sodium hydride (22 mg, 0.92 mmol) and then the product from Example 123D (120 mg, 0.40 mmol) in 1 mL of DMF via cannula.
  • the resultant brown slurry was stirred at ambient temperature for 2 hours and then partitioned between diethyl ether and water. The phases were separated and the organic phase was washed with water and concentrated in vacuo.
  • the crude material was purified by column chromatography (98:2 CHCl 3 :MeOH) to provide 87 mg (84%) of the title compound.
  • Example 135 N-C4- ⁇ l ⁇ 3 -fluoro-5-(4-mo ⁇ holinyl)phenoxy "
  • Pd(dba) 2 (19 mg, 0.033 mmol)
  • BINAP 59 mg, 0.095 mmol
  • mo ⁇ holine 50 ⁇ L, 0.46 mmol
  • sodium tert-butoxide 72 mg, 0.75 mmol.
  • Example 138 N.N-diethyl-N'-(4-(r3-fluoro-5-( ' 4-mo ⁇ holinyl ' )phenoxylmethyl ⁇ phenyl)-N'-methylurea
  • Pd(dba) 2 14 mg, 0.024 mmol
  • BINAP 47 mg, 0.076 mmol
  • mo ⁇ holine 40 ⁇ L, 0.36 mmol
  • sodium tert-butoxide 60 mg, 0.63 mmol
  • the crude material was purified by column chromatography (99:1 CHCl 3 :MeOH) to provide 103 mg (100%) of the title compound.
  • Example 139 N-(4- ⁇ [3 -fluoro-5 -f 2-methyl-3 -oxo- 1 -piperazinvDphenoxylmethyl I phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide
  • the product from Example 15D and 3-methyl-2-piperazinone were processed as described in Example 15E to provide the title compound as a yellow oil.
  • Example 140 A 4-(6-bromo-2-pyridinv0tetrahvdro-2H-pyran-4-ol n-Butyllithium (3.55 mL, 8.9 mmol) in 15 mL of THF was cooled to -78 °C and treated dropwise with 2,6-dibromopyridine (2.0 g, 8.4 mmol) in 10 mL of THF. After 10 minutes, the reaction mixture was treated with tetrahydro-4H-pyran-4-one (1 mL, 10.8 mmol) dropwise. After 2 hours at -78 °C, the mixture was warmed to 0 °C for 2 hours and then partitioned between ethyl acetate and water.
  • Example 140A The product from Example 140A (98 mg, 0.38 mmol) in 1 mL of DMF at 0 °C was treated in succession with sodium hydride (34 mg, 1.4 mmol) and the product from Example 15C (103 mg, 0.42 mmol) in 1 mL of DMF via cannula.
  • the cooling bath was removed and the mixture was warmed to 65 °C for 16 hours.
  • the mixture was allowed to cool to ambient temperature and then partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with water and concentrated in vacuo.
  • the crude material was purified by column chromatography (200: 1 CHCl 3 :MeOH) to provide 98 mg (60%) of the racemate.
  • Example 143 N.N-diethyl-N'- -C ( r6-(4-hvdroxytetrahvdro-2H-pyran-4-vn-2- pyridinylloxy ⁇ methyl)phenyl1-N'-methylurea
  • the product from Example 140A (261 mg, 1.0 mmol), the product from Example ID (227 mg, 0.95 mmol), and sodium hydride (80 mg, 3.33 mmol) were processed as described in Example 140B.
  • the resultant crude material was purified by column chromatography (99:1 CHCl 3 :MeOH) to afford 220 mg (55%) of the title compound as a clear oil.
  • Examples 144-150 Examples 144 to 150 were prepared using the following procedure.
  • Example 30F The product from Example 30F (659 mg, 1.48 mmol) in 5 mL of dry dioxane was treated with 4M HCl in dioxane (15 mL). After stirring for 1 hour at ambient temperature, the solvent was removed in vacuo and the resultant yellow oil residue was dried under vacuum at ambient temperature for 16 hours.
  • the crude hydrochloride salt was suspended in 10 mL of dry toluene, treated with triethylamine (4.04 mL, 29.0 mmol), stirred for 30 minutes at ambient temperature, and then filtered. The resulting clear yellow solution was transferred to eleven 20-mL screw-cap vials and cooled to 0 °C.
  • Examples 151 and 152 were prepared using the following procedure.
  • the product from Example 30F (606 mg, 1.36 mmol) in 5 mL of dry dioxane was treated with 4M HCl in dioxane (15 mL). After stirring for 1 hour at ambient temperature, the solvent was removed in vacuo and the resultant yellow oil residue was dried under vacuum at ambient temperature for 16 hours.
  • the crude hydrochloride salt was suspended in 10 mL of dry toluene, treated with triethylamine (3.80 mL, 27.6 mmol), stirred for 30 minutes at ambient temperature, and then filtered. The resulting clear yellow solution was transferred to ten 20-mL screw-cap vials.
  • Example 151 isopropyl 4-(
  • Example 152 propyl 4- ⁇ r3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl ⁇ phenylfmethvPcarbamate
  • the title compound was isolated as a light yellow oil.
  • Example 153 tert-butyl 4- ⁇ 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y Dphenoxylmethyl I phenvKmethyQcarbamate The title compound was prepared according to the procedures described in Example 30.

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Abstract

A method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of one or more compounds selected from formula (I) and/or from formula (II).

Description

INHIBITORS OF INTERLEUKIN 5 GENE EXPRESSION
TECHNICAL FIELD The present invention relates to novel organic compounds that inhibit interleukin 5 (IL-5) gene expression in mammals, to pharmaceutical compositions comprising these compounds, and to a method of treating asthma.
BACKGROUND OF INVENTION Asthma is a chronic inflammatory disease characterized by substantial inflammation of the airways. Although inflammatory responses in general are protective mechanisms for the host, excessive or inappropriate inflammatory responses occur in certain diseases such as asthma. Common allergens such as pollen, molds, cockroaches, animal dander, and dust-mite feces contain potent antigens that can give rise to allergic responses and inflammation characteristic of asthma. The Expert Panel Report issued in 1997 by the National Asthma Education and Prevention Program and the NIH emphasizes the critical role that inflammation plays in asthma (S. Murphy, et al., Expert Panel Report 2. NIH Publication No. 97-4051 (1997)). There is evidence that early intervention with anti-inflammatory therapy modifies the disease process and that persistent asthma is most effectively controlled with daily anti-inflammatory medications (S. Murphy, et al., Expert Panel Report 2. NIH Publication No. 97-4051 (1997)).
The recognition that asthma is an inflammatory disease has led to more aggressive use of inhaled steroids and other anti-inflammatory agents. However, currently available anti- inflammatory agents are not ideal, since most have significant side-effects and/or are not amenable to oral administration. The key unmet medical needs in the treatment of asthma include the development of more specific, safer, orally active anti-inflammatory agents.
Agents targeted specifically to critical events in the pathogenesis of asthma are expected to be efficacious and to have fewer side effects than most current agents.
Eosinophils and mast cells infiltrating the asthmatic airways play critical roles in the airway inflammation that occurs in asthma (G. Vogel, Science 276, 1643-1646 (1997)). In the 1980's, attention was focused on mast cells, since these cells release a variety of inflammatory mediators upon activation by antigen. However, more recent information indicates that eosinophils also play a major role in the bronchial hyperreactivity and inflammation that are characteristic of asthma. Infiltration and activation of eosinophils in the bronchial mucosa is considered to be a central event in the pathogenesis of asthma (A.J. Wardlaw, R. Moqbel, A.B. Kay, Adv. Immunol. 60, 151-266 (1995)). The activation of both eosinophils and mast cells is orchestrated by T lymphocytes, in particular by a subset of T helper cells designated Th2 cells (A.K., Abbas, K.M., Murphy, A. Sher, Nature 383, 787-793 (1996)). T lymphocytes are central regulators of the immune system and the integrated inflammatory response to antigens. When activated by antigen, Th2 cells synthesize specific cytokines, including interleukins 4 and 5 (IL-4 and IL-5). Interleukin 4 is required both for differentiation and expansion of Th2 cells, as well as for synthesis of IgE by B lymphocytes. IgE binds to receptors on mast cells and, following binding of antigen to the IgE, the mast cells release inflammatory mediators. Interleukin 5 is a critical cytokine that regulates both the differentiation and activation of eosinophils (C. J. Sanderson, Blood 79, 3101-3109 (1992); CJ. Bagley, A.F., Lopez, M.A. Vadas, J. Allergy Clin. Immunol. 99, 725-728 (1997)).
Selective inhibitors of IL-5 are expected to have highly specific effects in allergic diseases such as asthma, with few mechanism based side effects. In humans, only eosinophils and basophils are known to be affected by IL-5. The role for eosinophils in allergic late-phase bronchoconstriction is well established. Recently, basophils have also been found to participate in the pathogenesis of allergic late-phase reactions. Asthmatic patients have elevated numbers of activated T cells expressing IL-5 mRNA, which further increase following allergen challenge (D. Robinson et al. J. Allergy Clin. Immunol 92, 313- 324 (1993)). The levels of IL-5 and IL-5 -producing T cells in bronchial lavage of human asthmatics correlate with eosinophil infiltration, degranulation, and lung injury. Studies in experimental animals have demonstrated that IL-5 is required for generation of the eosinophilia and bronchial hyperreactivity that are characteristic of asthma. In an experimental asthma model, mice in which the IL-5 gene was ablated had significantly reduced numbers of eosinophils as well as significantly less severe airway hyperreactivity and lung damage than the IL-5 gene-containing litter mates (P.S. Foster, J. Exp. Med. 183, 195- 201 (1996)). Moreover, administration of anti-IL-5 antibodies to a variety of experimental animals decreased the airway hyperreactivity that occurred following antigen challenge of sensitized animals (R.W. Egan, In: Therapeutic Modulation of Cytokines. CRC Press (1996)). There are no known potent, selective, nontoxic, small molecule, inhibitors of IL-5 expression or action. Broad spectrum immunosuppressants, such as cyclosporin A, as well as glucocorticoids inhibit expression of multiple cytokines and exhibit unacceptable toxicities for chronic systemic use in treatment of asthma. The present invention describes the identification of compounds which are potent inhibitors of IL-5 gene expression. Such compounds may have therapeutic potential for the treatment of asthma as well as other allergic diseases such as chronic rhinitis/sinusitis.
SUMMARY OF THE INVENTION Broadly, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of one or more compounds selected from the group consisting of formula I
Figure imgf000004_0001
and/or formula II,
Figure imgf000005_0001
II, or pharmaceutically acceptable salts thereof. In formulas I and II: R, is selected from hydrogen and lower alkyl. Preferably, R, is methyl.
R2 is selected from hydrogen and lower alkyl. Preferably, R2 is methyl. R3 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR5R6 wherein R5 and Rg are each independently selected from hydrogen and alkyl. Preferably, R3 is selected from hydrogen and halogen. A preferred halogen substituent is fluorine.
R4 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NRJRJ; wherein R5 and Rg are as defined above. Preferably, R4 is selected from hydrogen and halogen. A preferred halogen substituent is chlorine.
A is selected from alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR7Rg wherein R7 and R8 are independently selected from the group consisting of alkenyl, alkoxy alkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl. Preferably, A is selected from alkyl, alkoxy, cycloalkyl, heterocycles selected from azepanyl, azetidinyl, azocanyl, furyl, piperdinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, tetrahydropyridyl, thiazolidinyl, and thiomorpholinyl, and NR7R8 wherein R7 and R8 are independently selected from alkenyl, alkoxyalkyl, alkyl, alkynyl, alkoxyalkyl, alkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (l,3-dioxolan-2-yl)alkyl, tetrahydro-2-furanylmethyl, hydroxyalkoxyalkyl, and hydroxyalkyl. B is selected from heterocycle and NRgR10 wherein R, and R,0 are independently selected from alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl. Preferably, B is selected from a heterocycle selected from morpholinyl, piperazinyl, piperdinyl, pyrrolidinyl, tetrahydro-2H- pyranyl, and thiomorpholinyl, and NR_,RI0 wherein R, and R,0 are independently selected from alkoxyalkyl, alkyl, and cycloalkyl. X is selected from CH2, and O.
Y is selected from CH and N.
DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of one or more compounds selected from formula I
Figure imgf000006_0001
I, or a pharmaceutically acceptable salt thereof wherein,
R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is selected from azepinyl, azetidinyl, azocanyl, furyl, piperdinyl, pyrrolyl, pyrrolidinyl, 2,5-dihydrolH-pyrrolyl, tetrahydropyridyl, thiazolidinyl, and thiomorpholinyl; B is selected from morpholinyl, piperazinyl, piperdinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, and thiomorpholinyl; X is selected from CH2 and O; and Y is selected from CH and N. Examples of compounds of this embodiment include, but are not limited to: ethyl 4-{3-fluoro-5-[(4-{methyl[(2-methyl-l - pyrrolidinyl)carbonyl]amino } benzyl)oxy]phenyl } - 1 -piperazinecarboxylate,
N-(4-{[3-(2,6-dimethyl-4-mo holinyl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(4-thiomorpholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-(4-hydroxy- 1 -piperidinyl)phenoxy]methyl } phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide, N-(4- { [3 -(4-acety 1- 1 -piperazinyl)-5-fluorophenoxy]methyl } phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4-{ [3-fluoro-5-(l -piperidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l-piperazinyl]phenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methyl-l-piperidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(l-pyrrolidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide, N-(4-{[3-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5 -(4-hydroxy-4-phenyl- 1 -piperidinyl)phenoxy]methyl } phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-(3 -hydroxy- 1 -pyrrolidinyl)phenoxy]methyl } phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N- [4-( { 3 -fluoro-5- [4-(2-methoxy ethyl)- 1 -piperazinyljphenoxy } methyl)phenyl] -N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azocanecarboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-3- hydroxy-N-methyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methy 1 } phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,5-trimethyl- 1 -pyrrolidinecarboxamide, (3R)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-3 -hydroxy-N-methyl- 1 -pyrrolidinecarboxamide,
3-ethyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,2,4-trimethyl-l-pyrrolidinecarboxamide,
N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl }phenyl)- N,2,5-trimethyl-2,5-dihydro-lH-pyrrole-l-carboxamide,
N-(4- { 2-[3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]ethyl } pheny 1)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 H-pyrrole- 1 -carboxamide, N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-2,5-dihydro- 1 H-pyrrole- 1 -carboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-3- (hydroxymethyl)-Nrmethyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 ,3 -thiazolidine-3 -carboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-4- (hydroxymethyl)-N-methyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-3- hydroxy-N-methyl- 1 -piperidinecarboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-4- hydroxy-N -methyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-4-thiomorpholinecarboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -piperidinecarboxamide, N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)-N- methyl-3,6-dihydro-l(2H)-pyridinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azepanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-4- (2-hydroxyethyl)-N-methyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azetidinecarboxamide,
(2R)-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-2-(hydroxymethyl)-N-methyl-l-pyrrolidinecarboxamide, (2S)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl} pheny l)-2-(hydroxymethyl)-N-methyl-l -pyrrolidinecarboxamide,
N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N ' -methyl- 1 , 3 -piperidinedicarboxamide,
N-(4-{[3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N- {4-[(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl } -N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-morpholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide, (-) N-(4-{ [3-fluoro-5-(4-morpholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l - pyrrolidinecarboxamide,
(+) N-(4-{[3-fluoro-5-(4-morpholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide, N-(4- { [3 -fluoro-5 -(2-methyl-3-oxo- 1 -piperazinyl)phenoxy]methyl } phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
(+) N-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy}methyl)phenyl]- N,2-dimethyl- 1 -pyrrolidinecarboxamide, (-) N-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy}methyl)phenyl]-
N,2-dimethyl- 1 -pyrrolidinecarboxamide, and
N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl }phenyl)-N- methyl-2-furamide.
In another embodiment, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or pharmaceutically acceptable salts thereof wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is NR7R8 wherein R7 and R8 are indpendently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (l,3-dioxolan-2-yl)alkyl, tetrahydro-2- furanylalkyl, hydroxyalkoxyalkyl, and hydroxyalkyl; B is selected from cyclohexyl, morpholinyl, piperazinyl, piperdinyl, tetrahydro-2H-pyranyl, pyrrolidinyl, and thiomorpholinyl; X is selected from CH2 and O; and Y is selected from CH and N.
Examples of compounds of this embodiment include, but are not limited to: ethyl 4-[3-({4-[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)-5-fluorophenyl]-
1 -piperazinecarboxylate,
N-(4-{[3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N',N'- diethyl-N-methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-thiomorpholinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-(4- { [3 -fiuoro-5-(4-hydroxy- 1 -piperidinyl)phenoxy]methyl } phenyl)- N'-methylurea,
N-(4-{[3-(4-acetyl-l-piperazinyl)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea, N,N-diethyl-N'-(4-{[3-fluoro-5-(l-piperidinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l- piperazinyl]phenoxy}methyl)phenyl]-N'-methylurea, N,N-diethyl-N'-(4-{[3-fluoro-5-(4-methyl-l-piperidinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(l-pyrrolidinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(2-methyl-3-oxo-l- piperazinyl)phenoxy]methyl}phenyl)-N'-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,N',N'-trimethylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,N'-dimethyl-N'-propylurea, N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N,N'-dimethylurea,
N-allyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N,N'-dimethylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxyethyl)-N,N'-dimethylurea,
N-(3-chloro-4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,N',N'-trimethylurea,
N-(cyclopropylmethyl)-N'-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methyl-N-propylurea, N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-isopropyl-N'-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,N'-dimethyl-N'-(2-propynyl)urea, N-(2-cyanoethyl)-N-cyclopropyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-allyl-N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
(2-methoxyethyl)-N,N'-dimethylurea,
N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N-(2 -hydroxy ethy l)-N'-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isopentyl-N,N'-dimethylurea,
N-[2-(l,3-dioxolan-2-yl)ethyl]-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N,N'-dimethylurea,
N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy]methyl } pheny l)-N,N'-dimethylurea, N,N-diallyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N',N'-dipropylurea,
N-butyl-N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methylurea,
N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methyl-N-propylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isopropyl-N,N'-dimethylurea, N'-cyclobutyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(tetrahydro-2-furanylmethyl)urea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-methoxyethyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-propylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
(2-hydroxy- 1 -methylethyl)-N-methylurea,
N'-( 1 -ethylpropyl)-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2,2,2-trifluoroethyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-neopentylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isobutyl-N-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-methylbutyl)urea,
N'-(2-ethylhexyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-propynyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxybutyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (3-hydroxy-2,2-dimethylpropyl)-N-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
[2-(2-hydroxyethoxy)ethyl]-N-methylurea,
N'-allyl-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methy 1 } phenyl)-N-methylurea, N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-y l)phenoxy]methyl } phenyl)-N'- (2-methoxy- 1 -methylethyl)-N-methylurea,
N'-(cyanomethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea, N'-cyclopropyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isopropyl-N-methyl-N'-propylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [(lR)-l-(hydroxymethyl)propyl]-N-methylurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)-N- methyl-N'-(2-methyl-2-propenyl)urea,
N'-(2-fluoroethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N-methy lurea, N'-ethyl-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxypropyl)-N-methylurea,
N'-(cyclopropylmethyl)-N-(4-{ [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methy 1 } phenyl)-N-methylurea,
N'-(2-ethylbutyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methy 1 } pheny l)-N-methy lurea,
N'-cyclopentyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea, N'-(l,2-dimethylpropyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N'-sec-butyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lurea, N'-[bicyclo[2.2.1]hept-2-yl]-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [2-(4-hydroxyphenyl)ethyl]-N-methylurea, N'-(2-cyanoethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxyethyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [1 -(hy droxymethyl)cyclopenty 1] -N-methy lurea,
N'-(2,2-dimethylcyclopentyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isopropyl-N-methylurea, N,N-diethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-(2-methoxyethyl)-N'-methylurea,
N-butyl-N-(cyanomethyl)-N'-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N'-methy lurea,
N-butyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N,N'-dimethy lurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)-N'- isopropyl-N'-(2-methoxyethyl)-N-methylurea, N,N-diethyl-N'-(4- { [3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N'-methylurea,
N-(4-{[3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,N' ,N'-trimethy lurea, N- [4-( { 3 -fluoro-5 - [4-(2-propynyloxy)tetrahydro-2H-pyran-4- yl]phenoxy}methyl)phenyl]-N,N',N'-trimethylurea,
N,N-diethyl-N'-(4-{[3-(4-ethyltetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- methylurea, ethyl 4-[3-({4-
[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)phenyl]tetrahydro-2H-pyran-4- carboxylate,
N,N-diethyl-N'-(4- { [3 -fluoro-5-( 1 -hydroxycyclohexyl)phenoxy]methyl } pheny 1)-N'- methylurea, N,N-diethyl-N'-{4-[(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl}-N'- methylurea, tert-butyl 4-[3-({4-[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)-5- fluorophenyl]-4-hydroxy- 1 -piperidinecarboxylate,
N-allyl-N'-(4- { [3 -(trans- 1 ,4-dimethoxycyclohexyl)-5-fluorophenoxy]methyl } phenyl)- N,N'-dimethylurea,
N-(4- { [3 -(trans- 1 ,4-dimethoxycyclohexyl)-5 -fluorophenoxyjmethyl }phenyl)-N',N'- diethyl-N-methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-morpholinyl)phenoxy]methyl}phenyl)-N'- methylurea, and N,N-diethyl-N'-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2- pyridinyl]oxy}methyl)phenyl]-N'-methylurea.
In another embodiment, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or pharmaceutically acceptable salts thereof wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is pyrrolidinyl; B is NR^R,,, wherein R<, and R10 are independently selected from hydrogen, alkoxyalkyl, and alkyl; X is selected from CH2 and O; and Y is selected from CH and N.
Examples of compounds of this embodiment include, but are not limited to: N-[4-({3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide and
N-[4-({3-[ethyl(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide. In another embodiment, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or a pharmaceutically acceptable salt thereof wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is NR7R8 wherein R7 and R8 are independently selected from hydrogen and alkyl; B is NI^R^ wherein , and R10 are independently selected from hydrogen, alkoxyalkyl, alkyl, and cycloalkyl; X is selected from CH2 and O; and Y is selected from CH and N.
Examples of compounds of this embodiment include, but are not limited to:
N-[4-({3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N',N'- diethyl-N-methylurea,
N-(4-{[3-(cyclopentylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea,
N-(4-{[3-(cyclohexylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea, and N,N-diethyl-N'-[4-({3-[ethyl(2-methoxyethyl)amino]-5- fluorophenoxy}methyl)phenyl]-N'-methylurea.
In another embodiment, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula I or a pharmaceutically acceptable salt thereof wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is selected from alkoxy, alkyl, and cycloalkyl; B is tetrahydro-2H-pyranyl; X is selected from CH2 and O; and Y is selected from CH and N.
Examples of compounds of this embodiment include, but are not limited to: N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,3,3-trimethylbutanamide,
2-ethyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylbutanamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N,2,2-trimethylpropanamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopentanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopropanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethylpropanamide, isopropyl 4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl(methyl)carbamate, propyl 4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl }phenyl(methyl)carbamate, and tert-butyl 4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy] methyl } pheny l(methy l)carbamate .
In another embodiment, the present invention discloses a method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from formula II
Figure imgf000018_0001
II, or pharmaceutically acceptable salts thereof wherein, R, is methyl; R2 is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; B is selected from cyclohexyl, piperdinyl, and tetrahydro-2H-pyranyl; X is selected from CH2 and O; and Y is selected from CH and N.
Examples of compounds of this embodiment include, but are not limited to:
5-{ [3-(l -benzyl-4-hydroxy-4-piperidinyl)-5-fluorophenoxy]methyl}-l ,3-dimethyl- l,3-dihydro-2H-benzimidazol-2-one,
5- { [3 -(trans- 1 ,4-dimethoxycyclohexy l)-5-fluorophenoxy]methyl } - 1 ,3 -dimethyl- 1,3- dihydro-2H-benzimidazol-2-one,
5-{[3-fluoro-5-(8-hydroxy-l,4-dioxaspiro[4.5]dec-8-yl)phenoxy]methyl}-l,3- dimethyl- 1 ,3 -dihydro-2H-benzimidazol-2-one, and 5-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}-l,3-dimethyl- l,3-dihydro-2H-benzimidazol-2-one.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-II or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method of treating allergic diseases comprising administering a therapeutically effective amount of a compound of formula I-II or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method of treating asthma comprising administering a therapeutically effective amount of a compound of formula I-II or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention are disclosed compounds of formula I
Figure imgf000019_0001
and of formula II
Figure imgf000020_0001
II, or pharmaceutically acceptable salts thereof wherein, in formulas I and II: R, is selected from hydrogen and lower alkyl; R2 is selected from hydrogen and lower alkyl;
R3 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR5R<; wherein R5 and Rf, are independently selected from hydrogen and alkyl;
R4 is selected from hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and wherein R5 and Rg are independently selected from hydrogen and alkyl; A is selected from the group consisting of alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR7Rg wherein R7 and R8 are independently selected from alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl; B is selected from the group consisting of heterocycle and NR^R^ wherein Rg and R10 are independently selected from alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl; X is selected from CH2 and O; and Y is selected from CH and N; provided that for compounds of formula I when R4 is hydrogen and A is piperdinyl, morpholinyl, thiomorpholinyl, piperazinyl, or NR7R8 and R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl then B is other than tetrahydro-2H-pyran-4-yl optionally substituted with 1 subsituent selected from the group consisting of hydroxy and alkoxy or cyclohexyl optionally substituted with 1 subsituent selected from the group consisting of hydroxy and alkoxy; and further provided that for compounds of formula II when R3 is hydrogen and R4 is hydrogen then B is other than cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkyl and hydroxy.
In another embodiment of the present invention are disclosed compounds of formula I wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is selected from azetidinyl, azepanyl, azocanyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, thiazolidinyl, and tetrahydropyridyl; B is selected from the group consisting of morpholinyl, piperazinyl, piperdinyl, tetrahydro-2H-pyranyl, pyrrolidinyl, thiomorpholinyl, and NR^R^ wherein R, and R10 are independently selected from alkoxyalkyl and alkyl; X is selected from CH2 and O; and Y is CH.
Examples of compounds of this embodiment include, but are not limited to: ethyl 4- { 3-fluoro-5-[(4- {methyl[(2-methyl- 1 - pyrrolidinyl)carbonyl] amino } benzyl)oxy]phenyl } - 1 -piperazinecarboxylate,
N-[4-({3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5 -(4-thiomorpholinyl)phenoxy]methyl }phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(4-hydroxy-l-piperidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-
1 -pyrrolidinecarboxamide,
N-(4- { [3-(4-acetyl- 1 -piperazinyl)-5-fluorophenoxy]methyl }phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-( 1 -piperidinyl)phenoxy]methyl } pheny l)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l-piperazinyl]phenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-(4-methyl- 1 -piperidiny l)phenoxy]methyl } phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide, N-[4-({3-[ethyl(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(l-pyrrolidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide, N-(4-{[3-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethy 1- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-hydroxy-4-phenyl-l-piperidinyl)phenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(3-hydroxy-l-pyrrolidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-[4-({3-fluoro-5-[4-(2-methoxyethyl)-l-piperazinyl]phenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N- methyl- 1 -azocanecarboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-3- hydroxy-N-methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,5-trimethyl- 1 -pyrrolidinecarboxamide,
(3R)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-3 -hydroxy-N-methyl- 1 -pyrrolidinecarboxamide, 3-ethyl-N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,2,4-trimethyl-l -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2 , 5 -trimethy 1-2, 5 -dihy dro- 1 H-pyrrole- 1 -carboxamide, N-(4-{2-[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]ethyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 H-pyrrole- 1 -carboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-2,5-dihydro- 1 H-pyrrole- 1 -carboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 ,3-thiazolidine-3-carboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-3 ,6-dihydro- 1 (2H)-pyridinecarboxamide,
N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N- methyl- 1 -azepanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azetidinecarboxamide, (2R)-N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-2-(hydroxymethyl)-N-methyl- 1 -pyrrolidinecarboxamide,
(2S)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-2-(hydroxymethyl)-N-methyl-l -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-{4-[(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl}-N,2-dimethyl-l- pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5 -(4-morpholinyl)phenoxy]methyl } pheny l)-N,2-dimethyl- 1 - pyrrolidinecarboxamide, (-) N-(4- { [3 -fluoro-5-(4-moφholinyl)phenoxy]methyl } phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
(+) N-(4-{[3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(2-methyl-3-oxo-l-piperazinyl)phenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide, and
N-(4-{ [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl} pheny 1)-N- methyl-2-fur amide. In another embodiment of the present invention are disclosed compounds of formula I wherein, R[ is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is NR7R8 wherein R7 and R8 are independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, (1,3- dioxolan-2-yl)alkyl, tetrahydro-2-furanylalkyl, hydroxyalkoxyalkyl, and phenylalkyl; B is selected from tetrahydro-2H-pyranyl and cyclohexyl; X is selected from CH2 and O; and Y is CH.
Examples of compounds of this embodiment include, but are not limited to: N-allyl-N'-(4-{ [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,N'-dimethylurea, N-(3-chloro-4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,N',N'-trimethylurea,
N-(cyclopropylmethyl)-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methyl-N-propylurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy]methyl } phenyl)- N,N'-dimethyl-N'-(2-propynyl)urea,
N-(2-cyanoethyl)-N-cyclopropyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-allyl-N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N'-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
(2-methoxyethyl)-N,N'-dimethylurea,
N-[2-(l,3-dioxolan-2-yl)ethyl]-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N,N'-dimethy lurea, N,N-diallyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methylurea,
N'-cyclobutyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lurea, N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl }phenyl)-N- methyl-N'-(tetrahydro-2-furanylmethyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-methoxyethyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-propynyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [2-(2-hydroxyethoxy)ethyl]-N-methylurea,
N'-allyl-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy ] methyl } pheny l)-N-methy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
(2-methoxy- 1 -methylethyl)-N-methylurea,
N'-(cyanomethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N'-cyclopropyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-methyl-2-propenyl)urea,
N'-(cyclopropylmethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N-methy lurea, N'-cyclopentyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lurea,
N'-[bicyclo[2.2.1]hept-2-yl]-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [2-(4-hydroxyphenyl)ethyl]-N-methylurea,
N'-(2-cyanoethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
[ 1 -(hydroxymethyl)cyclopentyl]-N-methylurea,
N'-(2,2-dimethylcyclopentyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-(2-methoxyethyl)-N'-methy lurea,
N-butyl-N-(cyanomethyl)-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N- [4-( { 3 -fluoro-5- [4-(2-propynyloxy)tetrahydro-2H-pyran-4- yl]phenoxy}methyl)phenyl]-N,N',N'-trimethylurea, N,N-diethyl-N'-(4- { [3 -(4-ethyltetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N'- methylurea, ethyl 4-[3-({4- [[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)phenyl]tetrahydro-2H-pyran-4- carboxylate, and N,N-diethyl-N'-{4-[(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl}-N'- methylurea.
In another embodiment of the present invention are disclosed compounds of formula I wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is selected from hydrogen and chlorine; A is NR7R8 wherein R4 and R5 are independently selected from hydrogen and alkyl; B is selected from moφholinyl, piperazinyl, piperdinyl, pyrrolidinyl, thiomoφholinyl, and
Figure imgf000026_0001
wherein R, and R10 are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, and cycloalkyl; X is selected from CH2 and O; and Y is CH.
Examples of compounds of this embodiment include, but are not limited to: ethyl 4-[3-({4-[ [(diethy lamino)carbony 1 ] (methy l)amino] benzyl } oxy )-5 -fluorophenyl] - 1 -piperazinecarboxylate,
N- [4-( { 3 - [bis(2-methoxyethyl)amino] -5-fluorophenoxy } methy l)phenyl]-N',N'- diethyl-N-methylurea, N-(4-{[3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N',N'- diethyl-N-methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-thiomoφholinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-(4- { [3 -fluoro-5 -(4-hydroxy- 1 -piperidiny l)phenoxy]methyl } phenyl)- N'-methylurea,
N-(4- { [3 -(4-acetyl- 1 -piperazinyl)-5-fluorophenoxy]methyl } phenyl)-N',N'-diethyl-N- methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(l-piperidinyl)phenoxy]methyl}phenyl)-N'- methylurea, N-(4-{[3-(cyclopentylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea,
N-(4-{[3-(cyclohexylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea,
N,N-diethyl-N*-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l- piperazinyl]phenoxy}methyl)phenyl]-N'-methylurea,
N,N-diethyl-N'-(4- { [3 -fluoro-5-(4-methyl- 1 -piperidinyl)phenoxy]methyl } phenyl)-N'- methylurea,
N,N-diethyl-N'-[4-({3-[ethyl(2-methoxyethyl)amino]-5- fluorophenoxy } methy l)pheny 1] -N' -methy lurea, N,N-diethyl-N'-(4- { [3 -fluoro-5 -( 1 -pyrrolidinyl)phenoxy]methyl } phenyl)-N'- methylurea,
N,N-diethyl-N'-(4-{ [3-fluoro-5-(2-methyl-3-oxo- 1 - piperazinyl)phenoxy]methyl } phenyl)-N'-methylurea, tert-butyl 4-[3-({4-[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)-5- fluorophenyl]-4-hydroxy-l -piperidinecarboxylate, and
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N'- methylurea. In another embodiment of the present invention are disclosed compounds of formula I wherein, R, is methyl; R3 is selected from hydrogen and fluorine; R4 is chlorine; A is NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; B is tetrahydro-2H-pyranyl; X is O; and Y is CH. An Example of compounds of this embodiment include, but are not limited to:
N-(3 -chloro-4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,N',N'-trimethylurea.
In another embodiment of the present invention are disclosed compounds of formula I wherein, R, is methyl; R3 is hydrogen; R4 is hydrogen; A is selected from the group consisting of pyrrolidinyl and NR7R8 wherein R7 and R8 are independently selected from hydrogen and alkyl; B is tetrahydro-2H-pyranyl; X is O; and Y is N.
Examples of compounds of this embodiment include, but are not limited to:
(+) N-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy}methyl)phenyl]- N,2-dimethyl- 1 -pyrrolidinecarboxamide, (-) N-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy}methyl)phenyl]-
N,2-dimethy 1- 1 -pyrrolidinecarboxamide, and
N,N-diethyl-N'-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2- pyridinyl]oxy}methyl)phenyl]-N'-methylurea.
In another embodiment of the present invention are disclosed compounds of formula I wherein, R, is methyl; R3 is selected from hydrogen and halogen; R4 is selected from hydrogen and halogen; A is selected from the group consisting of alkoxy, alkyl, and cycloalkyl; B is tetrahydro-2H-pyranyl; X is O; and Y is CH.
Examples of compounds of this embodiment include, but are not limited to: N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)- N, 3 , 3 -trimethy lbutanamide,
2-ethyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lbutanamide, N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N,2,2-trimethylpropanamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopentanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopropanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethylpropanamide, isopropyl 4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl(methyl)carbamate, propyl 4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl(methyl)carbamate, and tert-butyl 4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl(methyl)carbamate.
In another embodiment of the present invention are disclosed compounds of formula II wherein, R, is methyl; R2 is methyl; R3 is halogen; R, is selected from hydrogen and halogen; B is selected from cyclohexyl, piperdinyl, and tetrahydro-2H-pyranyl; X is O; and Y is CH.
Examples of compounds of this embodiment include, but are not limited to:
5 - { [3 -( 1 -benzyl-4-hydroxy-4-piperidinyl)-5-fluorophenoxy]methy 1 } - 1 ,3-dimethyl- 1 ,3-dihydro-2H-benzimidazol-2-one,
5 - { [3 -(trans- 1 ,4-dimethoxycyclohexyl)-5-fluorophenoxy]methy 1 } - 1 ,3 -dimethyl- 1,3- dihydro-2H-benzimidazol-2-one,
5-{[3-fluoro-5-(8-hydroxy-l,4-dioxaspiro[4.5]dec-8-yl)phenoxy]methyl}-l,3- dimethyl-1 ,3-dihydro-2H-benzimidazol-2-one, and 5 - { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-y l)phenoxy]methyl } - 1 ,3 -dimethyl- l,3-dihydro-2H-benzimidazol-2-one.
Definition of Terms As used throughout this specification and the appended claims, the following terms have the following meanings.
The term "alkenyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl and the like.
The term "alkenyloxy," as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkenyloxy include, but are not limited to, 2-propenyloxy (allyloxy), 2-butenyloxy, 3-butenyloxy, and the like. The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term "alkoxyalkoxy," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
The term "alkoxyalkoxyalkyl," as used herein, refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert- butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy )methyl, 2-(2- methoxyethoxy)ethyl, and the like.
The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl,'2-methoxyethyl, methoxymethyl, and the like.
The term "alkoxy carbonyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxy carbonyl, and the like.
The term "alkyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2-ethylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like. The term "alkylene," denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, and the like.
The term "alkylthio," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl, and the like.
The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term "alkynyloxy," as used herein, refers to an alkynyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkynyloxy include, but are not limited to, 2-propynyloxy, 2- butynyloxy, 3-butynyloxy, and the like.
The term "aryl," as used herein, refers to a monocyclic-ring system, or a bicyclic- fused ring system wherein one or both of the fused rings are aromatic. Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, dihydronaphthyl, tetrahydronaphthyl, and the like.
The aryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxy carbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, alkynyloxy, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, carboxy, cyano, ethylenedioxy, formyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NR^R,,, and (NR92R_93)carbony 1.
The term "arylalkoxy," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, benzyloxy, 2- phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term "arylalkoxyalkyl," as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkoxyalkyl include, but are not limited to, benzyloxymethyl, 2-phenylethoxymethyl, 3-naphth-2-ylpropoxymethyl, 5-phenylpentyloxymethyl, and the like. The term "arylalkoxycarbonyl," as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like. The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 2- (4-hydroxyphenyl)ethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like. The term "arylcarbonyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl, naphthoyl, and the like.
The term "carbonyl," as used herein, refers to a -C(O)- group. The term "carboxy," as used herein, refers to a -CO2H group.
The term "carboxyalkyl," as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxy ethyl, 3-carboxypropyl, and the like. The term "cyano," as used herein, refers to a -CN group.
The term "cyanoalkyl," as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, 3-cyanopropyl, and the like. The term "cycloalkyl," as used herein, refers to a monocychc, bicyclic, or tricyclic ring system. Monocychc ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Representative examples of monocychc ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Bicyclic ring systems are exemplified by a bridged monocychc ring system in which two non-adjacent carbon atoms of the monocychc ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, and the like. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonane, tricyclo[3.3.1.13'7]decane (adamantane), and the like. The cycloalkyl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, alkynyloxy, aryl, arylalkoxycarbonyl, carboxy, cyano, ethylenedioxy, formyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, oxo, -NR^R^, and (NR92R93)carbonyl. The term "cycloalkylalkyl," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like. The term "ethylenedioxy," as used herein, refers to a -O(CH2)2O- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring. The term "formyl," as used herein, refers to a -C(O)H group.
The term "halo" or "halogen," as used herein, refers to -CI, -Br, -I or -F. The term "haloalkoxy," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group of one to four carbons, as defined herein. Representative examples of haloalkoxy include, but are not limited to, bromomethoxy, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like.
The term "haloalkyl," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group of one to four carbons, as defined herein. Representative examples of haloalkyl include, but are not limited to, bromomethyl, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, and the like.
The term "heterocycle" or "heterocyclic," as used herein, refers to a monocychc ring system. Monocychc ring systems are exemplified by any 3 or 4 membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5, 6, 7, or 8 membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds. Representative examples of monocychc ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, azocanyl, diazepinyl, 2,5-dihydro-lH-pyrrolyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, moφholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydropyridyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomoφholinyl, 1,1-dioxidothiomoφholinyl, thiopyranyl, triazinyl, triazolyl, and the like.
The heterocycles of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, alkynyloxy, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkyl, arylcarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR^R,,, and (NR92R93)carbonyl. Representative examples of heterocycles substituted with 1, 2, or 3 substituents include, but are not limited to, 1,4-dioxa- 8-azaspiro[4.5]decane, 2-methylpyrrolidinyl, 4-hydroxy-4-phenyl-l -piperdinyl, 2- hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, 2 -hydroxy ethyl- 1 -piperazinyl, and the like. The term "heterocyclealkyl," as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, 2-(l,3-dioxolan-2-yl)ethyl, tetrahydro-2-furanylmethyl, and the like. The term "hydroxy," as used herein, refers to an -OH group.
The term "hydroxyalkyl," as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, and the like. The term "lower alkyl," as used herein, refers to a straight or branched chain hydrocarbon group containing from l-to-4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term "-NR^R^," as used herein, refers to two groups, R,,, and R^, which are appended to the parent molecular moiety through a nitrogen atom. R^ and Rg, are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl. Representative examples of -NR^R^, include, but are not limited to, amino, benzylamino, methylamino, acetylamino, acetylmethylamino, phenylamino, and the like.
The term
Figure imgf000036_0001
which are appended to the parent molecular moiety through a nitrogen atom. Rg2 and Rg3 are independently selected from hydrogen, alkyl, aryl, and arylalkyl. Representative examples of -NR^R^ include, but are not limited to, amino, benzylamino, methylamino, dimethylamino, ethylamino, phenylamino, and the like.
The term "(NR92R93)carbonyl," as used herein, refers to a -NR^R^ group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NR92R93)carbonyl include, but are not limited to, aminocarbonyl, benzylaminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, and the like.
The term "mercapto," as used herein, refers to a -SH group. The term "nitro," as used herein, refers to a -NO2 group. The term "oxo," as used herein, refers to a =O moiety. The term "oxy," as used herein, refers to a -O- moiety. The term "thio," as used herein, refers to a -S- moiety. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt," as used herein, refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p- toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quateraized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil- soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Compounds of the present invention can exist as stereoisomers, wherein asymmetric or chiral centers are present. Stereoisomers are designated "R" or "S," depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations as defined in (IUPAC 1974 Recommendations for Section E,
Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30). The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
The present invention contemplates pharmaceutically active metabolites formed by in vivo biotransformation of compounds of formula I-II. The term pharmaceutically active metabolite, as used herein, refers to a compound formed by the in vivo biotransformation of compounds of formula I-II. The present invention contemplates compounds of formula I-II and metabolites thereof. A thorough discussion of biotransformation is provided in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition).
Interleukin 5 Gene Expression Inhibition Determination
Compounds of the present invention were evaluated as inhibitors of interleukin 5 gene expression in an assay involving stimulated human T lymphocytes.
Cells of the human cutaneous T cell lymphoma cell line, HUT 78 (ATCC, Rockville, MD) were cultured in RPMI 1640 medium containing 10% (v/v) fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin (100 units/mL and 100 μg/mL final concentration, respectively) (Life Technologies, Gaithersburg, MD). Three days prior to stimulation, the HUT 78 cells were seeded at a density of 2 x 105 cells/mL. Three days later and immediately prior to stimulation, cells (at ~1 x lOVmL) were centrifuged at 1200 φm for 10 minutes at room temperature, and resuspended in fresh growth medium at a density of lxl 06cells/mL. Cells were then pretreated with compounds of the present invention, followed by stimulation with anti-CD3 (clone X-35, Coulter-Immunotech, Miami, FL) and phorbol 12-myristate 13-acetate (PMA) (Sigma, St. Louis, MO) as follows. Two hundred microliters of the cell suspension were added to each well of a 96-well cell culture plate and pretreated for 15 minutes at room temperature with or without various concentrations of compounds of the present invention by adding 8 μL of half-log serial dilutions of a stock solution of the compound in growth medium containing 1% dimethylsulfoxide (DMSO, Sigma). Cells in each well were then transferred to a second 96-well culture plate which had been pre-coated with 150 ng/well of anti-CD3, followed by the addition of PMA to a final concentration of 2 ng/mL. Cells were subsequently incubated for 30 hours at 37 °C in the presence of 5% CO2. After 30 hours, cells were harvested by centrifugation at 1200 φm for 10 minutes at 4 °C, and the supernatants harvested for measurement of IL-5 levels secreted from the cells using an enzyme linked immunosorbent assay (ELISA).
For the IL-5 ELISA assay, 100 μL of HUT 78 cell supernatants were added to wells of an Immulon 4 HBX plate (Dynex, Chantilly, VA) that had been pre-coated with 100 μL of a 1 μg/mL solution of rat anti-human IL-5 antibody (clone TRFK5, Pharmingen, San Diego, CA). After incubation for 2 hours at room temperature, the plate was washed and each well was subsequently incubated for 1 -2 hours at room temperature with 100 μL of a 1 μg/mL solution of biotinylated rat anti -human IL-5 antibody (clone JES1-5A10, Pharmingen). The plate was then washed again, and each well was incubated with 100 μL of a 1 μg/mL solution of streptavidin-horseradish peroxidase conjugate (Pierce, Rockford, IL) for 1 hour, followed by incubation with 100 μL substrate [0.3 g/L 2,2'-azino-di-(3-ethylbenzthiazoline-6- sulfonate); ABTS] (Kirkegaard & Perry Laboratories, Gaithersburg, MD) for 15-30 minutes. After addition of 100 μL of ABTS stop solution (Kirkegaard & Perry Laboratories, Gaithersburg, MD), the plate was read at an O.D. of 405 nm. Human IL-5 used in the standard curve was from R&D Systems, Inc., Minneapolis, MN. The percent inhibition of IL-5 expression produced by each concentration of compounds of the present invention was calculated relative to IL-5 levels produced by the stimulated control cells. The IC50 values, shown in Table 1 , were graphically determined from 8-point dose response curves generated for each compound. IL-5 protein levels in the supernatant from stimulated HUT 78 cells were approximately 1500 pg/mL, whereas no IL-5 was detectable from unstimulated cells.
Table 1 : ICS0 Values (nM)
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
The data in Table 1 demonstrates that compounds of the present invention are potent inhibitors of interleukin 5 gene expression and therefore may have utility in the treatment of allergic diseases, in particular, asthma, chronic sinusitus, and chronic rhinitis.
Pharmaceutical Compositions The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The present invention provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula I-II prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absoφtion of the injectable pharmaceutical form may be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absoφtion of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amoφhous material with poor water solubility. The rate of absoφtion of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absoφtion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof. If desired, and for more effective distribution, the compounds of the present invention can be incoφorated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incoφoration of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomesror microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incoφorating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this puφose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absoφtion accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
The compounds of the present invention, including but not limited to those specified in the examples, inhibit interleukin 5 gene expression. As IL-5 inhibitors, the compounds of the present invention may be useful for the treatment and prevention of allergic diseases such as asthma, chronic sinusitis, and chronic rhinitis.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the present invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.003 to about 50 mg/kg/day. For puφoses of oral administration, more preferable doses can be in the range of from about 0.01 to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for puφoses of administration, e.g. two to four separate doses per day.
Abbreviations The following abbreviations are used: Ac for acetyl, BINAP for 2,2'- bis(diphenylphosphino)-l , 1 '-binaphthyl, Bn for benzyl, Boc for tert-butoxycarbonyl, (Boc)2O for di-tert-butyl dicarbonate, n-BuLi for n-butyllithium, dba for dibenzyhdeneacetone, DBAD for di-tert-butyl azodicarboxylate, DEAD for diethyl azodicarboxylate, DIAD for diisopropyl azodicarboxylate, DDQ for 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, DMF for dimethylformamide, DMSO for dimethylsulfoxide, dppf for 1,1'- bis(diphenylphosphino)ferrocene, EtOH for ethanol, eq for equivalent, Me for methyl, MeOH for methanol, EtOAc for ethyl acetate, TEA for triethylamine, Tf2O for trifluoromethanesulfonic anhydride, and THF for tetrahydrofuran.
Preparation of Compounds of the Present Invention The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-12. Scheme 1
Figure imgf000052_0001
Compounds of general formula (6), wherein B is an optionally substituted cyclohexyl group or an optionally substituted heterocycle and A and R4 are as defined in formula I, can be prepared as described in Scheme 1. Benzoic acids of general formula (1), purchased or prepared using standard chemistry known to those of ordinary skill in the art, can be protected with a nitrogen protecting group, such as tert-butoxycarbonyl, by treating (1) with di-tert- butyl dicarbonate in 0.5M NaOH solution to provide N-protected benzoic acids. The N- protected benzoic acids can then be treated with a reducing agent, such as borane tetrahydrofuran complex or borane diethyl ether complex, to provide benzylic alcohols of general formula (2), wherein P is a nitrogen protecting group. Benzylic alcohols of general formula (2) can be treated with benzene compounds of general formula (3), prepared as described in Scheme 4, and sodium hydride to provide ethers of general formula (4). Ethers of general formula (4) can be deprotected by standard chemistry known to those of ordinary skill in the art to provide anilines of general formula (5). Anilines of general formula (5) can be treated with acid chlorides, chloroformates, or isocyanates under standard conditions known to those of ordinary skill in the art to provide amides, carbamates, or ureas of general formula (6).
Scheme 2
Figure imgf000053_0001
Compounds of general formula (6), wherein A is selected from NR7R8 or nitrogen containing heterocycles such as azetidine, azocane, azepane, moφholine, piperdine, piperazine, pyrrole, pyrroline, pyrrolidine, thiazolidine, tetrahydropiperdine, and thiomoφhoine, B is selected from cyclohexyl or heterocycle, and R4, R7, and R8 are as defined in formula I, can be prepared as described in Scheme 2. Anilines of general formula (5), from Scheme 1 , can be treated with phosgene in toluene at 0 °C to provide carbamoyl chlorides of general formula (7). Carbamoyl chlorides of general formula (7) can be treated with amines or nitrogen containing heterocycles to provide compounds of general formula (6) wherein A is an amine or nitrogen containing heterocycle and B is cyclohexyl or a heterocycle.
Scheme 3
Figure imgf000054_0001
Compounds of general formula (6), wherein A is selected from NR7R8 and nitrogen containing heterocycles such as azetidine, azocane, azepane, moφholine, piperdine, piperazine, pyrrole, pyrroline, pyrrolidine, thiazolidine, tetrahydropiperdine, and thiomoφhoine, B is selected from NR^R,,, and nitrogen containg heterocycles such as azetidine, azocane, azepane, moφholine, piperdine, piperazine, pyrrole, pyrroline, pyrrolidine, thiazolidine, tetrahydropiperdine, and thiomoφhoine, and R4, R7, R8, R<„ and R10 are as defined in formula I, can be prepared as described in Scheme 3. Isocyanates of general formula (9) can be treated with amines or nitrogen containing heterocycles to provide compounds of general formula (10) wherein R is alkyl. Compounds of general formula (10) can be treated with sodium hydride and iodomethane in DMF to provide compounds of general formula (11). Compounds of general formula (11) can be treated with reducing agents, such as lithium borohydride and methanol in THF, to provide alcohols of general formula (12). Alcohols of general formula (12) can be treated with l-bromo-3,5- difluorobenzene to provide ethers of general formula (13). Ethers of general formula (13) can be treated with a palladium catalyst such as Pd(dba)2, BI AP, and sodium tert-butoxide in toluene in the presence of an amine or nitrogen containing heterocycle to provide compounds of general formula (6) wherein A is an amine or nitrogen containing heterocycle and B is an amine or nitrogen containing heterocycle.
Figure imgf000055_0001
Figure imgf000055_0002
Compounds of general formula (3), wherein B is as defined in formula I, can be prepared as described in Scheme 4. Method A is exemplified by describing the synthesis of 4-(3,5-difluorophenyl)-4-methoxytetrahydro-2H-pyran, (16). Cyclohexanones or heterocycles containing an oxo moiety, such as tetrahydro-4H-pyran-4-one, can be treated with the Grignard reagent prepared from l-bromo-3,5-difluorobenzene, magnesium turnings, a catalytic amount of 1 ,2-dibromoethane, and an optional catalytic amount of iodine to provide alcohols such as 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol. The alcohols can be treated with sodium hydride, iodomethane, and a catalytic amount of 15-crown-5 to provide l-substituted-3,5-difluorobenzenes of general formula (3) such as 4-(3,5- difluorophenyl)-4-methoxytetrahydro-2H-pyran, (16). Method B demonstrates the replacement of bromine with amines and N-containing heterocycles using conditions as described in Scheme 3 or conditions described in (Wagaw, S. and Buchwald, S., J. Org. Chem. 61 (1996) 7240-7241; Harris, M.C. et al., J. Org. Chem. 64 (1999) 6019-6022). Method C demonstrates the replacement of bromine with aryl groups or heterocycles using well known Heck, Suzuki, or Stille chemistry as described in (Shaφ, M.J. and Snieckus, V., Tet. Lett. 26 (1985) 5997; Syn. Commun., 11 (1981) 513; J. Org. Chem., 49 (1984) 5237; Tet. Lett., 28 (1987) 5093; Tet. Lett., 28 (1987) 5097; Bailey, T.R., Tet. Lett., 27 (1986) 4407; and Tet. Lett. 28 (1987) 2645).
Scheme 5
Mitsunobu conditions
Figure imgf000056_0002
Figure imgf000056_0001
An alternate method of preparing compounds of general formula (6), wherein A is selected from NR7R8 and nitrogen containing heterocycles such as azetidine, azocane, azepane, moφholine, piperdine, piperazine, pyrrole, pyrroline, pyrrolidine, thiazolidine, tetrahydropiperdine, and thiomoφhoine, and R4, R7, R8, and B are as defined in formula I, is described in Scheme 5. Alcohols of general formula (12), from Scheme 3, can be treated with phenols of general formula (18), from Scheme 7, azo compounds such as DEAD, DBAD, and DIAD, and PPh3 in a solvent such as THF to provide compounds of general formula (6). Scheme 6
Figure imgf000057_0001
An alternate method of preparing compounds of general formula (6), wherein A is selected from NR7R8 and nitrogen containing heterocycles such as azetidine, azocane, azepane, moφholine, piperdine, piperazine, pyrrole, pyrroline, pyrrolidine, thiazolidine, tetrahydropiperdine, and thiomoφholine, and R4, R7, R8, and B are as defined in formula I, is described in Scheme 6. Alcohols of general formula (12), from Scheme 3, can be treated with phosphorous tribromide and pyridine in carbon tetrachloride to provide bromomethyl compounds of general formula (20). Analogous chloromethyl compounds can also be prepared by treating alcohols of general formula (12) with phosphorous trichloride. Bromomethyl compounds of general formula (20) or the analogous chloromethyl compounds can be treated with phenols of general formula (18), from Scheme 7, and sodium hydride in DMF to provide compounds of general formula (6).
Scheme 4
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Phenols of general formula (18), wherein B is as defined in formula I, can be prepared as described in Scheme 7. l-Bromo-3,5-difluorobenzene can be treated with benzyl alcohol and sodium hydride in DMF to provide l-(benzyloxy)-3-bromo-5-fluorobenzene. 1- (Benzyloxy)-3-bromo-5-fluorobenzene can be processed as described in Scheme 4 to provide compounds of general formula (22). Compounds of general formula (22) can be treated with a palladium catalyst such as 10% palladium on carbon under 1 atmosphere of hydrogen gas to provide phenols of general formula (18).
Scheme 8
Figure imgf000059_0001
Compounds of general formula (28), wherein R4 and B are as defined in formula I, can be prepared as described in Scheme 8. Methyl 3,4-diaminobenzoates of general formula (24), purchased or prepared using standard chemistry known to those in the art, can be treated with l,l'-carbonyldiimidazole to provide benzimidazoles of general formula (25). Benzimidazoles of general formula (25) can be dimethylated with sodium hydride and iodomethane, (26), and then treated with reducing agents such as lithium borohydride and MeOH in a solvent such as THF to provide alcohols of general formula (27). Alcohols of general formula (27) can be processed with benzenes of general formula (3), from Scheme 4, as described in Scheme 1 to provide compounds of general formula (28). Alternatively, alcohols of general formula (27) can be processed with phenols of general formula (18), from Scheme 7, using methodology described in Scheme 5 to provide compounds of general formula (28). Additionaly, alcohols of general formula (27) can be processed as described in Scheme 6 to provide bromides or chlorides of general formula (29). Bromomethyl compounds of general formula (29) or the analogous chloromethyl can be processed with phenols of general formula (18), from Scheme 7, using methodology described in Scheme 6 to provide compounds of general formula (28).
Scheme 9
Figure imgf000060_0001
Compounds of general formula (34), wherein A, B, and R4 are as defined in formula I, can be prepared as described in Scheme 9. Bromides of general formula (20), from Scheme 6, or the analogous chlorides can be treated with triphenylphosphine in xylenes with heat to provide phosphonium salts of general formula (30). Phenols of general formula (18), from Scheme 7, can be treated with triflic anhydride in pyridine to provide triflates of general formula (31). Triflates of general formula (31) can be treated with a palladium catalyst such as palladium(II) acetate, dppf, trioctylsilane, a base such as triethylamine under an atmosphere of carbon monoxide to provide benzaldehydes of general formula (32). Phosphonium salts of general formula (30) can be treated with sodium methoxide and benzaldehydes of general formula (32) to provide alkenes of general formula (33). Alkenes of general formula (33) can be treated with a palladium catalyst such as 10% palladium on carbon under 1 atmosphere of hydrogen gas to provide compounds of general formula (34).
Scheme 10
Compounds of general formula (36), wherein B and R4 are as defined in formula I, can be prepared as described in Scheme 10. Bromomethyl compounds of general formula (29), from Scheme 8, or the analogous chloromethyl compounds can be processed as described in Scheme 9 to provide compounds of general formula (36).
Scheme 1 1
Figure imgf000062_0001
Compounds of general formula (39) and general formula (40), wherein A, B, R4, and R5 are as defined in formula I, can be prepared as described in Scheme 1 1. 2,6- Dibromopyridines or the analogous 2,6-dichloropyridines can be processed using the methods described in Scheme 4 to provide pyridines of general formula (38). Pyridines of general formula (38) can be treated with alcohols of general formula (12), from Scheme 3, and sodium hydride in DMF to provide compounds of general formula (39). Pyridines of general formula (38) can also be treated with alcohols of general formula (27), from Scheme 8, and sodium hydride in DMF to provide compounds of general formula (40).
Scheme 12
Figure imgf000063_0001
Compounds of general formula (44), wherein A, B, R4, and R5 are as defined in formula I, can be prepared as described in Scheme 12. Phosphonium salts of general formula (30), from Scheme 9, can be processed with 6-substituted-2-formylpyridines of general formula (42) as described in Scheme 9 to provide alkenes of general formula (43). Alkenes of general formula (43), can be reduced as described in Scheme 9 to provide compounds of general formula (44).
Compounds of general formula (45), wherein B, R4, and R5 are as defined in formula I, can also be prepared as described in Scheme 12. Bromomethyl compounds of general formula (29), from Scheme 8, or the analogous chloromethyl compounds can be processed as described in Scheme 9 and Scheme 12 to provide compounds of general formula (45).
The compounds and methods of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Example 1 ethyl 4-[3-f 4-[[('diethylamino)carbonyl1(methyl)amino1benzyl}oxyV5-fluorophenyl]-l- piperazinecarboxylate
Example 1A ethyl 4-isocvanatobenzoate The title compound was purchased from Acros Organics.
Example IB ethyl 4-{ [(diethylamino)carbonyl"|amino}benzoate
The product from Example 1 A and diethylamine were processed as described in Example 15 A to provide the title compound.
Example 1C ethyl 4-|"r(diethylamino carbonyl1(methyl)amino]benzoate
The product from Example IB was processed as described in Example 133B to provide the title compound.
Example ID N,N-diethyl-N'-[4-fhvdroxymethyl)phenyl]-N'-methylurea
The product from Example 1C (3.5g, 13.26 mmol) in 100 mL of THF and 2 mL of MeOH was treated with lithium borohydride (1.5g, 68.8 mmol) and the reaction mixture was stirred overnight. After cooling on ice, the mixture was slowly quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The combined organic layers were washed with IN HC1, brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 2.8 grams (89%) of the title compound as a solid. Η NMR (300 MHz, DMSO-d6) δ 0.82 (t, 6, J= 6), 3.0 (s, 3), 3.05 (q, 4, J= 7), 4.45 (d, 2, J= 6), 5.18 (t, 1, J= 6), 7.02 (d, 2, J= 7), 7.28 (d, 2, J= 8); MS (APCI+) m/z 237( M+H)+. Example IE N-{4-r(3-bromo-5-fluorophenoxy)methyllphenyl)-N',N'-diethyl-N-methylurea The product from Example ID and l-bromo-3,5difluorobenzene were processed as described in Example 15D to provide the title compound.
Example IF ethyl 4-[3-({4-["[(diethylamino^carbonvn(methyl)amino]benzyl}oxy)-5-fluorophenyl1-l- piperazinecarboxylate The product from Example IE (49 mg, 0.12 mmol) in 2.2 mL of dry degassed toluene was treated with ethyl 1 -piperazinecarboxylate (2 equivalents), Pd(dba)2 (7 mg, 0.01 mmol), BINAP (23 mg, 0.037 mmol), and sodium tert-butoxide (41 mg, 0.43 mmol). The mixture was kept at 80 °C for 15 hours and then allowed to cool to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, and filtered through a silica gel sep-pak cartridge (Alltech 209150). The resulting solution was concentrated in vacuo to provide crude material. The crude residue was purified by preparative HPLC (Waters Nova-Pak® HR C18 6 μm 60 D 25x100 mm, 50- 95% MeCN/10 mM NH4OAc over 10 min at 40 mL/min) to provide 34.7 mg (59%) of the title compound as a light yellow oil. 'H NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.27 (t, 3, J=7.1), 3.11-3.19 (m, 11), 3.59 (m, 4), 4.15 (q, 2, J=7.1), 5.04 (s, 2), 6.23 (dt, 1, J=10.6, 2.1), 6.31 (dt, 1, J=12.0, 2.1), 6.37 (m, 1), 7.13 (d, 2, J=8.7), 7.44 (d, 2, J=8.7); MS (APCI+) m/z 487 (M+H)+.
Example 2 N-[4-({3-rbis(2-methoxyethyl')aminol-5-fluorophenoxy}methyl)phenyll-N',N'-diethyl-N- methylurea
The product from Example IE and N,N-bis(2-methoxyethyl)amine were processed as described in Example IF to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.34 (s, 6), 3.51 (m, 8), 5.03 (s, 2), 6.03 (dt, 1, J=10.6, 2.2), 6.06 (dt, 1, J=12.7, 2.2), 6.11 (m, 1), 7.13 (d, 2, J=8.6), 7.43 (d, 2, J=8.6); MS (APCI+) m/z 462 (M+H)+.
Example 3 N-(4-{r3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxylmethyl}phenyl -N',N'-diethyl-N- methylurea The product from Example IE and 2,6-dimethylmoφholine were processed as described in Example IF to provide a cis:trans (4:1) mixture of the title compound as a light yellow oil. Cis isomer: 'H NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.21 (d, 6, J=6.2), 2.31 (dd, 2, J=12.2, 10.5), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.49 (m, 2), 3.73 (m, 2), 5.04 (s, 2), 6.20 (dt, 1, J=10.4, 2.2), 6.28 (dt, 1, J=12.0, 2.2), 6.34 (m, 1), 7.13 (d, 2, J=8.5), 7.44 (d, 2, J=8.5). Trans isomer: 'H NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.26 (d, 6, J=6.5), 2.88 (dd, 2, J=12.0, 6.5), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.20 (dd, 2, J=12.0, 3.3), 4.11 (m, 2), 5.04 (s, 2), 6.19 (dt, 1, J=10.4, 2.2), 6.25 (dt, 1, J=12.1, 2.2), 6.30 (m, 1), 7.13 (d, 2, J=8.5), 7.44 (d, 2, J=8.5); MS (APCI+) m/z 444 (M+H)+.
Example 4 N,N-diethyl-N'-("4-(r3-fluoro-5- 4-thiomoφholinyl phenoxylmethyl|phenyl)-N'-methylurea The product from Example IE and thiomoφholine were processed as described in Example 1 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 2.65 (m, 4), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.56 (m, 4), 5.04 (s, 2), 6.18 (dt, 1, J=10.5, 2.1), 6.25 (dt, 1, J=12.2, 2.1), 6.30 (m, 1), 7.13 (d, 2, J=8.3), 7.44 (d, 2, J=8.3); MS (APCI+) m/z 432 (M+H)+.
Example 5
N,N-diethyl-N'-(4-{[3-fluoro-5-('4-hvdroxy-l-piperidinyl)phenoxylmethyl}phenyl)-N'- methylurea The product from Example IE and 4-hydroxypiperdine were processed as described in Example IF to provide the title compound as a yellow oil. 'H NMR (500 MHz, CD3OD) δ 0.93 (t, 6, 1=7.1), 1.58 (m, 2), 1.92 (m, 2), 2.89 (ddd, 1, J=12.8, 10.3, 2.9), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.55 (m, 2), 3.75 (m, 2), 5.03 (s, 2), 6.17 (dt, 1, J=10.6, 2.2), 6.28 (dt, 1, J=12.3, 2.2), 6.34 (m, 1), 7.13 (d, 2, J=8.5), 7.44 (d, 2, J=8.5); MS (APCI+) m/z 430 (M+H)+.
Example 6
N-(4- { [3 -(4-acetyl- 1 -piperazinyl)-5 -fluorophenoxylmethyl } phenylVN' Sf '-diethyl-N- methylurea The product from Example IE and 1 -acetylpiperazine were processed as described in Example IF to provide the title compound as a pale yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 2.13 (s, 3), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.16 (t, 2, J=5.2), 3.22 (t, 2, J=5.2), 3.66 (t, 2, J=5.2), 3.66 (t, 2, J=5.2), 5.04 (s, 2), 6.24 (dt, 1, J=10.5, 2.1), 6.32 (dt, 1, J=12.0, 2.1), 6.37 (m, 1), 7.13 (d, 2, J=8.4), 7.44 (d, 2, J=8.4); MS (APCI+) m/z 457 (M+H)+.
Example 7 N.N-diethyl-N'-('4-(r3-fluoro-5-('l-piperidinyl)phenoxylmethyl|phenyl')-N'-methylurea
The product from Example IE and piperdine were processed as described in Example IF to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.60 (m, 2), 1.67 (m, 4), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.15 (m, 4), 5.03 (s, 2), 6.16 (dt, 1, J=10.5, 2.2), 6.26 (dt, 1, J=12.4, 2.2), 6.32 (m, 1), 7.13 (d, 2, J=8.6), 7.43 (d, 2, J=8.6); MS (APCI+) m/z 414 (M+H)+.
Example 8 N-(4-|["3-(cyclopentylaminoV5-fluorophenoxylmethyl}phenyl)-N',N'-diethyl-N-methylurea The product from Example IE and cyclopentylamine were processed as described in Example IF to provide the title compound as a light yellow-green oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.46 (m, 2), 1.60 (m, 2), 1.72 (m, 2), 1.95 (m, 2), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.69 (m, 1), 4.99 (s, 2), 5.95 (m, 2), 6.02 (m, 1), 7.12 (d, 2, J=8.7), 7.42 (d, 2, J=8.7); MS (APCI+) m/z 414 (M+H)+. Example 9 N-(4-{[3-(cvclohexylamino)-5-fluorophenoxy]methyl)phenyl)-N',N'-diethyl-N-methylurea The product from Example IE and cyclohexylamine were processed as described in Example IF to provide the title compound as a light yellow-green oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.11-1.45 (m, 6), 1.65 (m, 1), 1.77 (m, 2), 1.97 (m, 2), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 4.99 (s, 2), 5.94 (m, 2), 6.01 (m, 1), 7.12 (d, 2, J=8.6), 7.42 (d, 2, J=8.6); MS (APCI+) m/z 428 (M+H)+.
Example 10 N,N-diethyl-N'-[4-({3-fluoro-5-[4-(2-hvdroxyethvπ-l-piperazinyl1phenoxy}methyl')phenyl1-
N'-methylurea The product from Example IE and l-(2-hydroxyethyl)piperazine were processed as described in Example IF to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 3.12 (s, 3), 3.15 (q, 4, J=7.1), 3.21 (br s, 2), 3.31 (m, 8), 3.89 (m, 2), 5.05 (s, 2), 6.32 (dt, 1, J=10.6, 2.1), 6.37 (dt, 1, J=l 1.7, 2.1), 6.42 (m, 1), 7.13 (d, 2, J=8.7), 7.44 (d, 2, J=8.7); MS (APCI+) m/z 459 (M+H)+.
Example 11 N.N-diethyl-N'-('4- { |"3 -fluoro-5-(4-methyl- 1 -piperidinvDphenoxylmethyl ) phenyl)-N'- methylurea
The product from Example IE and 4-methylpiperdine were processed as described in Example IF to provide the title compound as a light yellow oil. *H NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 0.97 (d, 3, J=6.6), 1.27 (m, 2), 1.53 (m, 1), 1.72 (m, 2), 2.68 (dt, 2, J=12.4, 2.7), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.63 (m, 2), 5.03 (s, 2), 6.16 (dt, 1, J=10.5, 2.2), 6.26 (dt, 1, J=12.4, 2.2), 6.33 (m, 1), 7.13 (d, 2, J=8.7), 7.43 (d, 2, J=8.7); MS (APCI+) m/z 428 (M+H)+. Example 12 N,N-diethyl-N'-r4-({3-rethyl(2-methoxyethyl)aminol-5-fluorophenoxy|methyl)phenyl]-N'- methylurea The product from Example IE and ethyl(2-methoxyethyl)amine were processed as described in Example IF to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.11 (t, 3, J=7.1), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.35 (s, 3), 3.37 (q, 2, J=7.1), 3.43 (t, 2, J=5.6), 3.51 (t, 2, J=5.6), 5.03 (s, 2), 6.01 (m, 2), 6.07 (m, 1), 7.13 (d, 2, J=8.4), 7.43 (d, 2, J=8.4); MS (APCI+) m/z 432 (M+H)+.
Example 13
N,N-diethyl-N'-(4-{[3-fluoro-5-(l-pyrrolidinyl)phenoxylmethv phenyl)-N'-methylurea The product from Example IE and pyrrolidine were processed as described in Example IF to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.92 (t, 6, J=7.1), 2.00 (m, 4), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.22 (m, 4), 5.03 (s, 2), 5.89 (dt, 1, J=12.0, 2.2), 5.95 (m, 1), 5.99 (dt, 1, J=10.9, 2.2), 7.13 (d, 2, J=8.6), 7.43 (d, 2, J=8.6); MS (APCI+) m z 400 (M+H)+.
Example 14 N,N-diethyl-N'-(4-{[3-fluoro-5-(2-methyl-3-oxo-l-piperazinyl)phenoxylmethyl}phenyl)-N'- methylurea
The product from Example IE and 3-methyl-2-piperazinone were processed as described in Example IF to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 6, J=7.1), 1.35 (d, 3, J=7.0), 3.12 (s, 3), 3.14 (q, 4, J=7.1), 3.34 (m, 2), 3.45 (m, 1), 3.58 (m, 1), 4.26 (q, 1, J=7.0), 5.05 (s, 2), 6.20 (dt, 1, J=10.6, 2.2), 6.25 (dt, 1, J=12.1, 2.2), 6.28 (m, 1), 7.13 (d, 2, J=8.7), 7.44 (d, 2, J=8.7); MS (APCI+) m/z 443 (M+H)+.
Example 15 ethyl 4-{3-fluoro-5-r(4-{methvir(2-methyl-l- pyrrolidinvDcarbonyll amino } benzyl)oxylphenyl ) - 1 -piperazinecarboxylate Example 15A ethyl 4-{ r(2-methyl-l -pyrrolidinvDcarbonyllaminolbenzoate The product from Example 1 A (3 g, 15.7 mmol) was treated with 1 -methylpyrrolidine (1.34 g, 15.7 mmol) in lmL of THF at 0 °C. After consumption of starting material was determined via TLC, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to provide 4.1 grams (95%) of the title compound as a white solid.
Example 15B ethyl 4- (methyl|Y2 -methyl- 1 -pyrrolidinyllcarbonyllaminolbenzoate The product from Example 15A was processed as described in Example 133B to provide the title compound.
Example 15C
N- 4-("hvdroxymethyl)phenyll-N,2-dimethyl-l-pyrrolidinecarboxamide The product from Example 15B was processed as described in Example ID to provide the title compound.
Example 15D
N-{4-r('3-bromo-5-fluorophenoxy)methyl]phenyl|-N.2-dimethyl-l-pyrrolidinecarboxamide The product from Example 15C (807 mg, 3.25 mmol) in 10 mL of DMF was treated with a suspension of NaH (126 mg, 5.25 mmol) in 5 mL of DMF and stirred at ambient temperature for 45 minutes to provide a yellowish, turbid solution. This solution was treated with l-bromo-3,5-difluorobenzene (0.450 mL, 3.90 mmol) in 5 mL of DMF and stirred at ambient temperature for 4 hours. The mixture was quenched with 5% aqueous NH4C1 and extracted with ethyl acetate. The organic extracts were washed with 5% aqueous NH4C1, saturated aqueous NaHCO3, water, brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide an oily yellow residue which was kept under vacuum at ambient temperature for 48 hours. The residue was dissolved in ethyl acetate and filtered through a silica gel sep-pak cartridge (Alltech 239310). The solution was concentrated in vacuo to provide 1.26 grams (92%) of the title compound as a light yellow oil. 'H NMR (400 MHz, CDC13) δ 1.24 (d, 3, J=6.2), 1.33 (m, 1), 1.64 (m, 2), 2.00 (m, 1), 2.61 (m, 1), 3.07 (m, 1), 3.24 (s, 3), 3.98 (m, 1), 4.98 (s, 2), 6.63 (dt, 1, J=10.5, 2.2), 6.87 (ddd, 1, J=8.0, 2.2, 1.6), 6.93 (m, 1), 7.13 (d, 2, J=8.4), 7.35 (d, 2, J=8.4); MS (APCI+) m/z 422/424 (M+H)+.
Example 15E ethyl 4-{3-fluoro-5-r(4-(methvirf2-methyl-l- pyrrolidinvDcarbonyllamino } benzyl)oxy]phenyl } - 1 -piperazinecarboxylate
The product from Example 15D (50 mg, 0.12 mmol), Pd(dba)2 (7 mg, 0.01 mmol), BINAP (23 mg, 0.037 mmol), ethyl 1 -piperazinecarboxylate (2 equivalents), and sodium tert- butoxide (40 mg, 0.42 mmol) were processed as described in Example IF. The resulting residue was dissolved in ethyl acetate and filtered through a silica gel sep-pak cartridge (Alltech 209150). The filtrate was concentrated in vacuo and the crude residue was purified by preparative HPLC (Waters Nova-Pak® HR C18 6 μm 60 D 25x100 mm, 50-95% MeCN/10 mM NH4OAc over 10 min at 40 mL/min) to provide 42.6 mg (72%) of the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.27 (t, 3, J=7.1), 1.36 (m, 1), 1.59 (m, 1), 1.69 (m, 1), 2.00 (m, 1), 2.62 (m, 1), 3.09 (ddd, 1, J=10.5, 7.6, 3.1), 3.15 (m, 4), 3.19 (s, 3), 3.58 (m, 4), 3.88 (m, 1), 4.15 (q, 2, J=7.1), 5.04 (s, 2), 6.24 (dt, 1, J=10.5, 2.2), 6.32 (dt, 1, J=12.0, 2.2), 6.37 (m, 1), 7.16 (d, 2, J=8.4), 7.44 (d, 2, J=8.4); MS (APCI+) m/z 499 (M+H)+.
Example 16 N- 4-f ( 3 - [bis(2-methoxyethyl)amino1-5-fluorophenoxy } methvDphenyl] -N,2-dimethyl- 1 - pyrrolidinecarboxamide The product from Example 15D and N,N-bis(2-methoxyethyl)amine were processed as described in Example 15E to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.36 (m, 1), 1.60 (m, 1), 1.69 (m, 1), 2.00 (m, 1), 2.62 (m, 1), 3.09 (ddd, 1, J=10.6, 7.5, 3.1), 3.19 (s, 3), 3.34 (s, 6), 3.51 (m, 8), 3.88 (m, 1), 5.02 (s, 2), 6.05 (m, 2), 6.12 (m, 1), 7.16 (d, 2, J=8.4), 7.43 (d, 2, J=8.4); MS (APCI+) m/z 474 (M+H)+.
Example 17 N-(4-{f3-("2.6-dimethyl-4-moφholinyl)-5-fluorophenoxy1methyl|phenvπ-N,2-dimethyl-l- pyrrolidinecarboxamide The product from Example 15D and 2,6-dimethylmoφholine were processed as described in Example 15E to provide a (4:1) cis:trans mixture of the title compound as a light yellow oil. Cis isomer: 'H NMR (500 MHz, CD3OD) δ 1.21 (d, 6, J=6.3), 1.22 (d, 3, J=6.1), 1.36 (m, 1), 1.60 (m, 1), 1.69 (m, 1), 2.00 (m, 1), 2.31 (m, 2), 2.61 (m, 1), 3.09 (ddd, 1, J=10.6, 7.5, 3.1), 3.19 (s, 3), 3.49 (m, 2), 3.74 (m, 2), 3.88 (m, 1), 5.03 (s, 2), 6.21 (dt, 1, J=10.6, 2.2), 6.29 (dt, 1, J=12.2, 2.2), 6.34 (m, 1), 7.16 (d, 2, J=8.6), 7.44 (d, 2, J=8.6). Trans isomer: 'H NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.26 (d, 6, J=6.4), 1.36 (m, 1), 1.60 (m, 1), 1.69 (m, 1), 2.00 (m, 1), 2.61 (m, 1), 2.88 (dd, 2, J=12.0, 6.2), 3.09 (ddd, 1, J=10.6, 7.5, 3.1), 3.19 (m, 2), 3.19 (s, 3), 3.88 (m, 1), 4.11 (m, 2), 5.03 (s, 2), 6.20 (dt, 1, J=10.6, 2.1), 6.26 (dt, 1, J=12.6, 2.1), 6.34 (m, 1), 7.16 (d, 2, J=8.6), 7.44 (d, 2, J=8.6); MS (APCI+) m/z 456 (M+H)+.
Example 18 N-(4- { [3 -fluoro-5-(4-thiomoφholinyl)phenoxy1methy 11 phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide The product from Example 15D and thiomoφholine were processed as described in Example 15E to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.37 (m, 1), 1.60 (m, 1), 1.69 (m, 1), 2.00 (m, 1), 2.62 (m, 1), 2.65 (m, 4), 3.09 (ddd, 1, J=10.6, 7.5, 3.1), 3.19 (s, 3), 3.56 (m, 4), 3.88 (m, 1), 5.03 (s, 2), 6.19 (dt, 1, J=10.5, 2.1), 6.26 (dt, 1, J=12.2, 2.1), 6.30 (m, 1), 7.16 (d, 2, J=8.3), 7.44 (d, 2, J=8.3); MS (APCI+) m/z 444 (M+H)+. Example 19 N-(4-{|~3-fluoro-5-(4-hvdroxy-l-piperidinyl)phenoxy]methyl}phenylVN,2-dimethyl-l- pyrrolidinecarboxamide The product from Example 15D and 4-hydroxypiperdine were processed as described in Example 15E to provide the title compound as a light yellow solid. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.36 (m, 1), 1.53-1.65 (m, 3), 1.69 (m, 1), 1.92 (m,2), 2.01 (m, 1), 2.62 (m, 1), 2.89 (ddd, 1, J=12.9, 10.1, 2.9), 3.09 (ddd, 1, J=10.6, 7.6, 3.1), 3.19 (s, 3), 3.55 (m, 2), 3.75 (m, 1), 3.88 (m, 1), 5.03 (s, 2), 6.18 (dt, 1, J=10.5, 2.2), 6.29 (dt, 1, J=12.3, 2.2), 6.35 (m, 1), 7.16 (d, 2, J=8.6), 7.44 (d, 2, J=8.6); MS (APCI+) m/z 442 (M+H)+.
Example 20 N-(4- { [3-(4-acetyl- 1 -piperazinyl)-5-fluorophenoxy]methyl }phenvIVN_ -dimethyl- 1 - pyrrolidinecarboxamide The product from Example 15D and 1 -acetylpiperazine were processed as described in Example 15E to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.36 (m, 1), 1.59 (m, 1), 1.68 (m, 1), 2.00 (m, 1), 2.13 (s, 3), 2.62 (m, 1), 3.09 (ddd, 1, J=10.5, 7.7, 3.0), 3.16 (t, 2, J=5.3), 3.19 (s, 3), 3.21 (t, 2, J=5.3), 3.66 (t, 2, J=5.3), 3.70 (t, 2, J=5.3), 3.88 (m, 1), 5.04 (s, 2), 6.25 (dt, 1, J=10.5, 2.2), 6.33 (dt, 1, J=12.0, 2.2), 6.38 (m, 1), 7.16 (d, 2, J=8.5), 7.44 (d, 2, J=8.5); MS (APCI+) m/z 469 (M+H)+.
Example 21 N-(4- { [3 -fluoro-5-( 1 -piperidinyDphenoxylmethyl } phenyl VN.2-dimethyl- 1 - pyrrolidinecarboxamide The product from Example 15D and piperdine were processed as described in
Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.21 (d, 3, J=6.1), 1.36 (m, 1), 1.60 (m, 3), 1.67 (m, 5), 2.00 (m, 1), 2.61 (m, 1), 3.09 (ddd, 1, J=10.5, 7.6, 3.1), 3.14 (t, 4, J=5.5), 3.19 (s, 3), 3.88 (m, 1), 5.02 (s, 2), 6.17 (dt, 1, J=10.5, 2.1), 6.27 (dt, 1, J=12.4, 2.1), 6.33 (m, 1), 7.16 (d, 2, J=8.3), 7.44 (d, 2, J=8.3); MS (APCI+) m/z 426 (M+H)+.
Example 22 N-r4-({3-fluoro-5-[4-(2-hydroxyethyl')-l-piperazinyl1phenoxy}methyl)phenyll-N,2-dimethyl-
1 -pyrrolidinecarboxamide The product from Example 15D and l-(2-hydroxyethyl)piperazine were processed as described in Example 15E to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.36 (m, 1), 1.59 (m, 1), 1.69 (m, 1), 2.00 (m, 1), 2.57- 2.65 (m, 3), 2.68 (m, 4), 3.09 (ddd, 1, J=10.6, 7.6, 3.1), 3.19 (s, 3), 3.20 (m, 4), 3.72 (t, 2,
J=6.0), 3.88 (m, 1), 5.03 (s, 2), 6.22 (dt, 1, J=10.5, 2.1), 6.30 (dt, 1, J=12.2, 2.1), 6.35 (m, 1), 7.16 (d, 2, J=8.5), 7.44 (d, 2, J=8.5); MS (APCI+) m/z 471 (M+H)+.
Example 23 N-(4-{ 3-fluoro-5-(4-methyl-l-piperidinyl')phenoxylmethyl)phenylN)-N.2-dimethyl-l- pyrrolidinecarboxamide The product from Example 15D and 4-methylpiperdine were processed as described in Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 0.97 (d, 3, J=6.5),1.22 (d, 3, J=6.1), 1.30 (dq, 2, J=12.4, 4.0), 1.36 (m, 1), 1.48-1.74 (m, 5), 2.00 (m, 1), 2.61 (m, 1), 2.68 (dt, 2, J=12.4, 2.7), 3.09 (ddd, 1, J=10.5, 7.6, 3.1), 3.19 (s, 3), 3.68 (br d, 2, J=12.5), 3.88 (m, 1), 5.02 (s, 2), 6.17 (dt, 1, J=10.5, 2.1), 6.27 (dt, 1, J=12.4, 2.2), 6.33 (m, 1), 7.16 (d, 2, J=8.3), 7.43 (d, 2, J=8.3); MS (APCI+) m/z 440 (M+H)+.
Example 24 N-|"4-({3-[ethyl(2-methoxyethyl)aminol-5-fluorophenoxy}methyl)phenyl]-N,2-dimethyl-l- pyrrolidinecarboxamide The product from Example 15D and ethyl(2-methoxyethyl)amine were processed as described in Example 15E to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.11 (d, 3, J=7.0), 1.21 (d, 3, J=6.1), 1.36 (m, 1), 1.60 (m, 1), 1.68 (m, 1), 2.00 (m, 1), 2.62 (m, 1), 3.09 (ddd, 1, J=10.6, 7.5, 3.0), 3.19 (s, 3), 3.34 (s, 3), 3.37 (q, 2, J=7.0), 3.43 (t, 2, J=5.8), 3.51 (t, 2, J=5.8), 3.88 (m, 1), 5.02 (s, 2), 6.02 (m, 2), 6.07 (m, 1), 7.16 (d, 2, J=8.5), 7.43 (d, 2, J=8.5); MS (APCI+) m/z 444 (M+H)+.
Example 25
N-(4-( 3-fluoro-5-fl-pyrrolidinyl)phenoxy1methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide The product from Example 15D and pyrrolidine were processed as described in Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.21 (d, 3, J=6.1), 1.36 (m, 1), 1.59 (m, 1), 1.67 (m, 1), 2.00 (m, 5), 2.62 (m, 1), 3.09 (ddd, 1, J=10.5, 7.6, 3.1), 3.19 (s, 3), 3.22 (s, 4), 3.88 (m, 1), 5.02 (s, 2), 5.89 (dt, 1, J=12.0, 2.1), 5.95 (m, 1), 6.00 (dt, 1, J=10.9, 2.1), 7.15 (d, 2, J=8.5), 7.43 (d, 2, J=8.5); MS (APCI+) m/z 412 (M+H)+.
Example 26
N-(4-{ 3-(L4-dioxa-8-azaspiro|'4.5 dec-8-yl)-5-fluorophenoxylmethyl>phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide The product from Example 15D and l,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.21 (d, 3, J=6.1), 1.35 (m, 1), 1.60 (m, 1), 1.68 (m, 1), 1.75 (br t, 4, J=5.8), 2.00 (m, 1), 2.61 (m, 1), 3.09 (ddd, 1, J=10.6, 7.5, 3.1), 3.19 (s, 3), 3.30 (m, 4), 3.88 (m, 1), 3.96 (s, 4), 5.03 (s, 2), 6.18 (dt, 1, J=10.5, 2.1), 6.29 (dt, 1, J=12.3, 2.1), 6.34 (m, 1), 7.16 (d, 2, J=8.5), 7.43 (d, 2, J=8.5); MS (APCI+) m/z 484 (M+H)+.
Example 27
N-(4-{r3-fluoro-5-(4-hvdroxy-4-phenyl-l-piperidinyl)phenoxylmethyl>phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide The product from Example 15D and 4-hydroxy-4-phenylpiperdine were processed as described in Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.21 (d, 3, J=6.1), 1.36 (m, 1), 1.59 (m, 1), 1.68 (m, 1), 1.80 (m, 2), 1.99 (m, 1), 2.16 (dt, 2, J=13.0, 4.4), 2.62 (m, 1), 3.08 (ddd, 1, J=10.6, 7.7, 3.2), 3.18 (s, 3), 3.23 (dt, 2, J=12.5, 2.5), 3.56 (m, 2), 3.88 (m, 1), 5.05 (s, 2), 6.20 (dt, 1, J=10.5, 2.2), 6.36 (dt, 1, J=12.3, 2.2), 6.41 (m, 1), 7.16 (d, 2, J=8.7), 7.23 (m, 1), 7.33 (m, 2), 7.45 (d, 2, J=8.7), 7.50 (m, 2); MS (APCI+) m/z 518 (M+H)+.
Example 28 N-(4-{ [3-fluoro-5-f3-hvdroxy-l -pyrrolidinvDphenoxylmethv pheny l)-N.2-dimethyl-l - pyrrolidinecarboxamide The product from Example 15D and 3-hydroxypyrrolidine were processed as described in Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 3, J=6.1), 1.36 (m, 1), 1.59 (m, 1), 1.69 (m, 1), 2.00 (m, 2), 2.13 (m, 1), 2.62 (m, 1), 3.09 (ddd, 1, J=10.5, 7.6, 3.1), 3.15 (br d, 1, J=10.6), 3.19 (s, 3), 3.28 (dt, 1, J=8.8, 3.5), 3.36-3.46 (m, 2), 3.88 (m, 1), 4.50 (m, 1), 5.03 (s, 2), 5.90 (dt, 1, J=l 1.9, 2.1), 5.95 (m, 1), 6.02 (dt, 1, J=10.9, 2.1), 7.16 (d, 2, J=8.3), 7.44 (d, 2, J=8.3); MS (APCI+) m/z 428 (M+H)+.
Example 29 N-[4-({3-fluoro-5-r4-(2-methoxyethylVl-piperazinyl]phenoxy>methyl)phenyll-N,2- dimethyl- 1 -pyrrolidinecarboxamide
The product from Example 15D and 1 -(2-methoxyethyl)piperazine were processed as described in Example 15E to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.21 (d, 3, J=6.1), 1.36 (m, 1), 1.59 (m, 1), 1.68 (m, 1), 2.00 (m, 1), 2.62 (m, 1), 2.65 (t, 2, J=5.5), 2.68 (m, 4), 3.08 (ddd, 1, J=10.6, 7.6, 3.1), 3.19 (s, 3), 3.19 (m, 4), 3.35 (s, 3), 3.57 (t, 2, J=5.5), 3.88 (m, 1), 5.03 (s, 2), 6.22 (dt, 1, J=10.5, 2.1), 6.29 (dt, 1, J=12.1, 2.1), 6.34 (m, 1), 7.15 (d, 2, J=8.6), 7.44 (d, 2, J=8.6); MS (APCI+) m z 485 (M+H)+. Example 30 N- 4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenyl)-N-methyl-
1 -azocanecarboxamide
Example 30A azocane hydrochloride Azocane was purchased from Aldrich Chemical Co.
Example 3 OB 4-[(tert-butoxycarbonyl)(methyl)aminolbenzoic acid
A solution of 4-(methylamino)benzoic acid (4.00 g, 26.5 mmol) in 60 mL of 0.5 M NaOH at 0° C was slowly treated with a solution of di(tert-butyl) dicarbonate (5.77 g, 2.65 mmol) in 60 mL of dioxane. After stirring at 0 °C for 30 minutes, the cold bath was removed and the pH adjusted to 12 with IM NaOH. After stirring at ambient temperature for 2 hours, a second portion of di(tert-butyl) dicarbonate (5.77 g, 2.65 mmol) in 10 mL of dioxane was added and the pH adjusted to 12 with IM NaOH. After stirring at ambient temperature for an additional 16 hours, the reaction mixture was concentrated in vacuo to half of the initial volume to provide a clear yellow solution. The solution was basified to pH 12 with IM NaOH, washed with ethyl acetate, acidified to pH 2-3 with 10% aqueous KHSO4, and extracted with ethyl acetate. The extracts were washed with 10% aqueous KHSO4 and brine and evaporated to dryness to provide 5.60 grams (86%) of the title compound as a white solid. Η NMR (400 MHz, CDC13) δ 1.49 (s, 9), 3.32 (s, 3), 7.38 (d, 2, J= 8.7), 8.07 (d, 2, J= 8.7); 1 C NMR (100 MHz, CDCl3) δ 28.2, 36.8, 81.2, 124.3, 125.5, 130.6, 148.6, 154.1, 171.5. MS (ESI-) m/z 250 (M-H)\
Example 3 PC tert-butyl 4-(hvdroxymethyl)phenyl(methyl)carbamate A solution of the product from Example 30B (2.80 g, 11.1 mmol) in 45 mL of dry THF at 0°C was treated dropwise with a 1.0 M solution of borane diethyl etherate in THF (45.0 mL, 45.0 mmol). After stirring at 0°C for 10 minutes, the reaction mixture was allowed to warm up slowly to ambient temperature. After stirring at ambient temperature for 3 hours, the reaction mixture was cooled in an ice bath and quenched with THF: water (1 :1) and then water. The mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine and evaporated in vacuo to provide 2.64 grams (100%) of the title compound as a white solid. Η NMR (400 MHz, CDC13) δ 1.33 (s, 9), 3.13 (s, 3), 4.50 (s, 2), 7.09 (d, 2, J=8.7), 7.22 (d, 2, J= 8.7); l3C NMR (100 MHz, CDC13) δ 27.7, 37.0, 63.5, 80.2, 125.2, 126.9, 138.5, 142.3, 154.9; MS (ESI+) m/z 238 (M+H)+.
Example 30D
4-(3,5-difluorophenyl)tetrahvdro-2H-pyran-4-ol The Grignard reagent prepared from magnesium metal (630 mg, 25.91 mmol), 5 drops of dibromoethane, and 3,5-difluorobromobenzene (5.00 g, 25.91 mmol) in 50 mL of diethyl ether was treated with tetrahydro-4H-pyran-4-one (2.40 mL, 25.91 mmol) in 25 mL of diethyl ether dropwise at ambient temperature. An additional 40 mL of diethyl ether was added and the reaction was allowed to stir at ambient temperature overnight. The reaction mixture was quenched with 150 mL of aqueous NH4C1 and extracted with diethyl ether (150 mL, 3X). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (0 to 2.5% CH3OH in CH2C12) to provide 3.74 grams (67%) of the title compound as a white solid. Η NMR (300 MHz, CDC13) δ 1.60 (d, 2, J=14.0), 2.06 (dt, 2, J=16.4, 6.8), 2.48 (br s, 1), 3.79-3.90 (m, 4), 6.69 (tt, 1, J=8.7, 2.3), 6.98 (d, 1, J=2.1), 7.00 (d, 1, J=2.1).
Example 30E 4-(3,5-difluorophenyl)-4-methoxytetrahvdro-2H-pyran
The product from Example 30D (3.00 g, 14.0 mmol) and 10 drops of 15-crown-5 in 20 mL of DMF was treated with sodium hydride (1.96 g, 49.0 mmol) 60% dispersion in mineral oil prewashed with hexanes (20 mL, 4X). After stirring for 45 minutes at ambient temperature, the reaction mixture was treated with methyl iodide (3.5 mL, 56.0 mmol) resulting in the formation of a white precipitate. An additional 10 mL of DMF was added and the reaction mixture was allowed to stir overnight. An additional 2 mL (32.1 mmol) of methyl iodide was added and after stirring for an additional 30 minutes, the mixture was carefully quenched with water and extracted with diethyl ether (150 mL, 3X). The combined extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified using flash chromatography (5% ethyl acetate in hexanes) and then recrystalized from ethyl acetate/hexanes to provide 2.52 grams (79%) of the title compound as a white solid. 'H NMR (300 MHz, CDC13) δ 1.88-2.03 (m, 4), 3.01 (s, 3), 3.84 (m, 4), 6.74 (tt, 1, J=8.6, 2.3 Hz), 6.91 (d, 1, J=2.4 Hz), 6.94 (d, 1, J=2.4 Hz).
Example 3 OF tert-butyl 4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- vDphenoxylmethyl } phenvKmethvDcarbamate The product from Example 30C (2.16 g, 9.10 mmol) in 10 mL of DMF was treated with sodium hydride (764 mg, 19.1 mmol), 60% in mineral oil, in portions. After stirring at ambient temperature for 45 minutes, the solution turned bright yellow. The bright yellow solution was treated with the product from Example 30E (1.09 g, 4.77 mmol) in 2.5 mL of DMF via cannula under positive N2 pressure. The reaction mixture was heated to 90 °C for 3 hours, allowed to cool to ambient temperature, and then carefully quenched with water. The mixture was extracted with diethyl ether (75 mL, 3X) and the combined extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified via flash chromatography ( 5 to 15% ethyl acetate in hexanes) to provide 1.02 grams (48%) of the title product: Η NMR (300 MHz, CDC13) δ 1.46 (s, 9), 1.88-2.03 (m, 4), 2.91 (s, 3), 3.27 (s, 3), 3.80-3.85 (m, 4), 5.02 (s, 2), 6.61 (d, 1H, J=10 Hz), 6.72 (d, 1, J=10 Hz), 6.81 (s, 1), 7.27 (app d, 2), 7.39 (d, 2, J=8.5 Hz); MS (ESI+) m/z 446 (M+H)+.
Example 30G 4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl')phenoxylmethyl|-N-methylaniline hydrochloride The product from Example 30F (659 mg, 1.48 mmol) in 5 mL of dry dioxane was treated with 4M HC1 in dioxane (15 mL). The mixture was stirred for 1 hour at ambient temperature. The solvent was removed in vacuo and the resultant oily yelllow residue was dried under vacuum at ambient temperature for 16 hours. The crude hydrochloride salt was used without further purification.
Example 3 OH 4-r3-({4-r(chlorocarbonyl)(methyl)aminolbenzyl}oxy)-5-fluorophenyll-4- methoxytetrahvdro-2H-pyran The crude product from Example 30G, suspended in 8 mL of dry toluene, was treated with triethylamine (0.740 mL, 5.31 mmol), stirred for 30 minutes at ambient temperature, and filtered. A vigorously stirred solution of phosgene (3.65 mL, 6.90 mmol) in 3 mL of toluene at 0 °C was slowly treated with the above filtrate via an addition funnel. After complete addition of the filtrate, the reaction mixture was stirred at 0 °C for 30 minutes and then allowed to warm up to ambient temperature. The solvent was removed in vacuo and the resultant yellow solid was suspended in 10 mL of THF and filtered to provide a solution of the title compound which was used immediately in preceding steps.
Example 301 N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl')phenoxy1methyl}phenyl)-N-methyl-
1 -azocanecarboxamide In a 20-mL screw-cap vial, a freshly prepared solution of the product from Example 30H (one aliquot, equivalent to 43 mg of the carbamoyl chloride, 0.11 mmol) was treated with an excess of the product from Example 30A (about 10 equivalents). The resulting cloudy mixture was stirred at ambient temperature for 30 minutes. The mixture was partitioned between 5% aqueous NH4C1 and ethyl acetate. The organic layer was separated and washed with 5% aqueous NH4C1 and then water. The organic layer was filtered through a silica gel sep-pak cartridge (Alltech 209150) and concentrated in vacuo to provide a yellow oil. The crude material was purified by preparative HPLC (Waters Nova-Pak® HR CI 8 6 μm 60D 25x100 mm, 50-95% MeCN/lOmM NH4OAc over 10 minutes at 40 mL/minute) to provide 39.0 mg (59%) of the title compound as a pale yellow oil. Η NMR (500 MHz, CDC13) δ 1.51 (br s, 6), 1.60 (m, 4), 1.87-2.00 (m, 4), 2.98 (s, 3), 3.15 (m, 4), 3.17 (s, 3), 3.78-3.87 (m, 4), 5.00 (s, 2), 6.61 (dt, 1, J=10.3, 2.2), 6.72 (ddd, 1, J=9.9, 2.2, 1.5), 6.80 (m, 1 ), 7.04 (d, 2, J=8.6), 7.31 (d, 2, J=8.6); MS (APCI+) m/z 485 (M+H)+.
Example 31 N-(4- { [3 -fluoro-5 -f 4-methoxytetrahy dro-2H-pyran-4-yl)phenoxylmethyl } phenylV 3 -hvdroxy-
N-methyl- 1 -pyrrolidinecarboxamide The product from Example 30H and 3-hydroxypyrrolidine were processed as described in Example 301 to provide 22.2 mg (35%) of the title compound as a colorless oil. Η NMR (500 MHz, CDC13) δ 1.76 (m, 1), 1.81-2.00 (m, 5), 2.98 (s, 3), 3.12 (br d, 1 J=l 1.7), 3.24 (s, 3), 3.24 (m, 3), 3.78-3.87 (m, 4), 4.32 (m, 1), 5.02 (s, 2), 6.62 (dt, 1, J=10.2, 2.2), 6.73 (br dt, 1, J=9.9, 1.7), 6.79 (m, 1), 7.16 (d, 2, J=8.1), 7.39 (d, 2, J=8.1); MS (APCI+) m/z 459 (M+H)+.
Example 32 N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl phenoxylmethyl|phenylVN,2- dimethyl- 1 -pyrrolidinecarboxamide The product from Example 30H and 2-methylpyrrolidine were processed as described in Example 301 to provide 35.0 mg (57%) of an oily, white solid. Η NMR (500 MHz, CDC13) δ 1.24 (d, 3, J=6.0), 1.34 (m, 1), 1.55-1.70 (m, 2), 1.87-2.03 (m, 5), 2.63 (m, 1), 2.98 (s, 3), 3.08 (m, 1), 3.24 (s, 3), 3.78-3.87 (m, 4), 3.98 (m, 1), 5.01 (s, 2), 6.62 (dt, 1, J=10.3, 2.2), 6.72 (ddd, 1, J=9.9, 2.2, 1.5), 6.81 (m, 1), 7.13 (d, 2, J=8.4), 7.38 (d, 2, J=8.2).
Example 33 N-("4-{[3-fluoro-5-C4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl}phenyl)-N-methyl-
1 -pyrrolidinecarboxamide The product from Example 3 OH and pyrrolidine were processed as described in Example 301 to provide 32.0 mg (51%) of the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.71 (m, 4), 1.90-2.01 (m, 4), 2.97 (s, 3), 3.06 (m, 4), 3.19 (s, 3), 3.74- 3.87 (m, 4), 5.10 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.75 (dt, 1, J=10.1, 1.9), 6.85 (m, 1), 7.17 (d, 2, J=8.5), 7.46 (d, 2, J=8.5); MS (APCI+) m/z 443 (M+H)+.
Example 34
N-(4-(|~3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenvπ-N,N',N'- trimethylurea The title compound was prepared as described in US 5,432,194.
Example 35 N-(4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyllphenvπ-N.N'- dimethyl-N'-propylurea The product from Example 3 OH and N-methyl-N-propylamine were processed as described in Example 301 to provide 31.0 mg (52%) of the title compound as a yellow oily solid. Η NMR (400 MHz, CD3OD) δ 0.81 (t, 3, J=7.4), 1.46 (m, 2), 1.87-2.02 (m, 4), 2.61 (s, 3), 3.09 (m, 2), 2.96 (s, 3), 3.15 (s, 3), 3.73-3.86 (m, 4), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.84 (m, 1), 7.11 (d, 2, J=8.6), 7.45 (d, 2, J=8.6); MS (APCI+) m/z 445 (M+H)+.
Example 36 N-(4-{ 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenyl)-N,N'- dimethylurea
Example 36 A 4-{methyl[(methylamino')carbonyllamino}benzoic acid A suspension of 4-(methylamino)benzoic acid (756 mg, 5.0 mmol), purchased from Aldrich Chemical Co., in toluene (20 mL) was treated with a four-fold excess of methyl isocyanate (1.2 mL, 20.0 mmol) at ambient temperature under a N2 atmosphere. The mixture was heated to near reflux temperature (~100 °C). The reaction mixture was insoluble, anhydrous THF (5 mL) was added, and the mixture was heated to reflux for an additional 1 hour. After TLC showed no starting material remaining, the mixture was allowed to cool to ambient temperature and stirred overnight. The mixture was then filtered to provide the title compound (948 mg, 91% yield), mp 219-220 °C (dec, gas evolved); MS (DCI NH3) m/z 209 (M+H)+, 226 (M+NH4)+.
Example 36B N- 4-(hvdroxymethyl)phenyll-N,N'-dimethylurea
The product from Example 36A (948 mg, 4.55 mmol) and N-methylmoφholine (0.6 mL, 5.4 mmol) in anhydrous dimethoxyethane (10 mL) and anhydrous DMF (3.0 mL) was cooled in ice water and treated with isobutyl chloroformate (0.7 mL, 5.4 mmol). The mixture was stirred at 0 °C for 35 minutes and then allowed to warm to ambient temperature and stirred an additional 40 minutes. The mixture was filtered and the filtrate treated with sodium borohydride (800 mg, 21.0 mmol) and then poured over a mixture of ethyl acetate/saturated NH4C1. The ethyl acetate layer was separated, dried over MgSO4, and concentrated to provide the title compound as a heavy colorless oil (550 mg) which began to crystallize, mp 71-87 °C (dec, gas evolved); MS (DCI/NH3) m/z 195 (M+H)+, 212 (M+NH4)+.
Example 36C N-[4-(chloromethyl)phenyll-N,N'-dimethylurea The product from Example 36B (297 mg, 1.53 mmol) in anhydrous methylene chloride (15 mL) was treated with phosphorous trichloride (157 mg, 1.1 mmol) at -78 °C. The temperature was allowed to slowly rise to -20 °C. After stirring at -20 °C for 3 hours, saturated NH4C1 solution (15 mL) was added to the cold mixture followed by addition of solid Na2CO3 until the mixture reached pH = 8. The layers were shaken and separated. The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound (122 mg). Example 36D 3-fluoro-5-('4-methoxytetrahvdro-2H-pyran-4-yl)phenol The title compound was prepared as described in WO 95/26346.
Example 36E N-(4-{[ -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy1methyl IphenvP-N.N'- dimethylurea A suspension of NaH (80% suspension in mineral oil, 35 mg, 1.2 mmol) in DMF (2 mL) was treated with the product from Example 36D (226 mg, 1.0 mmol) in dry DMF (2 mL) at ambient temperature. After stirring at ambient temperature for 1 hour, the reaction mixture was treated with the product from Example 36C in dry DMF (1 mL). The mixture was diluted with a saturated NH4C1 solution and extracted with a hexane: diethyl ether mixture (1 :1). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (silica gel, CH2C12 to 15% ethyl acetate in CH2C12, and then 10 % MeOH in CH2C12) to provide the title compound (33.9 mg). MS (DCI/NH3) m/z 403 (M+H)+, 420 (M+NH4)+.
Example 37 N-allyl-N'-(4-{ [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl )phenyl)-
N.N'-dimethylurea The product from Example 133C, the product from Example 30E, and sodium hydride were processed as described in Example 3 OF to provide the title compound. MS (APCI+) m z 443 (M+H)+.
Example 38 N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyllphenvπ-N,2.5- trimethyl- 1 -pyrrolidinecarboxamide The product from Example 3 OH and 2,6-dimethylpyrrolidine were processed as described in Example 301 to provide 36.0 mg (57%) of the title compound as a yellow solid. Η NMR (400 MHz, CD3OD) δ 1.03 (d, 6, J=6.3), 1.56 (m, 2), 1.82 (m, 2), 1.89-2.02 (m, 4), 2.97 (s, 3), 3.12 (s, 3), 3.66 (m, 2), 3.74-3.87 (m, 4), 5.10 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.0, 2.3, 1.5), 6.85 (m, 1), 7.12 (d, 2, J=8.7), 7.45 (d, 2, J=8.7); MS (APCI+) m/z 471 (M+H)+.
Example 39 N-('4-{r3-fluoro-5-('4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl|phenyl)-N'-(2- hydroxyethyl)-N,N'-dimethylurea
The product from Example 3 OH and 2-(methylamino)ethanol were processed as described in Example 301 to provide 12.0 mg (25%) of the title compound as a light yellow oil. Η NMR (500 MHz, CDC13) δ 1.88-2.01 (m, 4), 2.53 (s, 3), 2.99 (s, 3), 3.25 (s, 3), 3.41 (t, 2, J=4.8), 3.74-3.87 (m, 4), 3.77 (t, 2, J=4.8), 5.02 (s, 2), 6.61 (dt, 1, J=10.2, 2.2), 6.73 (dt, 1, J=9.8, 1.8), 6.81 (m, 1), 7.12 (d, 2, J=8.4), 7.41 (d, 2, J=8.4); MS (APCI+) m z 447 (M+H)+.
Example 40 N-(3 -chloro-4- { [3 -fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl I phenyl )- N.N'.N'-trimethylurea
Example 40A ethyl 4-amino-2-chlorobenzoate 4-Amino-2-chlorobenzoic acid (10.0 g, 58.2 mmol), purchased from Aldrich Chemical Co., and concentrated sulfuric acid (6.5 mL, 120 mmol) were combined in ethanol (150 mL) and refluxed for 1 hour. The reaction mixture was poured over ice and solid K2CO3 was added until pH=l 1. The mixture was filtered and the filtrate extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo to provide the title compound (1.25 g) as a pale yellow solid, mp 103-107 °C; MS (DCI/NH3) m/z 200 (M+H)+.
Example 40B ethyl 2-chloro-4-{ r(methylamino)carbonyl] amino Ibenzoate
The product from Example 40A (1.25 g, 6.26 mmol) and methyl isocyanate (1.5 mL, 25.0 mmol) in toluene (25 mL) were heated at 100 °C for 2 hours. The reaction mixture was treated with additional methyl isocyanate (0.5 mL) and heated at 100 °C overnight. The mixture was cooled in an ice bath and filtered. The filter cake was washed with diethyl ether and dried in vacuo to provide (0.66 g) of the title compound as a solid, mp 146-148 °C; MS (DCI/NH3) m/z 274 (M+NH4)+.
Example 40C ethyl 2-chloro-4-| (dimethylamino)carbonyl1(methyl)amino1benzoate The product from Example 40B (1.85 g, 7.20 mmol) in DMF was treated with 80% sodium hydride in mineral oil (540 mg, 18.0 mmol) at 0 °C. The mixture was allowed to warm to ambient temperature and stir for 30 minutes. The mixture was then recooled to 0 °C and treated with iodomethane (4.62 g, 30.0 mmol) and then allowed to warm to ambient temperature and stirred overnight. A solution of saturated NH4C1 was added and the mixture was extracted with diethyl ether :hexanes (1 :1). The organic phase was dried (MgSO4) and concentrated in vacuo to provide (1.89 g) of the title compound.
Example 40D N-[3-chloro-4-(hvdroxymethyl)phenyl -N,N',N'-trimethylurea The product from Example 40C was processed as described in Example ID to provide the title compound.
Example 40E N-|"3-chloro-4-(chloromethyl)phenyll-N,N',N'-trimethylurea The product from Example 40D (512 mg, 2.11 mmol) in anhydrous methylene chloride (12 mL) was treated with phosphorous trichloride (320 mg, 2.33 mmol) at -40 °C. The temperature was allowed to slowly rise to -20 °C. After stirring at -20 °C for 3 hours, saturated NaHCO3 solution and ethyl acetate were added and the layers separated. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo to provide the title compound (416 mg) as a yellow oil.
Example 40F N-(3 -chloro-4- ( [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-v0phenoxy1methyl IphenvD- N.N'.N'-trimethylurea
The product from Example 40E (416 mg, 1.59 mmol), the product from Example 36D (386 mg, 1.71 mmol), and 80% sodium hydride in mineral oil (59 mg, 1.95 mmol) were processed as described in Example 36E to provide crude product. The residue was purified by flash chromatography (silica gel, CH2C12 to 25% ethyl acetate in CH2C12) to provide the title compound (425 mg) as a pale yellow oil. 'H NMR (300 MHz, CDC13) δ 1.9-2.04 (m, 4), 2.75 (s, 6), 2.98 (s, 3), 3.18 (s, 3), 3.72-3.88 (m, 4), 5.16 (s, 2), 6.7(dt, 1, J=10.6, 2.2), 6.76(dt, 1, J=12.0, 2.2), 6.85 (d, 1, J=2.2), 7.03 (dd, 1, J=9, J=1.5), 7.18 (d, 1, J=1.5), 7.54 (d, 1, J=9); MS (DCI/NH3) m/z 451 (M+H)+; Analysis calculated for C23H28ClFN2O4: C, 61.26; H, 6.26; N, 6.21. Found: C, 60.90; H, 6.18; 6.19.
Example 41 (3RVN-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenyl)-3- hydroxy-N-methyl- 1 -pyrrolidinecarboxamide The product from Example 30H and (3R)-3-pyrrolidinol were processed as described in Example 301 to provide 28.8 mg (45%) of the title compound as a white oily solid. Η
NMR (500 MHz, CD3OD) δ 1.73 (m, 1), 1.81 (m, 1), 1.90-2.00 (m, 4), 2.97 (s, 3), 3.03 (br d, 1, J=11.7), 3.12 (dd, 1, J=11.7, 4.6), 3.16-3.28 (m, 2), 3.20 (s, 3), 3.74-3.86 (m, 4), 4.21 (m, 1), 5.09 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.18 (d, 2, J=8.6), 7.46 (d, 2, J=8.6); MS (APCI+) m/z 459 (M+H)+. Example 42 3-ethyl-N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl}phenyl')-
N,2,4-trimethyl- 1 -pyrrolidinecarboxamide The product from Example 30H and 3-ethyl-2,4-dimethylpyrrolidine were processed as described in Example 301 to provide 32.6 mg (47%) of the title compound as a mixture of isomers as a yellow oil. Major isomer: Η NMR (500 MHz, CD3OD) δ 0.81 (d, 3, J=6.5), 0.90 (t, 3, J=7.5), 1.10 (m, 1), 1.25 (d, 3, J=6.0), 1.39 (m, 1), 1.52 (m, 1), 1.66 (m, 1), 1.91- 2.01 (m, 4), 2.19 (t, 1, J=10.8), 2.97 (s, 3), 3.20 (s, 3), 3.23 (dd, 1, J=10.6, 7.0), 3.58 (m, 1), 3.74-3.86 (m, 4), 5.10 (s, 2), 6.69 (dt, 1, J=10.5, 2.2), 6.74 (ddd, 1, J=10.3, 2.2, 1.5), 6.86 (m, 1), 7.16 (d, 2, J=8.6), 7.47 (d, 2, J=8.6); MS (APCI+) m/z 499 (M+H)+.
Example 43 N-r4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenyl)-N,2,5- trimethyl-2,5-dihydro- 1 H-pyrrole- 1 -carboxamide
The product from Example 30H and 2,5-dimethyl-2,5-dihydro-lH-pyrrole were processed as described in Example 301 to provide 29.2 mg (45%) of the title compound as a yellowish solid. Η NMR (500 MHz, CD3OD) δ 1.22 (d, 6, J=6.3), 1.90-2.00 (m, 4), 2.97 (s, 3), 3.14 (s, 3), 3.74-3.85 (m, 4), 4.17 (q, 2, J=6.3), 5.08 (s, 2), 5.61 (s, 2), 6.69 (dt, 1, J=10.5, 2.2), 6.74 (ddd, 1, J=10.1, 2.2, 1.5), 6.85 (m, 1), 7.11 (d, 2, J=8.4), 7.45 (d, 2, J=8.4); MS (APCI+) m/z 469 (M+H)+.
Example 44 N-(cvclopropylmethyl)-N'-(4-{ 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N'-methyl-N-propylurea
The product from Example 3 OH and N-(cyclopropylmethyl)-N-propylamine were processed as described in Example 301 to provide 29.0 mg (56%) of the title compound as an off white solid. Η NMR (500 MHz, CDC13) δ 0.12 (m, 2), 0.45 (m, 2), 0.77 (t, 3, J=7.4), 0.85 (m, 1), 1.44 (m, 1), 1.85-2.03 (m, 4), 2.98 (s, 3), 3.00 (d, 2, J=6.9), 3.10 (m, 2), 3.18 (s, 3), 3.83 (m, 4), 5.01 (s, 2), 6.61 (dt, 1, J=10.3, 2.2), 6.72 (ddd, 1, J=9.9, 2.2, 1.5), 6.81 (m, 1), 7.11 (d, 2, J=8.6), 7.37 (d, 2, J=8.6); MS (APCI+) m/z 485 (M+H)+.
Example 45 N-ethyl-N'-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyllphenylV
N-isopropyl-N'-methylurea The product from Example 3 OH and N-ethyl-N-isopropylamine were processed as described in Example 301 to provide 13.0 mg (27%) of the title compound as a light yellow oil. 'H NMR (500 MHz, CDC13) δ 0.97 (d, 6, J=6.7), 1.05 (t, 3, J=7.0), 1.87-2.01 (m, 4), 2.98 (q, 2, J=7.0), 2.98 (s, 3), 3.16 (s, 3), 3.77-3.87 (m, 4), 4.08 (hept, 1, J=6.7), 5.01 (s, 2), 6.60 (dt, 1, J=10.3, 2.3), 6.72 (ddd, 1, J=9.9, 2.3, 1.5), 6.81 (m, 1), 7.10 (d, 2, J=8.5), 7.37 (d, 2, J=8.5); MS (APCI+) m/z 459 (M+H)+.
Example 46 N-(4-{r3-fluoro-5-(,4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethv phenyl)-N.N'- dimethyl-N'-(2-propynyl)urea The product from Example 30H and N-methyl-N-(2-propynyl)amine were processed as described in Example 301 to provide 27.0 mg (58%) of the title compound as a white solid. 'H NMR (500 MHz, CDC13) δ 1.87-2.02 (m, 4), 2.63 (s, 3), 2.98 (s, 3), 3.24 (s, 3), 3.83 (m, 4), 3.09 (d, 2, J=2.6), 5.01 (s, 2), 6.62 (dt, 1, J=10.3, 2.3), 6.72 (m, 1), 6.85 (m, 1), 7.13 (d, 2, J=8.4), 7.40 (d, 2, J=8.4); MS (APCI+) m/e 441 (M+H)+.
Example 47 N-(4-{2- 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenyllethyl)phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide
Example 47A N-r4-(bromomethyl)phenyl]-N,2-dimethyl-l-pyrrolidinecarboxamide The product from Example 15C was processed as described in Example 133D to provide the title compound.
Example 47B (A- (methyl[(2 -methyl- 1 -pyrrolidinvDcarbonyllamino I benzylXtriphenyDphosphonium bromide The product from Example 47A (0.225 g, 0.73 mmol) and triphenylphosphine (0.190 g, 0.73 mmol) in 15 mL of xylene were heated to reflux for 3 hours. The precipitate was filtered and washed with hexanes to provide 0.23 g (56%) of the title compound.
Example 47C 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenyl trifluoromethanesulfonate 3-Fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenol (0.630 g. 2.77 mmol), prepared as described in WO 95/26346, in anhydrous pyridine (10 ml) was treated with trifluoromethanesulfonic anhydride (0.56 mL, ~1.2 eq) at 0 °C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was partitioned between IN HCl and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated in vacuo to provide 0.93 g (93%) of 3-fluoro-5-(4- methoxytetrahydro-2H-pyran-4-yl)phenyl trifluoromethanesulfonate as a reddish oil. MS (APCI+) m/z 359 (M+H)+;
Example 47D 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)benzaldehyde The product from Example 47C (0.46 g. 1.27 mmol), Pd(OAc)2 (0.006 g, 2 mol %), and dppf (0.011 g, 2 mol %), in DMF (10 mL) was heated at 70 °C for 20 minutes and then treated with triethylamine (0.42 mL, ~2.5 eq) dropwise followed with trioctylsilane (1.15 mL, ~2 eq). The reaction was stirred under an atmosphere of carbon monoxide for 2 hours. The resultant crude residue was purified by chromatography (silica gel, 15% ethyl acetate in hexane) to provide the title compound (7 mg, 26%) as colorless oil. MS (APCI+) m z 239 (M+H)+.
Example 47E N-(4- { -2- 1~3 -fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenyl] ethenyl } phenylVN.2- dimethyl- 1 -pyrrolidinecarboxamide The product from Example 47B (0.18 g, 0.31 mmol) in 3 mL of dry MeOH was treated with sodium methoxide (0.094 mL 30 wt% in methanol) at ambient temperature. After stirring for 30 minutes, the product from Example 47D (0.075 g, 0.31 mmol) in 1 mL of MeOH was added dropwise. The mixture was stirred overnight and then partitioned between ethyl acetate and water. The combined organic phases were washed with brine and water, dried, and evaporated. The residue was purified by column chromatography on silica gel (55:45 hexanes:ethyl acetate) to provide 0.075g (54%) of the title compound. Η NMR (500 MHz, C6D6) δ 0.84-1.04 (m, 3), 1.05-1.34 (m, 4), 1.42-1.8 (m, 4), 2.62 (s, 3), 2.70 (s, 3), 3.58- 3.84 (m, 7), 6.31 (d, 1, J=12), 6.42 (d, 1, J=12), 6.8 (d, 1, J=8), 6.85 (d, 1, J=9), 6.88-6.94 (m, 1), 6.96-7.00 (m, 1), 7.04 (d, 1, J=8), 7.10 (s, 1), 7.2-7.4 (m, 1); MS (APCI+) m/z 453 ( M+H)+.
Example 47F N-(4-(2-r3-fluoro-5-(4-methoxytetrahvdro-2H-ρyran-4-yDphenyllethyl|phenyl)-N.2- dimethyl- 1 -pyrrolidinecarboxamide The product from Example 47E (0.031 g, 0.069 mmol) in EtOH (2 mL) was treated with Pd/C (10%, 0.008 g) under an atmosphere of hydrogen, overnight. The mixture was then filtered through celite and silica gel and evaporated to provide 0.025 g (81%) of the desired compound. Η NMR (300 MHz, DMSO-d6) δ 1.1 (d, 3, J=6), 1.2-1.3 (m, 1), 1.67 (m, 2), 1.8-1.95 (m, 5), 2.4-2.5 (m, 2), 2.85 (s, 3), 2.88-3.0 (m, 4), 3.02 (s, 3), 3.43-3.5 (m, 4), 3.7- 3.8 (q, 1, J=7.5), 6.9-7.01 (m, 5), 7.15 (d, 2, J=9); MS (DCI/NH3) m/z 455 (M+H)+; Anal calcd for C27H35FN2O4: C, 71.33; H, 7.76; N, 6.16; found: C, 71.25; H, 8.01 ; N, 5.97. Example 48 N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxylmethyl I phenyl)-N-methy 1-
2.5 -dihvdro-1 H-pyrrole- 1 -carboxamide The product from Example 30H and 2,5-dihydro-lH-pyrrole were processed as described in Example 301 to provide 32.0 mg (51%) of the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.89-2.00 (m, 4), 2.96 (s, 3), 3.21 (s, 3), 3.72-3.83 (m, 4) 3.85 (s, 4), 5.11 (s, 2), 5.67 (s, 2), 6.70 (dt, 1, J=10.5, 2.2), 6.75 (ddd, 1, J=10.1, 2.2, 1.5),
6.85 (m, 1), 7.21 (d, 2, J=8.6), 7.48 (d, 2, J=8.6); MS (APCI+) m/z 441 (M+H)+.
Example 49
N-(4-(|"3-fluoro-5-('4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl|phenyl)-N-methyl-
1 H-pyrrole- 1 -carboxamide In a 50-mL flask, the product from Example 48 (59 mg, 0.13 mmol) was dissolved in 10 mL of dry ethyl acetate and solid DDQ (34 mg, 0.15 mmol) was added. The solution was refluxed for 6 hours. The resulting brown solution was washed with H2O and brine then filtered through a silica gel sep-pak cartridge (Alltech 209150). The solution was concentrated in vacuo to give the crude material as a brown oil. The crude oil was purified by preparative HPLC (Waters Nova-Pak® HR C18 6 μm 60 D 25x100 mm, 50-95% MeCN/10 mM NH4OAc over 10 min at 40 mL/min) to provide 17.0 mg (29%) of the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.89-2.00 (m, 4), 2.96 (s, 3), 3.44 (s, 3), 3.74-
3.86 (m, 4), 5.10 (s, 2), 5.98 (t, 2, J=2.4), 6.68 (dt, 1, J=10.6, 2.2), 6.75 (dt, 1, J=10.3, 2.2), 6.76 (t, 2, J=2.4), 6.84 (m, 1), 7.18 (d, 2, J=8.3), 7.45 (d, 2, J=8.3); MS (APCI+) m/z 407 (M+H)+.
Example 50
N-(2-cyanoethyl)-N-cvclopropyl-N'-("4-{ [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4- vDphenoxylmethyl } phenyD-N'-methylurea The product from Example 3 OH and 3-(cyclopropylamino)propanenitrile were processed as described in Example 301 to provide 30.0 mg (59%) of the title compound as a colorless oily solid. 'H NMR (500 MHz, CDC13) δ 0.50 (m, 2), 0.65 (m, 2), 1.87-2.02 (m, 5),
2.68 (t, 2, J= 6.5), 2.98 (s, 3), 3.27 (s, 3), 3.62 (t, 2, J= 6.5), 3.83 (m, 4), 5.01 (s, 2), 6.60 (dt, 1, J= 10.3, 2.2), 6.72 (dt, 1, J= 9.9, 1.8), 6.81 (m, 1), 7.24 (d, 2, J= 8.4), 7.41 (d, 2, J= 8.7); MS (APCI+) 482 (M+H)+.
Example 51 N-allyl-N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy"|methyl} pheny lVN'-methylurea The product from Example 30H and N-allyl-N-ethylamine were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500
MHz, CDC13) δ 0.94 (t, 3, J= 7.1), 1.87-2.01 (m, 4), 2.98 (s, 3), 3.13 (q, 2, J= 7.1), 3.17 (s, 3),
3.69 (br d, 2, J= 6.1), 3.83 (m, 4), 5.01 (s, 2), 5.03 (m, 1), 5.06 (m, 1), 5.56 (m, 1), 6.61 (dt, 1, J= 10.3, 2.3), 6.72 (dt, 1, J= 9.9, 1.8), 6.81 (m, 1), 7.12 (d, 2, J= 8.5), 7.39 (d, 2, J= 8.7); MS (APCI+) m/z 457 (M+H)+.
Example 52 N-^-ieS-fluoro-S-^-methoxytetrahvdro^H-pyran^-vDphenoxylmethvUphenvπ-S- fhydroxymethylVN-methyl- 1 -piperidinecarboxamide The product from Example 3 OH and 3-hydroxymethylpiperdine were processed as described in Example 301 to provide the title compound as a white oily solid. Η NMR (400 MHz, CD3OD) δ 1.17-1.35 (m, 2), 1.51 (m, 1), 1.68 (m, 2), 1.87-2.02 (m, 4), 2.85 (m, 1), 2.99 (s, 3), 3.04 (dd, 1, J= 13.3, 7.4), 3.23 (s, 3), 3.29 (m, 1), 3.43 (d, 2, J= 6.7); 3.48 (dd, 1, J= 13.3, 2.7); 3.77-3.88 (m, 4), 5.01 (s, 2), 6.61 (dt, 1, J= 10.1, 1.9), 6.72 (br d, 1, J= 9.9), 6.81 (m, 1), 7.11 (d, 2, J= 8.1), 7.39 (d, 2, J= 8.1); MS (APCI+) m/z 487 (M+H)+.
Example 53 N-(4- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl ) phenvD-N-methyl-
1 ,3 -thiazolidine-3 -carboxamide The product from Example 30H and 1,3 -thiazolidine were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (400 MHz, CD3OD) δ 1.87-2.02 (m, 4), 2.87 (br s, 2), 2.99 (s, 3), 3.26 (s, 3), 3.51 (t, 2, J=6.3), 3.77-3.88 (m, 4), 4.15 (br s, 2), 5.02 (s, 2), 6.62 (dt, 1, J=10.2, 2.3), 6.73 (ddd, 1, J=9.9, 2.3, 1.5), 6.81 (m, 1), 7.19 (d, 2, J=8.6), 7.42 (d, 2, J=8.6); MS (APCI+) m/z 461 (M+H)+.
Example 54 N-(4- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N'-f 2- methoxyethyl)-N,N'-dimethylurea The product from Example 3 OH and N-(2-methoxyethyl)-N-methylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CDC13) δ 1.88-2.03 (m, 4), 2.63 (s, 3), 2.98 (s, 3), 3.12 (s, 3), 3.33 (s, 3), 3.42 (t, 2, J=5.4), 3.48 (t, 2, J=5.4), 3.78-3.88 (m, 4), 5.00 (s, 2), 6.62 (dt, 1, J=10.3, 2.1), 6.75 (dt, 1, J=9.9, 1.7), 6.81 (m, 1), 7.11 (d, 2, J=8.3), 7.38 (d, 2, J=8.3); MS (APCI+) m/z 461 (M+H)+.
Example 55 N-(4-{|~3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenyl)-4- (hydroxymethvD-N-methyl- 1 -piperidinecarboxamide The product from Example 3 OH and 4-hydroxymethylpiperdine were processed as described in Example 301 to provide the title compound as a white oily solid. Η NMR (500 MHz, CDC13) δ 1.02 (br q, 2, J=12.4), 1.58 (m, 3), 1.87-2.02 (m, 4), 2.59 (br t, 2, J=12.4), 2.98 (s, 3), 3.22 (s, 3), 3.43 (d, 2, J=5.9), 3.78-3.89 (m, 6), 5.01 (s, 2), 6.61 (dt, 1, J=10.2, 2.1), 6.75 (dt, 1, J=9.9, 1.6), 6.80 (m, 1), 7.1 1 (d, 2, J=8.3), 7.38 (d, 2, J=8.3); MS (APCI+) m/z 487 (M+H)+.
Example 56 N-ethyl-N'-(4-{[3-fluoro-5-('4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyllphenyl)-
N-(2-hvdroxyethyl)-N'-methylurea The product from Example 3 OH and 2-(ethylamino)ethanol were processed as described in Example 301 to provide the title compound as a white oily solid. Η NMR (500 MHz, CDC13) δ 0.74 (t, 2, J=7.1), 1.88-2.01 (m, 4), 2.99 (s, 3), 3.02 (q, 2, J=7.1), 3.20 (s, 3), 3.38 (t, 2, J=5.0), 3.73 (t, 2, J=5.0), 3.82 (m, 4), 5.03 (s, 2), 6.60 (dt, 1, J=10.3, 2.3), 6.72 (ddd, 1, J=9.9, 2.3, 1.5), 6.81 (m, 1), 7.14 (d, 2, J=8.5), 7.41 (d, 2, J=8.5); MS (APCI+) m/z 461 (M+H)+.
Example 57 N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isopentyl-N.N'-dimethylurea
The product from Example 3 OH and N-isopentyl-N-methylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CDC13) δ 0.86 (d, 6, J=6.6), 1.32 (m, 2), 1.47 (m, 1), 1.86-2.03 (m, 4), 2.61 (s, 3), 2.98 (s, 3), 3.16 (m, 2), 3.20 (s, 3), 3.82 (m, 4), 5.00 (s, 2), 6.61 (dt, 1, J=10.3, 2.3), 6.72 (ddd, 1, J=9.9, 2.3, 1.5), 6.81 (m, 1), 7.08 (d, 2, J=8.6), 7.38 (d, 2, J=8.6); MS (APCI+) m/z 473 (M+H)+.
Example 58 N-(4-(|'3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methv phenyl)-3-hvdroxy- N-methyl- 1 -piperidinecarboxamide
The product from Example 3 OH and 3-hydroxypiperdine were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CDC13) δ 1.31 (m, 1), 1.50-1.77 (m, 3), 1.87-2.01 (m, 4), 2.99 (s, 3), 3.03 (m, 1), 3.12 (m, 1), 3.23 (m, 1), 3.22 (s, 3), 3.55 (m, 1), 3.70 (m, 1), 3.77-3.87 (m, 4), 5.01 (s, 2), 6.61 (dt, 1, J=10.3, 2.3), 6.73 (ddd, 1, J=9.9, 2.3, 1.5), 6.80 (m, 1), 7.13 (d, 2, J=8.5), 7.39 (d, 2, J=8.5); MS (APCI+) m/z 473 (M+H)+. Example 59 N-(4-{ 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxylmethyl|phenyl)-4-hvdroxy-
N-methyl- 1 -piperidinecarboxamide The product from Example 3 OH and 4-hydroxypiperdine were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CDC13) δ 1.33 (m, 2), 1.71 (m, 2), 1.87-2.01 (m, 4), 2.89 (m, 2), 2.99 (s, 3), 3.22 (s, 3), 3.60 (m, 2), 3.75 (m, 1), 3.84 (m, 4), 5.01 (s, 2), 6.61 (dt, 1, J=10.3, 2.2), 6.72 (ddd, 1, J=9.9, 2.2, 1.5), 6.80 (m, 1), 7.12 (d, 2, J=8.6), 7.39 (d, 2, J=8.6); MS (APCI+) m/z 473 (M+H)+.
Example 60
N-(4- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl } phenyO-N-methyl-
4-thiomoφholinecarboxamide The product from Example 3 OH and thiomoφholine were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CDC13) δ 1.88-2.01 (m, 4), 2.40 (m, 4), 2.99 (s, 3), 3.21 (s, 3), 3.49 (m, 4), 3.83 (m, 4), 5.02 (s, 2), 6.61 (dt, 1, J=10.3, 2.3), 6.73 (ddd, 1, J=9.9, 2.3, 1.5), 6.81 (m, 1), 7.11 (d, 2, J=8.6), 7.41 (d, 2, J=8.6); MS (APCI+) m/z 475 (M+H)+.
Example 61 N-r2-d.3-dioxolan-2-vnethyll-N'-(,4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxylmethyl)phenyl)-N,N'-dimethylurea The product from Example 30H and N-[2-(l,3-dioxolan-2-yl)ethyl]-N-methylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CDC13) δ 1.38 (m, 2), 1.87-2.01 (m, 4), 2.61 (s, 3), 2.98 (s, 3), 3.20 (s, 3), 3.32 (m, 2), 3.83 (m, 6), 3.93 (m, 2), 4.83 (t, 1, J=4.7), 5.00 (s, 2), 6.61 (dt, 1, J=10.3, 2.3), 6.72 (ddd, 1, J=9.9, 1.7, 0.5), 6.81 (m, 1), 7.09 (d, 2, J=8.4), 7.38 (d, 2, J=8.4); MS (APCI+) m/z 503 (M+H)+. Example 62 N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl phenoxy1methyl } phenyl)-N,2- dimethyl- 1 -piperidinecarboxamide The product from Example 3 OH and 2-methylpiperdine were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CD3OD) δ 1.05 (d, 3, J= 6.9), 1.13-1.24 (m, 1), 1.39 (m, 2), 1.44-1.60 (m, 3), 1.89-2.02 (m, 4), 2.76 (dt, 1, J= 13.3, 2.9), 2.97 (s, 3), 3.15 (s, 3), 3.53 (br d, 1, J=13.3), 3.72-3.86 (m, 4), 4.22 (m, 1), 5.10 (s, 2), 6.68 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.15 (d, 2, J=8.7), 7.45 (d, 2, J=8.7); MS (APCI+) m/z 471 (M+H)+.
Example 63 N-(4- ( |~3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } pheny lVN-methyl-
1 -piperidinecarboxamide The product from Example 3 OH and piperdine were processed as described in Example 301 to provide the title compound as a white solid. 'H NMR (500 MHz, CD3OD) δ 1.35 (m, 4), 1.50 (m, 2), 1.89-2.00 (m, 4), 2.97 (s, 3), 3.17 (s, 7), 3.74-3.86 (m, 4), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.2), 6.74 (ddd, 1, J=10.1 , 2.2, 1.4), 6.84 (m, 1), 7.13 (d, 2, J=8.5), 7.45 (d, 2, J=8.5); MS (APCI+) m/z 457 (M+H)+.
Example 64
N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenyl)-
N,N'-dimethylurea The product from Example 3 OH and N-ethyl-N-methylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.00 (t, 3, J= 7.2), 1.87-2.07 (m, 4), 2.59 (s, 3), 2.97 (s, 3), 3.16 (s, 3), 3.21 (q, 2, J=7.2), 3.73-3.86 (m, 4), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.2), 6.74 (ddd, 1, J=10.1, 2.2, 1.5), 6.84 (m, 1), 7.12 (d, 2, J=8.3), 7.45 (d, 2, J=8.3); MS (APCI+) m/z 431 (M+H)+. Example 65 N-(4- { T3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl \ phenvD-N-methyl-
3.ό-dihydro- 1 (2H)-pyridinecarboxamide The product from Example 30H and 1,2,3,6-tetrahydropyridine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500
MHz, CD3OD) δ 1.85-2.01 (m, 6), 2.97 (s, 3), 3.19 (s, 3), 3.33 (t, 2, J= 5.7), 3.58 (m, 2), 3.74- 3.86 (m, 4), 5.10 (s, 2), 5.53 (m, 1), 5.72 (m, 1), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.84 (m, 1), 7.16 (d, 2, J=8.7), 7.46 (d, 2, J=8.7); MS (APCI+) m/z 455 (M+H)+.
Example 66
N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenyl)-N-methyl-
1 -azepanecarboxamide The product from Example 30H and azepane were processed as described in Example 301 to provide the title compound as a light yellow solid. lH NMR (400 MHz, CD3OD) δ 1.50 (m, 4), 1.57 (m, 4), 1.87-2.01 (m, 4), 2.97 (s, 3), 3.19 (s, 3), 3.18 (m, 4), 3.72-3.87 (m, 4), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.84 (m, 1), 7.10 (d, 2, J=8.7), 7.44 (d, 2, J=8.7); MS (APCI+) m/z 471 (M+H)+.
Example 67 N-(4-{ [3 -fluoro-5 -("4-methoxytetrahvdro-2H-pyran-4-vf)phenoxylmethyl}phenyl)-4-(2- hydroxyethvD-N-methyl- 1 -piperidinecarboxamide The product from Example 3 OH and 2-(4-piperidinyl)ethanol were processed as described in Example 301 to provide the title compound as a light yellow solid. Η NMR (400 MHz, CD3OD) δ 0.97 (br dt, 2, J= 12.3, 2.8), 1.39 (q, 2, J= 6.6), 1.46-1.59 (m, 3), 1.90- 2.03 (m, 4), 2.60 (dt, 2, J=12.9, 2.1), 2.97 (s, 3), 3.17 (s, 3), 3.54 (t, 2, J=6.6), 3.73-3.87 (m, 6), 5.09 (s, 2), 6.68 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.13 (d, 2, J=8.6), 7.45 (d, 2, J=8.6); MS (APCI+) m/z 501 (M+H)+. Example 68 N,N-diallyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy~|methyl I phenvD-N'-methylurea The product from Example 3 OH and N,N-diallylamine were processed as described in Example 301 to provide the title compound as a bright yellow solid. Η NMR (400 MHz, CD3OD) δ 1.87-2.02 (m, 4), 2.97 (s, 3), 3.14 (s, 3), 3.67 (br d, 4, J=6.0), 3.73-3.87 (m, 4), 5.04 (m, 4), 5.11 (s, 2), 5.46-5.59 (m, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.17 (d, 2, J=8.5), 7.47 (d, 2, J=8.5); MS (APCI+) m/z 469 (M+H)+.
Example 69
N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenvπ-N-methyl-
N'.N'-dipropylurea The product from Example 3 OH and N,N-dipropylamine were processed as described in Example 301 to provide the title compound as a yellow oily solid. 'H NMR (400 MHz, CD3OD) δ 0.77 (t, 6, J= 8.4), 1.41 (m, 4), 1.87-2.03 (m, 4), 2.97 (s, 3), 3.02 (m, 4), 3.13 (s, 3), 3.74-3.87 (m, 4), 5.10 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.14 (d, 2, J=8.6), 7.45 (d, 2, J=8.6); MS (APCI+) m/z 473 (M+H)+.
Example 70 N-butyl-N-ethyl-N'-r4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl } phenvD-N'-methylurea The product from Example 30H and N-butyl-N-ethylamine were processed as described in Example 301 to provide the title compound as a yellow solid. Η NMR (400 MHz, CD3OD) δ 0.84 (t, 3, J=7.3), 0.96 (t, 3, J=7.1), 1.17 (m, 2), 1.34 (m, 2), 1.87-2.01 (m, 4), 2.97 (s, 3), 3.04 (m, 2), 3.13 (s, 3), 3.15 (q, 2, J=7.1), 3.73-3.88 (m, 4), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.13 (d, 2, J=8.6), 7.46 (d, 2, J=8.6); MS (APCI+) m/z 473 (M+H)+. Example 71 N-ethyl-N'-('4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenvπ-
N'-methyl-N-propylurea The product from Example 3 OH and N-ethyl-N-propylamine were processed as described in Example 301 to provide the title compound as a bright yellow solid. Η NMR (400 MHz, CD3OD) δ 0.75 (t, 3, J=7.4), 0.95 (t, 3, J=7.1), 1.39 (m, 2), 1.87-2.02 (m, 4), 2.97 (s, 3), 3.00 (m, 2), 3.13 (s, 3), 3.15 (q, 2, J=7.2), 3.73-3.87 (m, 4), 5.10 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.0, 2.3, 1.5), 6.85 (m, 1), 7.14 (d, 2, J=8.7), 7.46 (d, 2, J=8.7); MS (APCI+) m/z 459 (M+H)+.
Example 72 N-(4-{ 3-fluoro-5-('4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl}phenyl)-N'- isopropyl-N.N'-dimethylurea The product from Example 3 OH and N-isopropyl-N-methylamine were processed as described in Example 301 to provide the title compound as a bright yellow solid. Η NMR (400 MHz, CD3OD) δ 1.02 (d, 6, J=6.8), 1.88-2.03 (m, 4), 2.43 (s, 3), 2.97 (s, 3), 3.16 (s, 3), 3.74-3.87 (m, 4), 4.26 (hept, 1, J=6.8), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.84 (m, 1), 7.12 (d, 2, J=8.7), 7.45 (d, 2, J=8.7); MS (APCI+) m/z 445 (M+H)+.
Example 73 N-(4- { r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl } phenyl)-N-methyl-
1 -azetidinecarboxamide The product from Example 3 OH and azetidine were processed as described in Example 301 to provide the title compound as a bright yellow oil. Η NMR (400 MHz,
CD3OD) δ 1.89-2.04 (m, 6), 2.97 (s, 3), 3.12 (s, 3), 3.57 (t, 4, J=7.7), 3.72-3.87 (m, 4), 5.13 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.28 (d, 2, J=8.4), 7.49 (d, 2, J=8.4); MS (APCI+) m/z 429 (M+H)+. Example 74 N'-cvclobuty l-N-(4- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea The product from Example 3 OH and cyclobutylamine were processed as described in Example 301 to provide the title compound as an off white solid. Η NMR (500 MHz, CD3OD) δ 1.62 (m, 2), 1.79-1.90 (m, 2), 1.92-2.02 (m, 4), 2.21 (m, 2), 2.98 (s, 3), 3.21 (s, 3), 3.74-3.87 (m, 4), 4.19 (quint, 1, J=8.0), 5.13 (s, 2), 6.72 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.29 (d, 2, J=8.5), 7.53 (d, 2, J=8.7); MS (APCI+) m/z 443 (M+H)+.
Example 75 N-(4-{|-3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methv phenyl)-N-methyl-
N'-ftetrahydro-Σ-furanylmethvDurea The product from Example 3 OH and tetrahydro-2-furanylmethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR
(500 MHz, CD3OD) δ 1.55 (m, 1), 1.86 (m, 2), 1.89-2.02 (m, 5), 2.97 (s, 3), 3.14 (m, 1), 3.23 (s, 3), 3.26 (m, 1), 3.67 (m, 1), 3.70-3.88 (m, 6), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.1), 6.75 (ddd, 1, J=10.1, 2.1, 1.5), 6.86 (m, 1), 7.32 (d, 2, J=8.5), 7.54 (d, 2, J= 8.5); MS (APCI+) m/z 473 (M+H)+.
Example 76 N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methvUphenyπ-N'-(2- methoxyethvD-N-methylurea The product from Example 3 OH and 2-methoxyethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.91-2.01 (m, 4), 2.97 (s, 3), 3.23 (s, 3), 3.29 (s, 3), 3.29 (t, 2, J=5.5), 3.39 (t, 2, J=5.5), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 447 (M+H)+. Example 77 N-(4-{f3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl}phenyl)-N-methyl-
N'-propylurea The product from Example 3 OH and propylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz,
CD3OD) δ 0.85 (t, 3, J=7.5); 1.46 (m, 2); 1.90-2.02 (m, 4), 2.98 (s, 3), 3.07 (t, 2, J=7.1); 3.22 (s, 3), 3.75-3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J= 10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.30 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 431 (M+H)+.
Example 78
N-(4- { \3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl I phenylVN'-t^- hydroxy- 1 -methylethylVN-methylurea
The product from Example 3 OH and 2-amino-l-propanol were processed as described in Example 301 to provide the title compound as an off white oily solid. Η NMR (500 MHz, CD3OD) δ 1.08 (d, 2, J=6.8), 1.91-2.01 (m, 4), 2.97 (s, 3), 3.24 (s, 3), 3.43 (dd, 2, J=5.2, 1.6),
3.74-3.89 (m, 5), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m,
1), 7.32 (d, 2, J=8.5), 7.53 (d, 2, J=8.5); MS (APCI+) m/z 447 (M+H)+.
Example 79 N'-('l-ethylpropylVN-(,4-{r3-fluoro-5-('4-methoxytetrahvdro-2H-ρyran-4- vPphenoxylmethyl ) phenyl)-N-methylurea The product from Example 3 OH and 1-ethylpropylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.86 (t, 6, J=7.4), 1.31 (m, 2), 1.46 (m, 2), 1.90-2.02 (m, 4), 2.98 (s, 3), 3.23 (s, 3), 3.54 (m, 1), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.0, 2.3, 1.5), 6.87 (m, 1), 7.31 (d, 2, J=8.5), 7.54 (d, 2, J=8.5); MS (APCI+) m z 459 (M+H)+. Example 80 N-(4- [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy1methyl } phenvD-N-methyl-
N'-(2.2.2-trifluoroethyl)urea The product from Example 30H and 2,2,2-trifluoroethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. 'H NMR (500 MHz, CD3OD) δ 1.91-2.01 (m, 4), 2.98 (s, 3), 3.25 (s, 3), 3.75-3.87 (m, 6), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.76 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.6), 7.55 (d, 2, J=8.6).
Example 81
N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy methvUphenyl')-N-methyl-
N'-neopentylurea The product from Example 30H and 2,2-dimethyl-l-propylamine were processed as described in Example 301 to provide the title compound as a light yellow solid. Η NMR (500 MHz, CD3OD) δ 0.81 (s, 9), 1.90-2.01 (m, 4), 2.95 (s, 2), 2.98 (s, 3), 3.24 (s, 3), 3.74- 3.87 (m, 4), 5.15 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.33 (d, 2, J=8.5), 7.56 (d, 2, J=8.5); MS (APCI+) m/z 459 (M+H)+.
Example 82 N-(4- 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-vπphenoxylmethyl)phenylVN'- isobutyl-N-methylurea The product from Example 3 OH and 2-mefhyl-l-propylamine were processed as described in Example 301 to provide .the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.84 (d, 6, J=6.7), 1.71 (hept, 1, J=6.8), 1.91-2.01 (m, 4), 2.93 (d, 2, J=7.0), 2.98 (s, 3), 3.23 (s, 3), 3.74-3.86 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.6), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 445 (M+H)+. Example 83 N-(4- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl } phenyl VN-methyl-
N'-(2-methylbutyl)urea The product from Example 3 OH and 2-methylbutylamine were processed as described in Example 301 to provide the title compound as a light yellow solid. Η NMR (500 MHz, CD3OD) δ 0.82 (d, 3, J=6.7), 0.88 (t, 3, J= 7.4), 1.07 (m, 1), 1.35 (m, 1), 1.50 (m, 1), 1.90- 2.01 (m, 4), 2.91 (dd, 1, J=13.3, 7.3), 2.98 (s, 3), 3.06 (dd, 1, J=13.3, 6.3), 3.23 (s, 3), 3.75- 3.86 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.30 (d, 2, J=8.3), 7.54 (d, 2, J=8.3); MS (APCI+) m/z 459 (M+H)+.
Example 84 N'-(2-ethylhexyπ-N-(4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl I phenylVN -methy lurea The product from Example 3 OH and 2-ethylhexylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz,
CD3OD) δ 0.86 (t, 3, J=7.5), 0.90 (m, 3), 1.16-1.36 (m, 8), 1.40 (m, 1), 1.91-2.02 (m, 4), 2.98 (s, 3), 3.06 (m, 2), 3.23 (s, 3), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.30 (d, 2, J=8.6), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 501 (M+H)+.
Example 85 N-(4-{|"3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl|phenyl)-N-methyl-
N'-(2-propynyl)urea The product from Example 3 OH and 2-propynylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz,
CD3OD) δ 1.91-2.01 (m, 4), 2.47 (t, 1, J=2.5), 2.98 (s, 3), 3.24 (s, 3), 3.75-3.86 (m, 4), 3.87 (d, 2, J=2.5), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.30 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 427 (M+H)+. Example 86 N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl}phenylVN'-(2- hydroxybutvD-N-methylurea The product from Example 30H and l-amino-2-butanol were processed as described in Example 301 to provide the title compound as a light yellow solid. Η NMR (500 MHz, CD3OD) δ 0.93 (t, 3, J=7.5), 1.36 (m, 1), 1.44 (m, 1), 1.90-2.02 (m, 4), 2.98 (s, 3), 3.00 (dd, 1, J=13.8, 7.5), 3.24 (s, 3), 3.28 (dd, 2, J=13.8, 3.9), 3.49 (m, 1), 3.75-3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.33 (d, 2, J=8.6), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 461 (M+H)+.
Example 87
N-(4- { [3 -fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N'-(3 - hvdroxy-2.2-dimethylpropyiyN-methylurea
I
The product from Example 30H and 3-amino-2,2-dimethyl-l-propanol were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CD3OD) δ 0.80 (s, 6), 1.91-2.02 (m, 4), 2.98 (s, 3), 3.02 (s, 2), 3.18 (s, 2), 3.24 (s, 3), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.72 (dt, 1, J=10.5, 2.3), 6.76 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.32 (d, 2, J=8.6), 7.55 (d, 2, J=8.6); MS (APCI+) m/z 475 (M+H)+.
Example 88
N-(4-{|"3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy"|methyl}phenyl)-N'-[2-(2- hvdroxyethoxy)ethyH-N-methylurea The product from Example 3 OH and 2-(2-aminoethoxy)ethanol were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.91-2.02 (m, 4), 2.98 (s, 3), 3.24 (s, 3), 3.32 (m, 2), 3.49 (m, 4), 3.61 (m, 2), 3.74-3.86 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 477 (M+H)+. Example 89 N'-allyl-N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl}phenylVN- methylurea The product from Example 3 OH and allylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.91-2.01 (m, 4), 2.97 (s, 3), 3.24 (s, 3), 3.73 (dt, 2, J= 5.3, 1.7), 3.75-3.86 (m, 4), 5.02 (dq, 1, J=10.3, 1.6), 5.09 (dq, 1, J=17.2, 1.7), 5.13 (s, 2), 5.81 (m, 1), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 429 (M+H)+.
Example 90 N-(4-{r3-fluoro-5-f4-methoxytetrahydro-2H-pyran-4-yl)phenoxylmethv phenyl)-N'-(2- methoxy- 1 -methylethvD-N-methylurea The product from Example 3 OH and 2-methoxy-l-methylethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR
(500 MHz, CD3OD) δ 1.07 (d, 3, J=6.8), 1.91-2.01 (m, 4), 2.97 (s, 3), 3.23 (s, 3), 3.28 (dd, 1, J=6.4, 5.3), 3.28 (s, 3), 3.31 (m, 1), 3.74-3.87 (m, 4), 3.96 (m, 1), 5.14 (s, 2), 6.71 (dt, 1 , J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.31 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 461 (M+H)+.
Example 91 N'-('cvanomethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxylmethyl I phenyl)-N-methylurea The product from Example 3 OH and aminoacetonitrile were processed as described in Example 301 to provide the title compound as an off white solid. Η NMR (500 MHz,
CD3OD) δ 1.91-2.01 (m, 4), 2.98 (s, 3), 3.25 (s, 3), 3.74-3.87 (m, 4), 4.02 (s, 2), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.76 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.32 (d, 2, J=8.5), 7.55 (d, 2, J=8.5). Example 92 N'-cyclopropyl-N-(4-l[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yDphenoxy] methyl I phenvD-N-methylurea The product from Example 3 OH and cyclopropylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz,
CD3OD) δ 0.40 (m, 2), 0.68 (m, 2), 1.90-2.01 (m, 4), 2.61 (m, 1), 2.97 (s, 3), 3.21 (s, 3), 3.73- 3.86 (m, 4), 5.12 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.26 (d, 2, J=8.6), 7.50 (d, 2, J=8.6); MS (APCI+) m/z 429 (M+H)+.
Example 93
N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl|phenylVN'- isopropyl-N-methyl-N'-propylurea The product from Example 3 OH and N-isopropyl-N-propylamine were processed as described in Example 301 to provide the title compound as an oily colorless solid. Η NMR (500 MHz, CD3OD) δ 0.79 (t, 3, J= 7.4), 0.95 (d, 6, J= 6.8), 1.47 (m, 2), 1.90-2.00 (m, 4),
2.84 (m, 2), 2.97 (s, 3), 3.13 (s, 3), 3.74-3.86 (m, 4), 4.05 (hept, 1, J=6.8), 5.10 (s, 2), 6.68 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.14 (d, 2, J=8.7), 7.46 (d, 2, J=8.7); MS (APCI+) m/z 473 (M+H)+.
Example 94
N-(4-{r3-fluoro-5-f4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenyl)-N'-r(lRVl-
(hvdroxymethyl)propyl"|-N-methylurea The product from Example 30H and (2R)-2-amino-l-butanol were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.89 (t, 3, J=7.5), 1.36 (m, 1), 1.55 (m, 1), 1.90-2.02 (m, 4), 2.97 (s, 3), 3.24 (s, 3), 3.47 (m, 2), 3.65 (m, 1), 3.74-3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J= 10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.33 (d, 2, J=8.5), 7.54 (d, 2, J=8.5); MS (APCI+) m/z 461 (M+H)+. Example 95 N-(4- ( |~3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl I phenvD-N-methyl-
N'-(2-methyl-2-propenyl)urea The product from Example 3 OH and 2-methyl-2-propenylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.68 (s, 3), 1.91-2.01 (m, 4), 2.97 (s, 3), 3.24 (s, 3), 3.67 (s, 2), 3.74-3.86 (m, 4), 4.75 (m, 2), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.33 (d, 2, J=8.6), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 443 (M+H)+.
Example 96
(2R)-N-(4-{|"3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl|phenylV2- (hydroxymethylVN-methyl- 1 -pyrrolidinecarboxamide The product from Example 3 OH and (2R)-pyrrolidinylmethanol were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CD3OD) δ 1.55-1.74 (m, 3), 1.89-2.01 (m, 5), 2.58 (m, 1), 2.97 (s, 3), 3.08 (m, 1), 3.20 (s, 3), 3.62 (dd, 1, J=10.9, 5.7), 3.67 (dd, 1, J=10.9, 4.1), 3.73-3.86 (m, 4), 4.01 (m, 1), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.84 (m, 1), 7.22 (d, 2, J=8.6), 7.45 (d, 2, J=8.6); MS (APCI+) m/z 473 (M+H)+.
Example 97
N'-(2-fluoroethyl)-N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxylmethyl } phenvD-N-methylurea The product from Example 3 OH and 2-fluoroethylamine were processed as described in Example 301 to provide the title compound as a yellow oil. 'H NMR (500 MHz, CD3OD) δ 1.91-2.01 (m, 4), 2.97 (s, 3), 3.24 (s, 3), 3.40 (dt, 2, J=24.7, 5.2), 3.74-3.87 (m, 4), 4.38 (dt, 2, J=47.5, 5.2), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 435 (M+H)+. Example 98 N'-ethyl-N-f4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-vπphenoxy1methyl)phenyl)-
N-methylurea The product from Example 3 OH and ethylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz,
CD3OD) δ 1.05 (t, 3, J=7.2), 1.91-2.01 (m, 4), 2.98 (s, 3), 3.15 (q, 2, J=7.2), 3.22 (s, 3), 3.74- 3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.29 (d, 2, J=8.6), 7.52 (d, 2, J=8.6); MS (APCI+) m/z 417 (M+H)+.
Example 99
N-(4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl)phenyl)-N'-('2- hydroxypropylVN-methylurea The product from Example 3 OH and l-amino-2-propanol were processed as described in Example 301 to provide the title compound as a yellowish solid. Η NMR (500 MHz, CD3OD) δ 1.03 (d, 3, J=6.3), 1.90-2.01 (m, 4), 2.98 (s, 3), 3.01 (dd, 1, J=13.7, 7.2), 3.20 (dd, 1, J=13.7, 4.3), 3.24 (s, 3), 3.74-3.87 (m, 5), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.33 (d, 2, J=8.5), 7.54 (d, 2, J=8.5); MS (APCI+) m/z 447 (M+H)+.
Example 100
N'-(cvclopropylmethyl)-N-(4-{r3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy~|methyl I phenvD-N-methylurea The product from Example 3 OH and cyclopropylmethylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 0.14 (m, 2), 0.41 (m, 2), 0.95 (m, 1), 1.90-2.01 (m, 4), 2.98 (s, 3), 2.99 (m, 2), 3.23 (s, 3), 3.74-3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.31 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 443 (M+H)+. Example 101 N'- -ethylbutylVN-('4-{r3-fluoro-5-C4-methoxytetrahvdro-2H-pyran-4- yf)phenoxy]mefhyl } phenvD-N-methylurea The product from Example 3 OH and 2-ethylbutylamine were processed as described in Example 301 to provide the title compound as an off white solid. Η NMR (500 MHz,
CD3OD) δ 0.86 (t, 6, J=7.4), 1.25 (m, 4), 1.34 (m, 1), 1.91-2.02 (m, 4), 2.98 (s, 3), 3.06 (d, 2, J=6.5), 3.23 (s, 3), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.30 (d, 2, J=8.5), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 473 (M+H)+.
Example 102
(2S)-N-(4- 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methyl|phenyl -2- (hvdroxymethvD-N-methyl- 1 -pyrrolidinecarboxamide The product from Example 30H and (2S)-pyrrolidinylmethanol were processed as described in Example 301 to provide the title compound as a white solid. Η NMR (500 MHz, CD3OD) δ 1.54-1.74 (m, 3), 1.87-2.01 (m, 5), 2.58 (m, 1), 2.97 (s, 3), 3.08 (m, 1), 3.20 (s, 3), 3.62 (dd, 1, J=10.9, 5.7), 3.67 (dd, 1, J=10.9, 4.1), 3.73-3.86 (m, 4), 4.01 (m, 1), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.2), 6.74 (ddd, 1, J=10.1, 2.2, 1.3), 6.84 (m, 1), 7.22 (d, 2, J=8.4), 7.45 (d, 2, J=8.4); MS (APCI+) m/z 473 (M+H)+.
Example 103
N'-cvclopentyl-N-(4-(["3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea The product from Example 3 OH and cyclopentylamine were processed as described in Example 301 to provide the title compound as an off white solid. Η NMR (500 MHz, CD3OD) δ 1.32 (m, 2), 1.49-1.65 (m, 4), 1.84-2.02 (m, 6), 2.97 (s, 3), 3.22 (s, 3), 3.74-3.86 (m, 4), 4.01 (quint, 1, J=7.1), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.29 (d, 2, J=8.6), 7.52 (d, 2, J=8.6); MS (APCI+) m/z 457 (M+H)+. Example 104 N'-(l,2-dimethylpropyl)-N-('4-(r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vOphenoxylmethyl } phenvD-N-methylurea The product from Example 3 OH and 1 ,2-dimethylpropylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.81 (d, 3, J=6.8), 0.84 (d, 3, J=6.8), 1.01 (d, 3, J=6.8), 1.60 (hept, 1, J=6.8), 1.90-2.02 (m, 4), 2.98 (s, 3), 3.23 (s, 3), 3.61 (m, 1), 3.75-3.86 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.6), 6.85 (m, 1), 7.31 (d, 2, J=8.5), 7.55 (d, 2, J=8.5); MS (APCI+) m/z 459 (M+H)+.
Example 105 N'-sec-butyl-N-(4-{|"3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxylmethyl } phenvD-N-methylurea The product from Example 3 OH and sec-butylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 0.86 (t, 3, J=7.4), 1.05 (d, 3, J=6.6), 1.39 (m, 2), 1.90-2.01 (m, 4), 2.98 (s, 3), 3.23 (s, 3), 3.69 (m, 1), 3.74-3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.2), 6.75 (ddd, 1, J=10.1, 2.2, 1.5), 6.87 (m, 1), 7.30 (d, 2, J=8.5), 7.53 (d, 2, J=8.5); MS (APCI+) m/z 445 (M+H)+.
Example 106
N'- rbicvclo f2.2.1 lhept-2-yl1-N-r4- ( 13 -fluoro-5 -('4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl } phenvD-N-methylurea The product from Example 30H and bicyclo[2.2.1]hept-2-ylamine were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.10 (m, 3), 1.19 (m, 2), 1.40-1.52 (m, 2), 1.67 (ddd, 1, J=13.0, 7.9, 2.3), 1.90-2.01 (m, 4), 2.13 (br d, 1, J=4.4), 2.17 (m, 1), 2.97 (s, 3), 3.22 (s, 3), 3.52 (br dd, 1, J=8.1, 3.6), 3.75-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.29 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 483 (M+H)+. Example 107 N-(4-{ 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxylmethv phenyl)-N'-[2-(4- hvdroxyphenyl)ethyl]-N-methylurea The product from Example 30H and 4-(2-aminoethyl)phenol were processed as described in Example 301 to provide the title compound as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.91-2.02 (m, 4), 2.64 (t, 2, J=7.1), 2.98 (s, 3), 3.20 (s, 3), 3.20 (t, 2, J=7.1), 3.74- 3.87 (m, 4), 5.12 (s, 2), 6.68 (d, 2, J=8.6), 6.72 (dt, 1, J=10.5, 2.3), 6.76 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 6.94 (d, 2, J=8.6), 7.18 (d, 2, J=8.6), 7.47 (d, 2, J=8.6); MS (APCI+) m/z 509 (M+H)+.
Example 108 N'-(2-cvanoethyl)-N-('4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxyl methyl IphenylVN-methy lurea The product from Example 3 OH and 3-aminopropanenitrile were processed as described in Example 301 to provide the title compound as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.91-2.02 (m, 4), 2.62 (t, 2, J=6.6), 2.98 (s, 3), 3.24 (s, 3), 3.36 (t, 2, J=6.6), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (dt, 1, J=10.1, 1.7), 6.86 (m, 1), 7.33 (d, 2, J=8.3), 7.54 (d, 2, J=8.3).
Example 109
N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy1methvUphenyl)-N'-(2- hydroxyethvD-N-methylurea The product from Example 3 OH and 2-aminoethanol were processed as described in Example 301 to provide the title compound as an oily white solid. Η NMR (500 MHz, CD3OD) δ 1.90-2.02 (m, 4), 2.98 (s, 3), 3.24 (s, 3), 3.24 (t, 2, J= 5.7), 3.54 (t, 2, J= 5.7), 3.74- 3.87 (m, 4), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.32 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 433 (M+H)+. Example 110 N-(4- { T3 -fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl ) phenvD-N'- f 1 - (hydroxymethyl)cvclopentyl]-N-methylurea The product from Example 3 OH and (l-aminocyclopentyl)methanol were processed as described in Example 301 to provide the title compound as a tan solid. Η NMR (500 MHz, CD3OD) δ 1.59 (m, 2), 1.66 (m, 4), 1.75 (m, 2), 1.91-2.01 (m, 4), 2.97 (s, 3), 3.21 (s, 3), 3.38 (s, 2), 3.74-3.87 (m, 4), 5.14 (s, 2), 6.71 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.34 (d, 2, J=8.6), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 487 (M+H)+.
Example 111
N'-(2.2-dimethylcyclopentyl')-N-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- vDphenoxylmethvUphenylVN-mefhylurea The product from Example 30H and 2,2-dimethylcyclopentylamine were processed as described in Example 301 to provide the title compound as a tan solid. Η NMR (500 MHz, CD3OD) δ 0.65 (s, 3), 0.98 (s, 3), 1.31 (m, 1), 1.43 (m, 2), 1.57 (m, 2), 1.90-2.03 (m, 5), 2.98 (s, 3), 3.24 (s, 3), 3.74-3.87 (m, 5), 5.15 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.33 (d, 2, J=8.5), 7.56 (d, 2, J=8.6); MS (APCI+) m/z 485 (M+H)+.
Example 112 N-(4-{ 3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-vπphenoxy]methyl}phenyl)-N'- isopropyl-N-methylurea The product from Example 3 OH and isopropylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.08 (d, 6, J=6.6), 1.90-2.01 (m, 4), 2.98 (s, 3), 3.22 (s, 3), 3.74-3.85 (m, 4), 3.89 (hept, 1, 6.6), 5.13 (s, 2), 6.71 (dt, 1, J=10.5, 2.9), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.29 (d, 2, J=8.6), 7.53 (d, 2, J=8.6); MS (APCI+) m/z 431 (M+H)+. Example 113 N.N-diethyl-N'-(4- { |~3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4- vDphenoxy"|methyl } phenvD-N'-methylurea The product from Example 3 OH and diethylamine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (400 MHz, CDC13) δ 0.94 (t, 6, J=7.1), 1.90-2.01 (m, 4), 2.97 (s, 3), 3.12 (q, 4, J=7.1), 3.15 (s, 3), 3.75-3.87 (m, 4), 5.00 (s, 2), 6.60 (dt, 1, J=10.3, 2.3), 6.70 (ddd, 1, J=9.9, 2.0, 1.6), 6.80 (m, 1), 7.09 (d, 2, J=8.4), 7.37 (d, 2, J=8.4); MS (APCI+) m/z 445 (M+H)+.
(292753) Example 114
N-ethyl-N'-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl phenoxylmethyl}phenylV
N-(2-methoxyethyl)-N'-rnethylurea The product from Example 3 OH and N-ethyl-N-(2-methoxyethyl)amine were processed as described in Example 301 to provide the title compound as a light yellow solid. 'H NMR (400 MHz, CD3OD) δ 0.93 (t, 3, J= 7.1), 1.88-2.02 (m, 4), 2.97 (s, 3), 3.12 (q, 2, J=7.1), 3.14 (s, 3), 3.28 (s, 3), 3.34 (m, 4), 3.73-3.87 (m, 4), 5.09 (s, 2), 6.69 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.17 (d, 2, J=8.7), 7.45 (d, 2, J=8.7); MS (APCI+) m/z 475 (M+H)+.
Example 115
N-butyl-N-(cvanomethvP-N'-(4-{ [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl I phenyD-N'-methylurea The product from Example 30H and (butylamino)acetonitrile were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 0.78 (t, 3, J=7.4), 1.07 (m, 2), 1.24 (m, 2), 1.90-2.00 (m, 4), 2.98 (s, 3), 3.00 (m, 2), 3.19 (s, 3), 3.74-3.86 (m, 4), 4.13 (s, 2), 5.12 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.22 (d, 2, J=8.5), 7.51 (d, 2, J=8.5); MS (APCI+) m/z 501 (M+H2O)+. Example 116 N ' -(A- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl>)phenoxy1methyl ) phenyl)-N' - methyl- 1 ,3-piperidinedicarboxamide The product from Example 3 OH and 3 -piperidinecarboxamide were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 1.30 (m, 1), 1.46-1.62 (m, 2), 1.85 (m, 1), 1.90-2.01 (m, 4), 2.28 (m, 1), 2.63 (ddd, 1, J=13.9, 11.0, 2.2), 2.83 (dd, 1, J=13.2, 10.5), 2.97 (s, 3), 3.19 (s, 3), 3.60 (m, 1), 3.73- 3.87 (m, 5), 5.09 (s, 2), 6.70 (dt, 1, J=10.5, 2.2), 6.75 (dt, 1, J=10.1, 1.8), 6.85 (m, 1), 7.16 (d, 2, J=8.4), 7.47 (d, 2, J=8.4); MS (APCI+) m/z 500 (M+H)+.
Example 117 N-butyl-N'-(4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl phenoxylmethyllphenyl)-
N.N'-dimethylurea The product from Example 3 OH and N-butyl-N-methylamine were processed as described in Example 301 to provide the title compound as a colorless oil. 'H NMR (500
MHz, CD3OD) δ 0.89 (t, 3, J=7.4), 1.23 (m, 2), 1.41 (m, 2), 1.86-1.98 (m, 4), 2.62 (s, 3), 2.97 (s, 3), 3.13 (m, 2), 3.16 (s, 3), 3.74-3.86 (m, 4), 5.09 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J= 10.1, 2.3, 1.5), 6.85 (m, 1), 7.11 (d, 2, J=8.5), 7.45 (d, 2, J=8.5); MS (APCI+) m/z 459 (M+H)+.
Example 118 N-(4- { |~3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-vπphenoxy1methyl } phenyl)-N'- isopropyl-N'-(2-methoxyethyl)-N-methylurea The product from Example 30H and N-isopropyl-N-(2-methoxyethyl)amine were processed as described in Example 301 to provide the title compound as a colorless oil. Η NMR (500 MHz, CD3OD) δ 0.90 (d, 6, J=6.7), 1.90-2.00 (m, 4), 2.97 (s, 3), 3.13 (s, 3), 3.18 (t, 2, J=6.1), 3.32 (s, 3), 3.41 (t, 2, J=6.1), 3.74-3.86 (m, 4), 3.97 (hept, 1, J=6.7), 5.10 (s, 2), 6.68 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.18 (d, 2, J=8.5), 7.45 (d, 2, J=8.5); MS (APCI+) m/z 489 (M+H)+. Example 119 N,N-diethyl-N'-f4- ( r3-fluoro-5-(4-hvdroxytetrahvdro-2H-pyran-4- yllphenoxylmethyl } phenyl)-N'-methy lurea The product from Example ID (248 mg, 1.05 mmol) in 2 mL of DMF at 0 °C was treated with sodium hydride (76 mg, 3.17 mmol). The cooling bath was removed and the reaction mixture was treated with the product from Example 30D (214 mg, 1.0 mmol) in 1 mL of DMF. After 3 hours at ambient temperature, the mixture was warmed to 65 °C for 4 days and then 90 °C for 16 hours. The mixture was partitioned between diethyl ether and water and the organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (98:2 CHCl3:MeOH) to provide 176 mg (41%) of the title compound as a clear oil. Η NMR (400 MHz, CDC13) δ 0.95 (t, 6, J=7.0), 1.65 (d, 2, J=12.8), 2.10 (dt, 2, J=13.2, 5.6), 3.11 (q, 4, J=7.0), 3.15 (s, 3), 3.90 (m, 4), 5.00 (s, 2), 6.58 (dt, 1, J=10.0, 2.0), 6.82 (br d, 1, J=10.0), 6.90 (br s, 1), 7.10 (d, 2, J=8.4), 7.35 (d, 2, J= 8.4); l3C NMR (100 MHz, CDC13) δ 19.9, 38.6, 39.6, 42.0, 63.7, 69.9, 70.6, 100.8 (d), 104.4 (d), 107.5 (d), 123.6, 128.7, 132.2, 147.2, 151.9 (d), 159.9 (d), 162.0 (d), 164.8; IR 3393, 2962, 2870, 1613, 1434 cm"'; HRMS calcd for C24H32FN2O4 431.2346; found: 431.2352.
Example 120
N-("4-{[3-fluoro-5-(4-hvdroxytetrahydro-2H-pyran-4-yl)phenoxylmethyl}phenyl)-N.2- dimethyl- 1 -pyrrolidinecarboxamide The product from Example 15C, the product from Example 30D, and sodium hydride were processed as described in Example 119. The residue was purified by column chromatography (98:2 CHCl3:MeOH) to provide the title compound as a colorless oil. Η
NMR (300 MHz, CDC13) δ 1.25 (d, 3, J=6.0), 1.3-1.4 (m, 1), 1.56-1.7 (m, 3), 1.95-2.2 (m, 5), 2.55-2.67 (m, 1), 3.02-3.25 (m, 2 ), 3.23 (s, 3), 3.84-4.02 (m, 4), 5.0 (s, 2), 6.59(dt, 1, J=10.6, 2.2), 6.86(dt, 1, J=12.0, 2.2), 6.94 (m,l), 7.14 (d, 2, J=9), 7.39 (d, 2, J=9); MS (APCI+) m/z 443 (M+H)+. Example 121 N-(4-{[3-fluoro-5-(4-hydroxytetrahvdro-2H-pyran-4-yl)phenoxylmethyllphenyl)-N.N'.N'- trimethylurea
Example 121 A N-[4-(hvdroxymethyl)phenyl]-N,N',N'-trimefhylurea The title compound was prepared using dimethylamine and the procedure(s) described in Example 1A through Example ID.
Example 12 IB N-(4-{r3-fluoro-5-(4-hvdroxytetrahydro-2H-pyran-4-yl)phenoxylmethyl)phenylVN.N'.N'- trimethylurea The product from Example 121 A and the product from Example 30D were processed as described in Example 119 to provide the title compound. Η NMR (300 MHz, CDC13) δ 1.55-1.65 (m,2), 2.02-2.2 (m, 2), 2.65(s, 6), 3.23 (s, 3), 3.82-3.98 (m, 4), 5.0 (s, 2), 6.60(dt, 1, J=10.3, 2.3), 6.83(ddd, 1, J=10.3, 2.3, 1.6), 6.94 (m,l), 7.0 (d, 2, J=8.5), 7.3 (d, 2, J=8.5); MS (APCI+) m/z 403 (M+H)+.
Example 122
N- 1~4-( { 3 -fluoro-5- [4-(2-propynyloxy')tetrahvdro-2H-pyran-4-yl")phenoxy ) methvDphenyll-
N.N',N'-trimethylurea The product from Example 12 IB, propargyl bromide, and sodium hydride were processed as described in Example 119 to provide the title compound. Η NMR (300 MHz, CD3OD) δ 1.84-1.94 (m, 4), 2.6 (s, 6), 2.69 (t, 1, J=2.5), 3.08 (s, 3), 3.66 (d, 2, J=2.5), 3.68 (m, 2), 3.82 (m, 2) 5.0 (s, 2), 6.71 (dt, 1, J=10.5, 2.2), 6.77 (ddd, 1, J=10.0, 2.3, 1.5), 6.88 (m, 1), 7.10 (d, 1, J=8.6), 7.45 (d, 1, J=8.6); MS (DCI/NH3) m/z 441 (M+H)+. Example 123 N.N-diethyl-N'-(4-(r3-(4-ethyltetrahvdro-2H-pyran-4-yl)phenoxy methyl)phenyl)-N'- methylurea
Example 123 A
4-[3-(benzyloxy)phenylltetrahydro-2H-pyran-4-carbaldehvde The title compound was prepared according to the procedure described in EP 0 462
830 A2.
Example 123B
4-[3-(benzyloxy)phenyl"]-4-vinyltetrahydro-2H-pyran Methyltriphenylphosphonium bromide (0.15 g, 0.41 mmol) in 8 mL of anhydrous THF:Et2O (3:1) was slowly treated with a solution of n-butyllithium in hexane (2.5 M, 0.17 mL, 0.41 mmol) via syringe. After 2 hours at ambient temperature, the reaction mixture was treated with the product from Example 123 A (0.1 1 g, 0.37 mmol) in 3 mL of diethyl ether. The reaction mixture was stirred overnight and the resultant precipitate was filtered, washed with diethyl ether, and chromatographed on silica gel (90:10 hexanes: acetone) to provide 0.025 grams (25%) of the title compound as a glassy solid. Η NMR (300 MHz, CDC13) δ 1.98 (dt, 2, J=12, 7.5), 2.1-2.2 (m, 2), 3.7-3.8 (m, 4), 4.95 (dd, 1, J=18.0, 1.0), 5.05 (s, 2), 5.15 (dd, 1, J=10.5,l), 5.82 (dd, 1, J=18,10.5), 6.82 (dd, 1, J=7.5, 2), 6.92 (m, 2), 7.25 (s,l), 7.3- 7.49 (m, 5).
Example 123C 3-(4-ethyltetrahvdro-2H-pyran-4-yl)phenol The product from Example 123B (0.048 g, 0.163 mmol) in EtOH (2 mL) was treated with 10% Pd/C (0.03 g) under an atmosphere of hydrogen overnight. The mixture was then filtered through Celite and a 0.2 micron filter and evaporated in vacuo to provide 0.025 grams (75%) of the title compound as a white solid. Η NMR (300 MHz, CDC13) δ 0.56 (t, 3, J=7.5), 1.62 (q, 2, J=7.5), 1.7-1.82 (m, 2), 2.02-2.18 (m, 2), 3.5-3.62 (dt, 2, J=8, 3), 3.72-3.82 (m, 2), 4.05 (q, 2, J=9), 6.65 (dd, 1, J=8, 2), 6.78 (m, 1), 6.82 (d, 1, J=8), 7.2 (t, 1, J=8); MS (DCI/NH3) m/z 224 (M+NH4)+.
Example 123D N-r4-(bromomethyl)phenyl]-N',N'-diethyl-N-methylurea
The product from Example ID (1.6 g, 6.8 mmol) in 10 mL of CC14 was treated with pyridine (0.27 mL, 3.4 mmol) followed by phosphorous tribromide (1.3 mL, 14.1 mmol) at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and then allowed to warm to ambient temperature and stirred overnight. The mixture was poured into iced water and extracted with CH2C12 (50 mL, 2X). The combined organic phases were combined, washed with brine, water, dried over MgSO4, filtered, and concentrated in vacuo to provide 1.56 grams (77%) of the title compound as a semisolid. Η NMR (300 MHz, CDC13) δ 0.95 (t, 6, J=7), 3.3.1-3.15 (m, 7), 4.49 (s, 2), 7.04 (d, 2, J=9), 7.44 (d, 2, J=9); MS (APCI+) m/z 299, 301 (M+H)+.
Example 123E
N.N-diethyl-N'- 4-{ 3-(4-ethyltetrahvdro-2H-pyran-4-vπphenoxylmethyl}phenyl)-N'- methylurea The product from Example 123C (0.021 g, 0.11 mmol) in lmL of DMF was treated with solid sodium hydride (0.005 g, 0.2 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was treated with the product from Example 123D (0.036 g, 0.12 mmol) in 0.5 mL of DMF. The mixture was stirred overnight. The mixture was quenched with water and saturated aqueous NH4C1 (3 ml) and extracted with diethyl ether and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to provide an oily residue (0.109 g), which was chromatographed on silica gel (80:20 hexanes:acetone) to provide 0.018 grams (36%) of the title compound as a glassy solid. Η NMR (300 MHz, CDC13) δ 0.56 (t, 3, J=7.5), 0.9-1.01 (m, 6),1.58-1.66 (dd, 2, J=7.5), 1.7-1.82 (ddd, 2, J=10, 3, 3), 2.04-2.18 (dt, 2, J=7.5, 3), 3.05-3.25 (m, 7), 3.5-3.6 (dt, 2, J=10, 3), 3.72-3.82 (m, 2), 5.02 (s, 2), 6.82 (dd, 1, J=8, 2), 6.89 (m, 2), 7.1 (d, 2, J=8), 7.25 (m,l), 7.4 (d, 2, J=8); MS (APCI+) m/z 425 (M+H)+. Example 124 ethyl 4- [3 -( (4- |~|Ydiethylamino)carbonyl] (methyl)amino]benzyl } oxy)phenyl]tetrahvdro-2H- pyran-4-carboxylate
Example 124 A ethyl 4-r3-(benzyloxy)phenylltetrahvdro-2H-pyran-4-carboxylate The title compound was prepared according to the procedure described in EP 0 462 830 A2.
Example 124B ethyl 4-(3 -hvdroxyphenyl')tetrahvdro-2H-pyran-4-carboxylate The product from Example 124A (0.74g, 2.17 mmol) in EtOH (2 mL) was treated with 10%) Pd/C (0.34 g) under an atmosphere of hydrogen overnight. The mixture was filtered through celite and a 0.2 micron filter and evaporated in vacuo to provide 0.49 grams (90%) of the title compound as a white solid. Η NMR (300 MHz, CDC13) δ 1.2 (t, 3, J= 7.5), 1.9-2.04 (m, 2), 2.5 (dd, 2, J=12, 3), 3.58 (dt, 2, J=10.5, 3), 3.98 (dt, 2, J=10.5, 3), 4.06 (q, 2, J= 7.5), 5.08 (s,l), 6.75 (d, 1, J=9), 6.88 (m,l), 6.95 (d, 1, J=9), 7.25 (t, 1, J=9); MS (APCI+) m/z 341 (M+H)+.
Example 124C ethyl 4-[3-("(4-["[(diethylamino)carbonyll(methyl')amino]benzyl}oxy')phenyl]tetrahvdro-2H- pyran-4-carboxylate The product from Example 124B (0.078 g, 0.26 mmol) in lmL of DMF was treated with solid sodium hydride (0.007g, 0.28 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was treated with the product from Example 123D (0.06 g, 0.24 mmol) in 0.5 mL. The mixture was stirred overnight. The mixture was quenched with water and saturated aqueous NH4C1 (3 mL) and extracted with diethyl ether and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to provide an oily residue (0.109 g), which was chromatographed on silica gel (80:20 hexanes: acetone) to provide 0.027 grams (24%) of the title compound as a glassy solid. Η NMR (300 MHz, CDC13) δ 0.95 (t, 6, J=7.5), 1.2 (t, 3, J=7.5), 1.9-2.04 (m, 2), 2.48- 2.55 (m, 2), 3.09-3.16 (m, 7), 3.5-3.62 (dt, 2, J=10.5, 3), 3.88-3.97 (dt, 2, J=10.5, 3), 4.05 (q, 2, J=7.5), 5.0 (s, 2), 6.9 (dt, 1, J=12, 2), 6.98-7.05 (m, 2), 7.1 (d, 2, J=9), 7.25 (m,l), 7.1 (d, 2, J=9); MS (APCI+) m/z 469 (M+H)+.
Example 125 N.N-diethyl-N'-(4-{r3-fluoro-5-(l-hvdroxycvclohexyl)phenoxylmethyl|phenyl)-N'- methylurea
Example 125 A l-F3-(benzyloxy)-5-fluorophenyllcyclohexanol The product from Example 128 A and cyclohexanone were processed as described in Example 128B to provide the title compound.
Example 125B 3-fluoro-5-(T-hvdroxycyclohexyl)phenol The product from Example 125 A was processed as described in Example 126C to provide the title compound.
Example 125C N.N-diethyl-N'-(4- { [3-fluoro-5-( 1 -hydroxycvclohexyDphenoxylmethyl } phenyl)-N'- methylurea The product from Example 125B (0.17 g, 0.81 mmol) in 3 mL of DMF was treated with solid sodium hydride (0.048 g, 2.0 mmol) at ambient temperature. After stirring for 20 minutes, the reaction mixture was treated with the product from Example 123D (0.22 g, 1.05 mmol) in 2 mL of DMF and allowed to stir overnight. The mixture was quenched with water and saturated aqueous ammonium hydroxide (5 mL) and extracted with diethyl ether and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide an oily residue (0.2 g), which was chromatographed on silica gel (80:20 hexanes: acetone) to provide 0.065 grams (19%) of the title compound as a white solid. 'H NMR (300 MHz, CDC13) δ 0.98 (m, 6), 1.64-1.81 (m, 10), 3.08-3.18 (m, 4), 3.21 (s, 3), 5.0 (s, 2), 6.55 (dt, 1, J=10.5, 3), 6.8 (dt, 1, J=10.5, 3), 6.92 (m,l), 7.1 (d, 2, J=7.5), 7.38 (d, 2, J=7.5); MS (APCI+) m/z 463 ( M+C1)+.
Example 126 N-{4-[(3-fluoro-5-tetrahvdro-2H-pyran-4-ylphenoxy)methyllphenyl|-N.2-dimethyl-l- pyrrolidinecarboxamide
Example 126 A 4-r3-("benzyloxy)-5-fluorop_henylltetrahvdro-2H-pyran-4-ol The product from Example 128 A and tetrahydro-4H-pyran-4-one were processed as described in Example 128B to provide the title compound.
Example 126B 4- f 3 -(benzyloxy -5 -fluorophenvntetrahydro-2H-pyran The product from Example 126A (250 mg, 0.83 mmol) in 5 mL of trifluoroacetic acid and 1 mL of CH2C12 was treated with triethylsilane (5 mL). After 10 hours, the mixture was concentrated in vacuo and the crude material was purified by column chromatography (CHC13) to provide 102 mg (43%) of a colorless oil. Η NMR (400 MHz, CDC13) δ 1.60-1.70 (m, 4), 2.62 (m, 1), 3.40 (m, 2), 3.97 (m, 2), 4.93 (s, 2), 6.46 (m, 2), 6.56 (t, 1, J=2.1), 7.20- 7.35 (m, 5); 13C NMR (100 MHz, CDC13) δ 34.5, 42.3, 69.0, 71.1, 100.9 (d), 107.0 (d), 110.3 (d), 128.3, 128.9, 129.4, 137.3, 149.8 (d), 160.9 (d), 165.7; HRMS calcd for C18H19FO2: 286.1369; found 286.1367.
Example 126C 3-fluoro-5-tetrahvdro-2H-pyran-4-ylphenol The product from Example 126B (100 mg) in 10 mL of ethanol was treated with 10% Pd/C under an atmosphere of hydrogen for 5 hours. The mixture was filtered through a plug of celite and concentrated in vacuo to provide the title compound. Η NMR (400 MHz, CDC13) δ 1.70 (m, 4), 2.70 (m, 1), 3.55 (m, 2), 4.00 (dt, 2, J=11.2, 3.0), 6.32 (dt, 1, J=10.5, 2.2), 6.44 (dt, 1, J=10.2, 1.7), 6.48 (t, 1, J=1.7).
Example 126D N-{4-r(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyllphenyl}-N,2-dimethyl-l- pyrrolidinecarboxamide The product from Example 126C (34 mg, 0.17 mmol) and the product from Example
47A (80 mg, 0.26 mmol) in 1 mL of DMF were treated with sodium hydride (16 mg, 0.67 mmol). After 2 hours, the mixture was partitioned between diethyl ether and water. The phases were separated and the organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (200:1 CHCl3:MeOH) to provide 45 mg (62%) of the title compound. Η NMR (400 MHz, CDC13) δ 1.16 (d, 2,
J=6.0), 1.26 (m, 1), 1.55 (m, 2), 1.68 (m, 4), 1.92 (m, 1), 2.56 (m, 1), 2.64 (m, 1), 3.00 (dq, 1, J=10.6, 3.0), 3.16 (s, 3), 3.43 (m, 2), 3.90 (sext, 1, J=6.8), 4.00 (dt, 2, J=11.4, 3.0), 4.91 (s, 2), 6.48 (m, 2), 6.57 (t, 1, J=1.7), 7.06 (d, 2, J=8.7), 7.30 (d, 2, J=8.7); 13C NMR (100 MHz, CDC13) δ 20.0, 24.8, 29.6, 33.6, 39.0, 41.5, 49.1, 54.0, 100.0 (d), 106.2 (d), 109.4 (d), 124.5, 128.6, 132.2, 149.0 (d), 159.9 (d), 161.0 (d), 164.8; IR 2924, 2852, 1644, 1612, 1381 cm 1; HRMS calcd for 427.2397, found 427.2392.
Example 127 N.N-diethyl-N'-{4-[(3-fluoro-5-tetrahvdro-2H-pyran-4-ylphenoxy')methyl1phenv -N'- methylurea
The product from Example 123D (78 mg, 0.26 mmol) and the product from Example 126C (38 mg, 0.19 mmol) were processed as described in Example 126D. The resultant crude material was purified by column chromatography (200:1 CHCl3:MeOH) to afford 38 mg (48%) of the title compound. Η NMR (400 MHz, CDC13) δ 0.88 (t, 6, J=7.2), 1.68 (m, 4), 2.63 (m, 1), 3.06 (q, 4, J=7.2), 3.10 (s, 3), 3.43 (m, 2), 4.00 (m, 2), 4.92 (s, 2), 6.46 (m, 2), 6.56 (m, 1), 7.02 (d, 2, J=8.6), 7.30 (d, 2, J=8.6); l3C NMR (100 MHz, CDC13) δ 12.9, 29.7, 33.6, 41.5, 42.1, 68.1, 69.8, 100.1 (d), 106.2 (d), 109.5 (d), 123.7, 128.7, 132.4, 149.0 (d), 159.9 (d), 162.0 (d), 164.8; IR 1649, 1614, 1458 cm 1; HRMS calcd for 415.2397, found 415.2377.
Example 128 tert-butyl 4-|"3-({4-rr(diethylamino)carbonyl1(methvπamino]benzyl}oxy)-5-fluorophenyl1-4- hydroxy- 1 -piperidinecarboxylate
Example 128 A l-(benzyloxy)-3-bromo-5-fluorobenzene Benzyl alcohol and l-bromo-3,5-difluorobenzene were processed as described in Example 15D to provide the title compound.
Example 128B tert-butyl 4-[3-(benzyloxy)-5-fluorophenyll-4-hvdroxy-l-piperidinecarboxylate The Grignard reagent prepared from magnesium turnings (0.75 g, 28.5 mmol), a few drops of 1 ,2-dibromoethane, a crystal of iodine, and the product from Example 128 A (8 g, 28.5 mmol) in dry diethyl ether (50 mL) was treated with tert-butyl 4-oxo-l- piperidinecarboxylate (6.25 g, 31.4 mmol) in diethyl ether (100 mL) dropwise. The mixture was stirred overnight and then partitioned between diethyl ether and saturated aqueous NH4C1. The combined organic phases were washed with brine, water, dried over MgSO4, and evaporated in vacuo to provide 7.2 grams (65%) of the title compound as a white crystalline solid. Η NMR (300 MHz, CDC13) δ 1.5 (s, 9), 1.58-1.62 (m, 2), 1.88-2.0 (m, 2), 3.1-3.29 (m, 2), 3.98-4.12 (br m, 2), 5.05 (s, 2), 6.6 (dt, 1, J=10.5, 2), 6.78 (dt, 1, J=10.5, 2), 6.9 (m, 1), 7.34-7.45 (m, 5); MS (APCI+) m/z 302 ( M+H-Boc)+. Example 128C tert-butyl 4-(3-fluoro-5-hvdroxyphenyl)-4-hydroxy- 1 -piperidinecarboxylate The product from Example 128B was processed as described in Example 126C to provide the title compound.
Example 128D tert-butyl 4-[3-("{4-[[(diethylamino)carbonyll(methyl)amino]benzylloxy)-5-fluorophenyll-4- hydroxy-1 -piperidinecarboxylate The product from Example 128C (0.9 g, 3.81 mmol) in 6 mL of DMF was treated with solid sodium hydride (0.2 g, 8.33 mmol) at ambient temperature. After 30 minutes of stirring, the reaction mixture was treated with the product from Example 123D (1.3 g, 4.15 mmol) in 2 mL of DMF. The mixture was heated at 75 °C overnight. After cooling to ambient temperature, the mixture was quenched with water and saturated aqueous NH4C1 (3 ml), and extracted with diethyl ether and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide an oily residue (0.9 g), which was chromatographed on silica gel (70 :30 hexanes: acetone) to provide 0.26 grams (13%) of the title compound as a white solid. Η NMR (300 MHz, CDC13) δ 0.95 (t, 6, J=7), 1.5 (s, 9), 1.62-1.74 (m, 2), 1.88-2.2 (m, 2), 3.06-3.3 (m, 9), 3.98-4.11 (br m, 2), 5.0 (s, 2), 6.58 (dt, 1, J=10.5, 3), 6.8 (dt, 1, J=10.5, 2), 6.9 (bs,l), 7.1 (d, 2, J=7.5), 7.38 (d, 2, J=7.5); MS (APCI+) m/z 530 (M+H)+.
Example 129 5-(["3-(l-benzyl-4-hvdroxy-4-piperidinyl')-5-fluorophenoxy]methyl|-l,3-dimethyl-1.3- dihvdro-2H-benzimidazol-2-one
Example 129 A methyl 2-oxo-23-dihvdro-lH-benzimidazole-5-carboxylate Methyl 3,4-diaminobenzoate (1.8 g, 10.85 mmol) in 20 mL of THF:DMF (1 :1) was treated with l,l'-carbonyldiimidazole (1.95 g, 11.95 mmol). A pale white solid slowly precipitated during overnight stirring. The solid was filtered, washed with a small amount of THF, and dried in vacuo to provide 1.75 g (84%) of the title compound. Η NMR (300 MHz, DMSO-d6) δ 3.83 (s, 3), 7.02 (d, 1, J=7.5), 7.48 (dd, 1, J=7.5, 2.0), 7.64 (dd, 1, J=7.5, 2.0), 10.92 (br s,l), 11.05 (br s,l); MS (DCI/NH3) 193 (M+H)+; 210 (M+NH4)+.
Example 129B methyl 1.3-dimethyl-2-oxo-2.3-dihvdro-lH-benzimidazole-5-carboxylate The product from Example 129A (10.2 g, 53.13 mmol) in 300 mL of THF:DMF (1 :3) was treated with sodium hydride (2.8 g, 117 mmol). After 20 minutes, the suspension was treated with methyl iodide (8 mL) via syringe and the reaction monitored by TLC
(hexane: acetone 3:2). The reaction mixture was diluted with water and extracted with an excess of diethyl ether. The combined organic phases were washed with 100 mL of brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 9.8 g (84%) of the title compound. 'H NMR (300 MHz, DMSO-d6) δ 3.34 (s, 3), 3.38 (s, 3), 3.85 (s, 3), 7.25 (d, 1, J=7.5), 7.69 (d, 1 , J=2.0), 7.77 (dd, 1 , J=7.5, 2.0); MS (APCI+) m/z 221 (M+H)+.
Example 129C 5-(hydroxymethyl)- 1.3 -dimethyl- 1 ,3 -dihydro-2H-benzimidazol-2-one The product from Example 129B (10 g, 45.5 mmol) in 350 mL of THF and 2 mL of MeOH was treated with lithium borohydride (5 g, 229 mmol) and then refluxed for 3 hours. After cooling on ice, the mixture was slowly quenched by the addition of saturated aqueous NH4C1 followed by addition of water. The mixture was extracted with ethyl acetate (1.5 L) and the combined organic layers were washed with IN HCl, brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 6.9 g (79%) of the title compound as a solid. Η NMR (300 MHz, CDC13) δ 3.42 (s, 6), 4.74 (s, 2), 6.92 (d, 1, J=7.5), 7.05 (s, 1), 7.08 (d, 1, J=7.5); *H NMR (300 MHz, DMSO-d6) δ 3.34 (s, 6), 4.52 (d, 2, J=6.0), 5.15 (t, 1, J=6.0), 7.02 (d, 1, J=7.5), 7.08 (d, 1, J=2.0), 7.1 l(s, 1); MS (DCI/NH3) m/z 193 ( M+H)+; 210 (M+NH4)+. Example 129D 1 -benzyl-4-(3 ,5-difluorophenyl")-4-piperidinol A solution of the Grignard reagent, prepared from l-bromo-3,5-difluorobenzene (10 g, 51.8 mmol), three drops of 1 ,2-dibromoethane, one crystal of iodine, and magnesium turnings (1.35 g, 56.25 mmol) in dry diethyl ether (60 mL), was treated with a solution of l-benzyl-4- piperidinone (10.1 g, 53.5 mmol) in diethyl ether (60 mL) dropwise at ambient temperature. The mixture was stirred overnight and then partitioned between diethyl ether and saturated aqueous NH4C1. The organic phase was washed with brine, water, dried over MgSO4, and concentrated in vacuo to provide the title compound (6.1 g, 38%) as a solid. Η NMR (300 MHz, CDC13) δ 1.72 (m, 2), 2.05-2.2 (dt, 2, J=12, 3), 2.4-2.5 (dt, 2, J=10.5, 3), 2.75-2.95 (br d, 2, J=10.5), 3.6 (s, 2), 6.69 (tt, 1, J=10.5, 3), 7.04 (m, 2 ), 7.28-7.4 (m, 5); MS (APCI+) m/z 303 ( M+H)+.
Example 129E 5- ( [3 -( 1 -benzyl-4-hvdroxy-4-piperidinyl)-5-fluorophenoxylmethyl 1-1.3 -dimethyl- 1,3- dihydro-2H-benzimidazol-2-one The product from Example 129C (0.5 g, 2.6 mmol) in 5 mL of DMF was treated with sodium hydride (0.190 g, 7.9 mmol) at ambient temperature. The resulting mixture was stirred for 30 minutes and then treated with a solution of the product from Example 129D (0.91 g, 3 mmol) in 3 mL of DMF. The mixture was heated at 60 °C overnight. After cooling to ambient temperature, the mixture was quenched with water and saturated aqueous NH4C1 (3 mL), and extracted with diethyl ether and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a solid, which was crystallized from MeOH and ethyl acetate to provide 0.72 g (58%) of the title compound as a solid. Η NMR (300 MHz, DMSO-d6) δ 1.68-1.85 (m, 2), 2.26-2.48 (m, 2), 3.2-3.3 (m, 4), 3.31-3.42 (m, 6), 4.36 (m, 2), 5.1 (s, 2), 6.78-6.88 (m, 2), 6.92 (br s,l), 7.10-7.22 (m, 3), 7.42-7.54 (m, 5); MS (APCI+) m/z 476 (M+H)+. Example 130 5- { [3 -(trans- 1.4-dimethoxycvclohexy l)-5-fluorophenoxy1methyl } - 1.3 -dimethyl- 1.3 -dihvdro-
2H-benzimidazol-2-one The title compound [Registry Number 155821-58-2] was prepared according to the procedure described in WO 94/05638.
Example 131 5-([3-fluoro-5-(8-hvdroxy-1.4-dioxaspiro 4.51dec-8-yl)phenoxylmethyl}-1.3-dimethyl-1.3- dihydro-2H-benzimidazol-2-one
Example 131 A 8-(3.5-difluorophenviyi.4-dioxaspiror4.5]decan-8-ol The Grignard reagent prepared from magnesium turnings (1.3 g, 53.5 mmol), 1- bromo-3,5-difluorobenzene (10 g, 51.8 mmol), and several drops of 1 ,2-dibromoethane in 100 mL of diethyl ether was treated with l,4-dioxaspiro[4.5]decan-8-one (8.2 g, 52.6 mmol) in 100 mL of diethyl ether over 1 hour dropwise. After 16 hours, the mixture was quenched by the addition of 200 mL of saturated aqueous NH4C1. The phases were separated and the organic phase was concentrated in vacuo. The crude material was crystallized from 20 mL of hot ethyl acetate to provide 8.6 grams (61%) of the title compound as a white solid. Η NMR (400 MHz, CDC13) δ 1.70 (m, 4), 2.05 (m, 4), 2.32 (br s, 1), 3.95 (s, 4), 6.66 (tt, 1, J=8.7, 2.3), 7.04 (m, 2); 13C NMR (100 MHz, CDC13) δ 30.5, 36.3, 64.1, 64.2, 72.2, 102.0, 108.1 (m), 153.2 (t), 161.7 (d), 164.1 (d); IR 3513, 1625, 1595, 1439 cm 1; Anal calcd for C14H,6F2O3: C, 62.22; H, 5.97; found: C, 62.38; H, 5.93.
Example 13 IB
5-{[3-fluoro-5-(8-hvdroxy-1.4-dioxaspiro 4.51dec-8-yl)phenoxylmethyl}-1.3-dimethyl-1.3- dihydro-2H-benzimidazol-2-one The product from Example 129C (0.2 g, 1.05 mmol) in 5 mL of DMF was treated with sodium hydride (0.075 g, 3.1 mmol) at ambient temperature. After stirring for 30 minutes, the mixture was treated with the product from Example 131 A (0.3 g, 1.1 mmol) in 1.5 mL of DMF. The mixture was heated at 60 °C overnight. After cooling to ambient temperature, the mixture was quenched with water and saturated aqueous NH4C1 (3 mL), and extracted with diethyl ether and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to provide an oily residue which was chromatographed on silica gel (60:40 hexane: acetone) to provide 0.16g (32%) of the title compound as a white solid. 'H NMR (300 MHz, CDC13) δ 1.71(d, 2, J=10.5), 1.78 (d, 2, J=10.5), 2.0-2.2 (m, 4), 3.45 (2s, 6), 3.98-4.05 (m, 4), 5.08 (m, 2), 6.6 (dt, 1, J=10.5, 3), 6.85 (dt, 1, J=10.5, 3), 6.98 (m, 2), 7.08 (s,l), 7.15 (d, 1, J=9); MS: APCI ( M+Cl-neg.ion) 477; FAB (HRMS) calculated for C24H28O5N2F: 443.1982. Found: 443.1966.
Example 132 5- { [3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl } - 1 ,3-dimethyl- 1.3- dihydro-2H-benzimidazol-2-one The product from Example 129C (0.2 g, 1.05 mmol) in 5 mL of DMF was treated with solid sodium hydride (0.075 g, 3.1 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was treated with the product from Example 131 A (0.3 g, 1.1 mmol) in 1.5 mL of DMF and then heated at 60 °C overnight. After cooling to ambient temperature, the mixture was quenched with water and saturated aqueous NH4C1 (3 mL), and extracted with diethyl ether and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to provide an oily residue (0.2 g), which was chromatographed on silica gel (60:40 hexanes: acetone) to provide 0.16 g (32%) of the title compound as a white solid. Η NMR (300 MHz, CDC13) δ 1.71(d, 2, J=10.5), 1.78 (d, 2, J=10.5), 2.0-2.2 (m, 4), 3.45 (2s, 6), 3.98-4.05 (m, 4), 5.08 (m, 2), 6.6 (dt, 1, J=10.5, 3), 6.85 (dt, 1, J=10.5, 3), 6.98 (m, 2), 7.08 (s,l), 7.15 (d, 1, J=9); MS (APCI-) m/z ( M-H+Cl)" 477; FAB HRMS: calculated for: C24H28O5N2F: 443.1982. Found: 443.1966. Example 133 N-allyl-N'-(4-{r3-(trans-l,4-dimethoxycvclohexyπ-5-fluorophenoxylmethyl|phenyl)-N.N'- dimethy lurea
Example 133 A methyl 4- ( [(allylamino)carbonyllamino } benzoate Methyl 4-aminobenzoate (19.7 g, 130 mmol) in 100 mL of THF was treated with allylisocyanate (18 mL, 204 mmol), refluxed for 16 hours, and then concentrated in vacuo. The crude material was crystallized from 500 mL of hot ethyl acetate to afford 23.9 g (79%) of the title compound as a white solid. Η NMR (400 MHz, CDC13) δ 3.68 (br s, 1), 3.83 (m, 2), 3.87 (s, 3), 5.10 (br d, 1, J=8.9), 5.20 (br d, 1, J=17.3), 5.85 (m, 1), 7.43 (m, 2), 7.90 (m, 2); 13C NMR (100 MHz, CDCl3) δ 41.9, 51.6, 115.3, 117.3, 122.9, 130.6, 134.6, 144.1, 155.6, 167.2; IR 3372, 1678, 1590, 1531 cm 1; Anal calcd for C ,l|22Hl ll]44Nl l22OX___ 33: C, 61.53; H, 6.02; N,
11.96; found: C, 61.74; H, 6.11 : N, 12.04.
Example 133B methyl 4- { rallvKmethyllaminolcarbonyl) (methyOamino]benzoate The product from Example 133A (1.08 g, 4.62 mmol) in 15 mL of DMF was treated with CsCO3 (4.4 g, 13.5 mmol) and methyl iodide (1 mL, 16.1 mmol). After 3 days at ambient temperature, the mixture was partitioned between 50 mL of diethyl ether and 50 mL of water and the phases were separated. The organic phase was washed with water, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by column chromatography (80:20 hexanes:ethyl acetate) to provide 436 mg (36%) of the title compound. ■H NMR (400 MHz, CDC13) δ 2.62 (s, 3), 3.26 (s, 3), 3.80 (br d, 2, J=6.3), 3.90 (s, 3), 5.14 (m, 2), 5.72 (ddt, 1, J=16.5, 10.6, 6.3), 7.06 (d, 2, J=8.9), 7.98 (d, 2, J=8.9); 1 C NMR (100 MHz, CDC13) δ 35.3, 38.3, 51.9, 52.5, 117.8, 120.9, 124.6, 130.9, 132.9, 150.4, 160.8, 166.4; IR 1719, 1655, 1606 cm"'; Anal calcd for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.37; H, 6.81 ; N, 10.39. Example 133C N-allyl-N'-[4-(hvdroxymethyl)phenyl]-N,N'-dimethylurea The product from Example 133B (3.75 g, 14.3 mmol) in 50 mL of diethyl ether was cooled to 0 °C and treated with lithium aluminum hydride (595 mg, 15.7 mmol). After 3 hours at 0 °C, the cooling bath was removed and stirring continued for an additional 2 hours. The reaction mixture was quenched by the successive addition of 0.6 mL of water, 0.6 mL of 2N NaOH, and 1.8 mL of water The mixture was partitioned between IN HCl and diethyl ether and the phases were separated. The organic phase was washed with water and concentrated in vacuo to give 1.6 g (48%) of the title compound, which was used without further purification. Η NMR (400 MHz, CDC13) δ 2.55 (s, 3), 3.20 (s, 3), 3.75 (d, 2, J=6.3), 4.68 (s, 3), 5.10 (m, 2), 5.64 (ddt, 1, J=16.5, 10.6, 6.3), 7.08 (d, 2, J=8.5), 7.34 (d, 2, J=8.5).
Example 133D N-allyl-N'-[4-(bromomethyl)phenvH-N,N'-dimethylurea The product from Example 133C (647 mg, 2.76 mmol) in 30 mL of CC14 was cooled to 0 °C and treated with pyridine (110 μL, 1.36 mmol) and then PBr3 (520 μL, 5.53 mmol). After 20 minutes, the cooling bath was removed and the reaction mixture was allowed to stir for 10 minutes at ambient temperature. The white mixture was partitioned between methylene chloride and water and the phases were separated. The organic phase was washed with water and concentrated in vacuo to provide 800 mg of the title compound as a colorless oil, which was used without further purification. Η NMR (400 MHz, CDC13) δ 2.55 (s, 3), 3.18 (s, 3), 3.75 (d, 2, J=5.9), 4.40 (s, 2), 5.10 (m, 2), 5.64 (m, 1), 7.11 (d, 2, J=8.5), 7.35 (d, 2, J=8.1).
Example 133E
3-(trans-l,4-dimethoxycyclohexyl)-5-fluorophenol The title compound was prepared using the procedure described in US 5,407,959. Example 133F N-allyl-N'-('4- { |"3 -(trans- 1 ,4-dimethoxycvclohexyl)-5 -fluorophenoxylmethyl } phenyl)-N.N'- dimethylurea Sodium hydride (18 mg, 0.45 mmol) in 0.5 mL of DMF was treated with the product from Example 133E (50 mg, 0.20 mmol) in 0.5 mL of DMF. After stirring for 2 hours at ambient temperature, the product from Example 133D (57 mg, 0.19 mmol) in 1 mL of DMF was added to the reaction mixture. After 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water and the phases separated. The organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (99:1 CHCl3:MeOH) to provide 61 mg (68%) of the title compound as a clear oil. Η NMR (400 MHz, CDC13) δ 1.81 (m, 6), 1.95 (m, 2), 2.56 (s, 3), 2.98 (s, 3), 3.21 (s, 3), 3.32 (s, 3), 3.50 (m, 1), 3.75 (m, 2), 5.0 (m, 2), 5.10 (m, 2), 5.64 (m, 1), 6.57 (dt, 1, J=10.4, 2.2), 6.75 (ddd, 1, J=10.0, 2.4, 1.2), 6.84 (m, 1), 7.06 (d, 1, J=8.4), 7.10 (d, 2, J=8.4), 7.30 (d, 1, J=8.4), 7.38 (d, 2, J=8.4); l3C NMR (100 MHz, CDC13) δ 25.1, 29.4, 35.5, 39.6, 52.7, 55.6, 69.8, 74.2, 100.8 (d), 105.9 (d), 108.7 (d), 117.4, 123.8, 128.7, 132.4, 133.4, 146.7, 149.3, 159.8 (d), 162.0 (d), 164.8.
Example 134 N-(4-{[3-(trans-L4-dimethoxycyclohexyl)-5-fluorophenoxylmethyl}phenyl)-N'.N'-diethyl-N- methylurea
The product from Example 133E (90 mg, 0.35 mmol) in 1 mL of DMF was treated with sodium hydride (22 mg, 0.92 mmol) and then the product from Example 123D (120 mg, 0.40 mmol) in 1 mL of DMF via cannula. The resultant brown slurry was stirred at ambient temperature for 2 hours and then partitioned between diethyl ether and water. The phases were separated and the organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (98:2 CHCl3:MeOH) to provide 87 mg (84%) of the title compound. *H NMR (400 MHz, CDC13) δ 0.95 (t, 6, J=7.1), 1.8 (m, 6), 1.95 (m, 2), 3.12 (q, 4, J=7.1), 3.16 (s, 3), 3.32 (s, 3), 3.50 (m, 1), 5.00 (s, 2), 6.57 (dt, 1, J=10.2, 2.2), 6.75 (dt, 1, J=10.2, 1.7), 6.84 (br s, 1), 7.10 (d, 2, J=8.5), 7.38 (d, 2, J=8.5); 13C NMR (100 MHz, CDC13) δ 12.9, 25.1, 29.4, 39.7, 42.0, 50.1, 55.7, 65.8, 69.8, 74.2, 101.0 (d), 105.9 (d), 108.8 (d), 123.7, 128.7, 132.3, 147.2, 149.3 (d), 159.8 (d), 161.8 (d), 165.3; IR 2933, 1651, 1613, 1587, 1432 cm 1; Anal calcd for C27H37FN2O4F: C, 68.62; H, 7.89; N, 5.93. Found: C, 68.38; H, 7.90; N, 5.88.
Example 135 N-C4- { l~3 -fluoro-5-(4-moφholinyl)phenoxy"|methyl } phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide The product from Example 15D (125 mg, 0.30 mmol) in 1.5 mL of degassed toluene was treated with Pd(dba)2 (19 mg, 0.033 mmol), BINAP (59 mg, 0.095 mmol), moφholine (50 μL, 0.46 mmol) and sodium tert-butoxide (72 mg, 0.75 mmol). The mixture was heated to 60 °C for 18 hours and then cooled and partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (99:1 CHCl3:MeOH) to provide 86 mg (67%) of the title compound. Η NMR (400 MHz, CDC13) δ 1.23 (d, 3,
J=6.4), 1.34 (m, 1), 1.55-1.65 (m, 2), 2.0 (m, 1), 2.62 (m, 1), 3.07 (m, 1), 3.13 (m, 4), 3.22 (s, 3), 3.82 (m, 4), 3.97 (m, 1), 4.97 (s, 2), 6.20 (m, 2), 6.30 (m, 1), 7.12 (d, 2, J=8.0), 7.35 (d, 2, J=8.0); 13C NMR (100 MHz, CDC13) δ 20.0, 24.8, 33.3, 39.0, 48.7, 49.1, 54.0, 66.6, 69.8, 93.3 (d), 95.5 (d), 98.2 (d), 124.5, 128.6, 132.3, 146.4, 153.1 (d), 159.5, 161.4 (d), 165.6; IR 2964, 1627, 1585 cm 1; Anal calcd for C24H30FN3O3: C, 67.43; H, 7.07; N, 9.83. Found: C, 67.81; H, 7.33; N, 9.47.
Example 136 (- N-(4- { |"3-fluoro-5 -(4-moφholinyl)phenoxy]methyl } phenyl)-N.2-dimethyl- 1 - pyrrolidinecarboxamide
The enantiomers from Example 135 were separated by chiral HPLC (Daicel OJ column, 90:10 hexanes: EtOH). [α]23 D -177° (c 0.09, CH2C12); Η NMR (400 MHz, CDC13) δ 1.23 (d, 3, J=6.4), 1.34 (m, 1), 1.55-1.65 (m, 2), 2.0 (m, 1), 2.62 (m, 1), 3.07 (m, 1), 3.13 (m, 4), 3.22 (s, 3), 3.82 (m, 4), 3.97 (m, 1), 4.97 (s, 2), 6.20 (m, 2), 6.30 (m, 1), 7.12 (d, 2, J=8.0), 7.35 (d, 2, J=8.0); ,3C NMR (100 MHz, CDC13) δ 20.0, 24.8, 33.3, 39.0, 48.7, 49.1, 54.0, 66.6, 69.8, 93.3 (d), 95.5 (d), 98.2 (d), 124.5, 128.6, 132.3, 146.4, 153.1 (d), 159.5, 161.4 (d), 165.6; IR 2964, 1627, 1585 cm 1.
Example 137
(2RVN-(4- { T3 -fluoro-5-(4-morpholinyl)phenoxy]methyl ) phenyl)-N.2-dimethyl- 1 - pyrrolidinecarboxamide The enantiomers from Example 135 were separated by chiral HPLC (Daicel OJ column, 90:10 hexanes:EtOH). [α]23 D +199° (c 0.13, CH2C12); 'H NMR (400 MHz, CDC13) δ 1.23 (d, 3, J=6.4), 1.34 (m, 1), 1.55-1.65 (m, 2), 2.0 (m, 1), 2.62 (m, 1), 3.07 (m, 1), 3.13 (m, 4), 3.22 (s, 3), 3.82 (m, 4), 3.97 (m, 1), 4.97 (s, 2), 6.20 (m, 2), 6.30 (m, 1), 7.12 (d, 2, J=8.0), 7.35 (d, 2, J=8.0); 13C NMR (100 MHz, CDC13) δ 20.0, 24.8, 33.3, 39.0, 48.7, 49.1, 54.0, 66.6, 69.8, 93.3 (d), 95.5 (d), 98.2 (d), 124.5, 128.6, 132.3, 146.4, 153.1 (d), 159.5, 161.4 (d), 165.6; IR 2964, 1627, 1585 cm 1.
Example 138 N.N-diethyl-N'-(4-(r3-fluoro-5-('4-moφholinyl')phenoxylmethyl}phenyl)-N'-methylurea The product from Example IE (101 mg, 0.25 mmol), Pd(dba)2 (14 mg, 0.024 mmol), BINAP (47 mg, 0.076 mmol), moφholine (40 μL, 0.36 mmol), and sodium tert-butoxide (60 mg, 0.63 mmol) were processed as described in Example IF. The crude material was purified by column chromatography (99:1 CHCl3:MeOH) to provide 103 mg (100%) of the title compound. Η NMR (400 MHz, CDC13) δ 0.95 (t, 6, J= 7.0), 3.10 (m, 8), 3.16 (s, 3), 3.80 (m, 4), 4.97 (s, 2), 6.22 (tt, 2, J=10.2, 2.1), 6.28 (m, 1), 7.08 (m, 2, J=8.4), 7.36 (d, 2, J=8.4); 13C NMR (100 MHz, CDC13) δ 12.9, 39.6, 42.0, 48.7, 66.6, 69.7, 93.3 (d), 95.5 (d), 98.2 (d), 123.6, 128.6, 132.4, 147.2, 153.1 (d), 160.5 (d), 162.4 (d), 165.6; IR 2967, 1646, 1585 cm"1.
Example 139 N-(4- { [3 -fluoro-5 -f 2-methyl-3 -oxo- 1 -piperazinvDphenoxylmethyl I phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide The product from Example 15D and 3-methyl-2-piperazinone were processed as described in Example 15E to provide the title compound as a yellow oil. MS (APCI+) m/z 455 (M+H)+.
Example 140 + N- 4-({[6-(4-hvdroxytetrahvdro-2H-pyran-4-yl)-2-pyridinylloxy}methyl phenyll-N.2- dimethyl- 1 -pyrrolidinecarboxamide
Example 140 A 4-(6-bromo-2-pyridinv0tetrahvdro-2H-pyran-4-ol n-Butyllithium (3.55 mL, 8.9 mmol) in 15 mL of THF was cooled to -78 °C and treated dropwise with 2,6-dibromopyridine (2.0 g, 8.4 mmol) in 10 mL of THF. After 10 minutes, the reaction mixture was treated with tetrahydro-4H-pyran-4-one (1 mL, 10.8 mmol) dropwise. After 2 hours at -78 °C, the mixture was warmed to 0 °C for 2 hours and then partitioned between ethyl acetate and water. The phases were separated and the organic phase was concentrated in vacuo. The crude material was crystallized from 10 mL of ethyl acetate to provide 1.3 grams (60%) of the title compound as white crystals. !H NMR (400 MHz, CDC13) δ 1.60 (br d, 2, J=13.5), 2.12 (m, 2), 3.96 (m, 4), 4.22 (s, 1), 7.35 (dd, 1 , J=7.8, 0.7), 7.42 (dd, 1, J=7.8, 0.7), 7.60 (t, 1, J=7.8); 13C NMR (75 Hz, CDC13) δ 38.2, 63.9, 70.5, 117.7, 126.6, 139.5, 140.7, 166.4; IR 3371, 1580, 1548 cm 1; Anal calcd for C10H,2BrNO2: C, 46.53; H, 4.69; N, 5.43; found: C, 46.89; H, 4.63; N, 4.20.
Example 140B (+) N-r4-({r6-(4-hvdroxytetrahydro-2H-pyran-4-yl)-2-pyridinylloxy|methyl)phenyl1-N.2- dimethyl- 1 -pyrrolidinecarboxamide
The product from Example 140A (98 mg, 0.38 mmol) in 1 mL of DMF at 0 °C was treated in succession with sodium hydride (34 mg, 1.4 mmol) and the product from Example 15C (103 mg, 0.42 mmol) in 1 mL of DMF via cannula. The cooling bath was removed and the mixture was warmed to 65 °C for 16 hours. The mixture was allowed to cool to ambient temperature and then partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with water and concentrated in vacuo. The crude material was purified by column chromatography (200: 1 CHCl3:MeOH) to provide 98 mg (60%) of the racemate. The enantiomers were separated by chiral HPLC (Daicel OJ column, 90:10 hexanes:EtOH). [α]23 D +131° (c 0.4, CH2C12); Η NMR (400 MHz, CDC13) δ 1.24 (d, 3,
J=6.4), 1.32 (m, 1), 1.56 (m, 2), 1.6-1.7 (m, 2), 2.00 (m, 2), 2.14 (dt, 2, J=12.2, 5.5), 2.62 (m, 1), 3.06 (m, 1), 3.22 (s, 3), 3.90 (m, 4), 4.44 (s, 1), 5.36 (s, 2), 6.74 (d, 1, J=8.1), 6.98 (d, 1, J=7.6), 7.12 (d, 2, J=8.4), 7.39 (d, 2, J=8.4), 7.65 (dd, 1, J= 7.6, 8.1); 13C NMR (100 MHz, CDC13) δ 20.0, 24.8, 29.6, 33.3, 38.4, 49.1, 54.0, 64.1, 67.3, 70.4, 109.5, 111.4, 124.5, 128.7, 133.0, 140.0, 146.2, 159.6, 162.3, 162.5; IR 3403, 2960, 1623, 1609, 1578 cm 1; HRMS calcd for C24H31N3O4 425.2315; found 425.2308.
Example 141 (-) N-r4-({r6-(4-hvdroxytetrahydro-2H-pyran-4-vπ-2-pyridinylloxy}methyl')phenyl1-N.2- dimethyl- 1 -pyrrolidinecarboxamide
The title compound was isolated from the chiral chromatography described in Example 140B. [α]23 D -121° (c 0.35, CH2C12); Η NMR (400 MHz, CDC13) δ 1.24 (d, 3, J=6.4), 1.32 (m, 1), 1.56 (m, 2), 1.6-1.7 (m, 2), 2.00 (m, 2), 2.14 (dt, 2, J=12.2, 5.5), 2.62 (m, 1), 3.06 (m, 1), 3.22 (s, 3), 3.90 (m, 4), 4.44 (s, 1), 5.36 (s, 2), 6.74 (d, 1, J=8.1), 6.98 (d, 1, J=7.6), 7.12 (d, 2, J=8.4), 7.39 (d, 2, J=8.4), 7.65 (dd, 1, J=7.6, 8.1); 13C NMR (100 MHz,
CDC13) δ 20.0, 24.8, 29.6, 33.3, 38.4, 49.1, 54.0, 64.1, 67.3, 70.4, 109.5, 111.4, 124.5, 128.7, 133.0, 140.0, 146.2, 159.6, 162.3, 162.5; IR 3403, 2960, 1623, 1609, 1578 cm 1.
Example 143 N.N-diethyl-N'- -C ( r6-(4-hvdroxytetrahvdro-2H-pyran-4-vn-2- pyridinylloxy}methyl)phenyl1-N'-methylurea The product from Example 140A (261 mg, 1.0 mmol), the product from Example ID (227 mg, 0.95 mmol), and sodium hydride (80 mg, 3.33 mmol) were processed as described in Example 140B. The resultant crude material was purified by column chromatography (99:1 CHCl3:MeOH) to afford 220 mg (55%) of the title compound as a clear oil. Η NMR (400 MHz, CDC13) δ 0.94 (t, 6, J=7.2), 1.58 (d, 2, J=12.3), 2.10 (dt, 2, J=12.7, 5.5), 3.11 (q, 4, J=7.2), 3.16 (s, 3), 3.90 (m, 4), 4.40 (s, 1), 5.35 (s, 3), 6.72 (d, 1, J=8.1), 6.97 (d, 1, J=7.2), 7.08 (d, 2, J=8.5), 7.40 (d, 2, J=8.5), 7.64 (t, 1, J=7.8); 13C NMR (100 MHz, CDC13) δ 12.9, 38.5, 39.6, 42.0, 64.1, 67.3, 70.4, 109.6, 111.4, 123.6, 128.9, 133.0, 140.0, 147.0, 161.6, 162.3, 162.5; IR 3407, 2962, 1647, 1625 cm 1; HRMS calcd for C23H31N3O4, 413.2315. Found 413.2314.
Examples 144-150 Examples 144 to 150 were prepared using the following procedure.
The product from Example 30F (659 mg, 1.48 mmol) in 5 mL of dry dioxane was treated with 4M HCl in dioxane (15 mL). After stirring for 1 hour at ambient temperature, the solvent was removed in vacuo and the resultant yellow oil residue was dried under vacuum at ambient temperature for 16 hours. The crude hydrochloride salt was suspended in 10 mL of dry toluene, treated with triethylamine (4.04 mL, 29.0 mmol), stirred for 30 minutes at ambient temperature, and then filtered. The resulting clear yellow solution was transferred to eleven 20-mL screw-cap vials and cooled to 0 °C. The acid chlorides were added in excess (about 10 equivalents) and the resulting turbid yellow to dark yellow mixtures were stirred at 0 °C for 30 minutes and then allowed to warm up slowly to ambient temperature and stirred at ambient temperature for additional 5 hours. N,N-Diethylethylenediamine (0.387 mL, 2.69 mmol) was added to each vial and the mixtures were stirred at ambient temperature for 12 hours. The mixtures were each partitioned between 5% aqueous NH4C1 and ethyl acetate. Each organic layer was separated, washed with 5% aqueous NH4C1, saturated aqueous NaHCO3, filtered through a silica gel sep-pak cartridge (Alltech 209150) and concentrated in vacuo to provide the crude product as yellow to dark yellow oils. The crude materials were purified by preparative HPLC (Waters Nova-Pak® HR C18 6 μm 60 D 25x100 mm, 50-95% MeCN/10 mM NH4OAc over 10 min at 40 mL/min). Example 144 N-('4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl|phenyl)-N.3.3- trimethylbutanamide The title compound was isolated as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.93 (s, 9), 1.90-2.01 (m, 4), 2.09 (br s, 2), 2.97 (s, 3), 3.24 (br s, 3), 3.74-3.87 (m, 4), 5.16 (s, 2), 6.72 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.87 (m, 1), 7.27 (d, 2, J=8.3), 7.55 (d, 2, J=8.3); MS (APCI+) m/z 444 (M+H)+.
Example 145 2-ethyl-N-('4-{[3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl')phenoxylmethyl}phenyl)-N- methylbutanamide The title compound was isolated as a yellow solid. ]H NMR (500 MHz, CD3OD) δ 0.80 (t, 6, J=7.5), 1.37 (m, 2), 1.56 (m, 2), 1.89-2.01 (m, 4), 2.21 (m, 1), 2.97 (s, 3), 3.26 (s, 3), 3.73-3.87 (m, 4), 5.17 (s, 2), 6.74 (m, 2), 6.87 (m, 1), 7.28 (d, 2, J=8.3), 7.57 (d, 2, J=8.3); MS (APCI+) m/z 444 (M+H)+.
Example 146 N-(4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxylmethyl}phenyl)-N.2.2- trimethylpropanamide The title compound was isolated as a light yellow oil. Η NMR (500 MHz, CD3OD) δ
1.04 (s, 9), 1.89-2.00 (m, 4), 2.97 (s, 3), 3.20 (s, 3), 3.73-3.87 (m, 4), 5.17 (s, 2), 6.72 (dt, 1, J=10.4, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.32 (d, 2, J=8.3), 7.53 (d, 2, J=8.7); MS (APCI+) m/z 430 (M+H)+.
Example 147
N-(4- { [3 -fluoro-5 -(4-methoxytetrahvdro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N- methylcvclopentanecarboxamide The title compound was isolated as a yellow oil. Η NMR (500 MHz, CD3OD) δ 1.42 (m, 2), 1.63 (m, 2), 1.71 (m, 4), 1.88-2.01 (m, 4), 2.60 (m, 1), 2.97 (s, 3), 3.24 (br s, 3), 3.73- 3.87 (m, 4), 5.16 (s, 2), 6.74 (m, 2), 6.86 (m, 1), 7.30 (d, 2, J= 8.0), 7.56 (d, 2, J=8.0); MS (APCI+) m/z 442 (M+H)+.
Example 148 N-("4-{r3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-vπphenoxy]methylφhenvπ-N- methylcvclopropanecarboxamide The title compound was isolated as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.67 (br d, 2, J= 4.1), 0.92 (m, 2), 1.42 (m, 1), 1.89-2.00 (m, 4), 2.96 (s, 3), 3.27 (br s, 3), 3.73-3.86 (m, 4), 5.16 (s, 2), 6.72 (dt, 1, J=10.5, 2.3), 6.75 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.38 (d, 2, J=8.3), 7.57 (d, 2, J=8.3); MS (APCI+) m/z 414 (M+H)+.
Example 149 N-(4-([3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-vπphenoxy1methyl>phenvπ-N.2- dimethylpropanamide The title compound was isolated as a yellow solid. 'H NMR (500 MHz, CD3OD) δ
1.00 (d, 6, J=7.0), 1.90-2.01 (m, 4), 2.53 (m, 1), 2.97 (s, 3), 3.23 (s, 3), 3.73-3.87 (m, 4), 5.17 (s, 2), 6.73 (dt, 1, J=10.5, 2.3), 6.76 (ddd, 1, J=10.1, 2.3, 1.5), 6.86 (m, 1), 7.31 (d, 2, J=8.1), 7.57 (d, 2, J=8.1); MS (APCI+) m/z 416 (M+H)+.
Example 150
N-(4-{|"3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4-yl phenoxy1methyl}phenyl")-N-methyl-
2-furamide The title compound was isolated as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 1.91-2.02 (m, 4), 2.98 (s, 3), 3.42 (s, 3), 3.74-3.87 (m, 4), 5.17 (s, 2), 5.98 (br d, 1, J=3.6), 6.30 (dd, 1, J=3.6, 1.7), 6.71 (dt, 1, J=10.5, 2.3), 6.77 (ddd, 1, J=10.1, 2.3, 1.5), 6.88 (m, 1), 7.30 (d, 2, J=8.6), 7.44 (dd, 1, J=1.7, 0.7), 7.54 (d, 2, J=8.6); MS (APCI+) m/z 440 (M+H)+.
Examples 151 and 152 Examples 151 and 152 were prepared using the following procedure. The product from Example 30F (606 mg, 1.36 mmol) in 5 mL of dry dioxane was treated with 4M HCl in dioxane (15 mL). After stirring for 1 hour at ambient temperature, the solvent was removed in vacuo and the resultant yellow oil residue was dried under vacuum at ambient temperature for 16 hours. The crude hydrochloride salt was suspended in 10 mL of dry toluene, treated with triethylamine (3.80 mL, 27.6 mmol), stirred for 30 minutes at ambient temperature, and then filtered. The resulting clear yellow solution was transferred to ten 20-mL screw-cap vials. Chloroformates were added in excess (about 10 equivalents) and the mixtures were stirred at ambient temperature for 24 hours. N,N-Diethylethylenediamine (0.387 mL, 2.69 mmol) was added to each vial and the mixtures were stirred at ambient temperature for 4 hours. The mixtures were each partitioned between 5% aqueous NH4C1 and EtOAc. Each organic layer was separated, washed with 5% aqueous NH4C1, saturated aqueous NaHCO3, filtered through a silica gel sep-pak cartridge (Alltech 209150), and concentrated in vacuo to provide the crude materials as yellow to dark yellow oils. The crude materials were purified by preparative HPLC (Waters Nova-Pak® HR C 18 6 μm 60 D 25x100 mm, 50-95% MeCN/10 mM NH4OAc over 10 min at 40 mL/min).
Example 151 isopropyl 4-( |"3-fluoro-5-(4-methoxytetrahvdro-2H-pyran-4- yl)phenoxy]methyl I phenyldnethvDcarbamate
The title compound was isolated as a light yellow oil. ■H NMR (500 MHz, CD3OD) δ 1.22 (d, 6, J=6.3), 1.90-2.01 (m, 4), 2.96 (s, 3), 3.27 (s, 3), 3.74-3.87 (m, 4), 4.91 (hept, 1, J=6.3), 5.11 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.28 (d, 2, J=8.4), 7.45 (d, 2, J=8.4); MS (APCI+) m/z 432 (M+H)+.
Example 152 propyl 4- { r3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenylfmethvPcarbamate The title compound was isolated as a light yellow oil. Η NMR (500 MHz, CD3OD) δ 0.90 (t, 3, J= 7.3), 1.61 (m, 2), 1.90-2.01 (m, 4), 2.96 (s, 3), 3.28 (s, 3), 3.74-3.86 (m, 4), 4.05 (t, 2, J=6.5), 5.11 (s, 2), 6.70 (dt, 1, J=10.5, 2.3), 6.74 (ddd, 1, J=10.1, 2.3, 1.5), 6.85 (m, 1), 7.29 (d, 2, J=8.6), 7.46 (d, 2, J=8.6).
Example 153 tert-butyl 4- { 3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y Dphenoxylmethyl I phenvKmethyQcarbamate The title compound was prepared according to the procedures described in Example 30. 'H NMR (300 MHz, CDC13) δ 1.46 (s, 9), 1.88-2.03 (m, 4), 2.91 (s, 3), 3.27 (s, 3), 3.80- 3.85 (m, 4), 5.02 (s, 2), 6.61 (d, 1, J=10), 6.72 (d, 1, J=10), 6.81 (s, 1), 7.27 (app d, 2), 7.39 (d, 2, J=8.5 Hz); MS (APCI+) m/z 446 (M+H)+.

Claims

WE CLAIM:
1. A method of inhibiting interleukin 5 gene expression in a mammal comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound selected from the group of those falling within formula I
Figure imgf000142_0001
I and formula II
Figure imgf000142_0002
II, or mixtures thereof as well as their pharmaceutically acceptable salts wherein, in formulas I and II,
R, is selected from the group consisting of hydrogen and lower alkyl;
R2 is selected from the group consisting of hydrogen and lower alkyl;
R3 is selected from the group consisting of hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR5R,; wherein R5 and R^ are independently selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NRsR^ A is selected from the group consisting of alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR7R8 wherein R7 and R8 are independently selected from the group consisting of alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl;
B is selected from the group consisting of cyclohexyl, heterocycle and NR_3R,0 wherein Rg and R10 are independently selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
2. The method according to claim 1 wherein the compound is selected from the group of those falling within formula I and
R, is lower alkyl; R3 is selected from the group consisting of hydrogen and halogen;
R4 is selected from the group consisting of hydrogen and halogen;
A is heterocycle;
B is heterocycle;
X is selected from the group consisting of CH2 and O; and Y is selected from the group consisting of CH and N.
3. The method according to claim 1 wherein the compound is selected from the group of those falling within formula I and
R, is methyl; R3 is selected from the group consisting of hydrogen and fluorine;
R4 is selected from the group consisting of hydrogen and chlorine;
A is selected from the group consisting of azepanyl, azetidinyl, azocanyl, furyl, piperdinyl, pyrrolyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, tetrahydropyridyl, thiazolidinyl, and thiomoφholinyl;
B is selected from the group consisting of moφholinyl, piperazinyl, piperdinyl, pyrrolidinyl, tetrahydro-2H-pyranyl, and thiomoφholinyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
4. The method according to claim 3 wherein the compound is selected from the group consisting of ethyl 4-{3-fluoro-5-[(4-{methyl[(2-methyl-l- pyrrolidinyl)carbony 1] amino } benzyl)oxy]phenyl } - 1 -piperazinecarboxylate, N-(4-{ [3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-thiomoφholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-hydroxy-l-piperidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -(4-acetyl- 1 -piperazinyl)-5-fluorophenoxy]methyl } pheny l)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5 -( 1 -piperidiny l)phenoxy] methyl } pheny l)-N,2-dimethy 1- 1 - pyrrolidinecarboxamide, N-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l-piperazinyl]phenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methyl-l-piperidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide, N-(4- { [3-fluoro-5-( 1 -pyrrolidinyl)phenoxy]methyl } phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4-{[3-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(4-hydroxy-4-phenyl-l-piperidinyl)phenoxy]methyl}phenyl)-N,2- dimethy 1- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(3-hydroxy-l-pyrrolidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N- [4-( { 3 -fluoro-5 - [4-(2-methoxy ethyl)- 1 -piperazinyljphenoxy } methy l)pheny 1] -N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azocanecarboxamide,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy]methy 1 } pheny l)-3 - hydroxy-N-methyl- 1 -pyrrolidinecarboxamide, N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,5-trimethyl- 1 -pyrrolidinecarboxamide,
(3R)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-3-hydroxy-N-methyl-l-pyrrolidinecarboxamide,
3-ethyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl} phenyl)-N,2,4-trimethyl- 1 -pyrrolidinecarboxamide, N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-
N,2,5-trimethyl-2,5-dihydro- 1 H-pyrrole- 1 -carboxamide,
N-(4-{2-[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]ethyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 H-pyrrole- 1 -carboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}pheny1)-N- methyl-2,5-dihydro- 1 H-pyrrole- 1 -carboxamide, N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-3-
(hydroxymethy l)-N-methyl- 1 -piperidinecarboxamide,
N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}pheny1)-N- methyl-l,3-thiazolidine-3-carboxamide,
N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-4- (hydroxymethyl)-N-methyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-3- hydroxy-N-methyl- 1 -piperidinecarboxamide,
N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-4- hydroxy-N-methyl- 1 -piperidinecarboxamide, N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}pheny1)-N- methyl-4-thiomoφholinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}pheny1)- N,2-dimethy 1- 1 -piperidinecarboxamide,
N-(4- { [3 -fluoro- 5 -(4-methoxytetrahy dro-2H-pyran- 4-yl)phenoxy]methyl}pheny1)-N- methyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-N- methyl-3 ,6-dihydro- 1 (2H)-pyridinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}pheny1)-N- methyl- 1 -azepanecarboxamide, N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran- ■4-yl)phenoxy]methyl}phenyl)-4-
(2-hydroxyethyl)-N-methyl- 1 -piperidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- ■4-yl)phenoxy]methyl}pheny1)-N- methyl- 1 -azetidinecarboxamide, (2R)-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-2-(hydroxymethyl)-N-methyl-l -pyrrolidinecarboxamide,
(2S)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-2-(hydroxymethyl)-N-methyl-l-py__τolidinecarboxamide, N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N ' -methyl- 1 ,3 -piperidinedicarboxamide,
N-(4- { [3 -fluoro-5-(4-hydroxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N- {4-[(3 -fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl } -N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
(-) N-(4- { [3 -fluoro-5 -(4-moφholinyl)phenoxy]methyl } pheny l)-N,2-dimethyl- 1 - pyrrolidinecarboxamide, (+) N-(4-{ [3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l - pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-(2-methyl-3 -oxo- 1 -piperazinyl)phenoxy]methyl} phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
(+) N-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy}methyl)phenyl]- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
(-) N-[4-( { [6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy } methy l)phenyl]- N,2-dimethyl-l -pyrrolidinecarboxamide, and
N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl }phenyl)-N- methyl-2-furamide.
5. The method according to claim 1 wherein the compound is selected from those falling within formula I and
R, is lower alkyl;
R3 is selected from the group consisting of hydrogen and halogen; R4 is selected from the group consisting of hydrogen and halogen;
A is NR7Rg wherein R7 and R8 are independently selected from the group consisting of alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl;
B is selected from the group consisting of cycloalkyl and heterocycle;
X is selected from the group cosisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
6. The method according to claim 1 wherein the compound is selected from those falling within formula I and R, is methyl;
R3 is selected from the group consisting of hydrogen and fluorine; R4 is selected from the group consisting of hydrogen and chlorine; A is NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, 2-(4-hydroxyphenyl)ethyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, 2-(l,3-dioxolan-2-yl)ethyl, tetrahydro-2- furanylmethyl, hydroxyalkoxyalkyl, and hydroxyalkyl;
B is selected from the group consisting of cyclohexyl, moφholinyl, piperazinyl, piperdinyl, tetrahydo-2H-pyranyl, pyrrolidinyl, and thiomoφholinyl; X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
7. The method according to claim 6 wherein the compound is selected from the group consisting of: ethyl 4-[3-({4-[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)-5-fluorophenyl]- 1 -piperazinecarboxylate,
N-(4-{[3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N',N'- diethyl-N-methylurea, N,N-diethyl-N'-(4- { [3 -fluoro-5-(4-thiomoφholinyl)phenoxy]methyl } phenyl)-N'- methylurea,
N,N-diethyl-N'-(4- { [3 -fluoro-5-(4-hydroxy- 1 -piperidinyl)phenoxy]methyl } phenyl)- N'-methylurea, N-(4-{[3-(4-acetyl-l-piperazinyl)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(l-piperidinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l- piperaziny l]phenoxy } methyl)phenyl] -N'-methy lurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-methyl-l-piperidinyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(l-pyrrolidinyl)phenoxy]methyl}phenyl)-N'- methylurea, N,N-diethyl-N'-(4-{[3-fluoro-5-(2-methyl-3-oxo-l- piperaziny l)phenoxy]methy 1 } phenyl)-N'-methy lurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)- N,N',N'-trimethylurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahydro-2H-pyran-4-y l)phenoxy]methy 1 } pheny 1)- N,N'-dimethyl-N'-propylurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-y l)phenoxy]methy 1 } pheny 1)- N,N'-dimethylurea,
N-allyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methy 1 } pheny l)-N,N'-dimethy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
(2-hydroxyethyl)-N,N'-dimethylurea,
N-(3-chloro-4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,N',N'-trimethylurea, N-(cyclopropylmethyl)-N,-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy]methy 1 } pheny l)-N'-methyl-N-propy lurea,
N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-isopropyl-N'-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N,N'-dimethyl-N'-(2-propynyl)urea,
N-(2-cyanoethyl)-N-cyclopropyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-allyl-N-ethyl-N,-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)-N'- (2-methoxyethyl)-N,N'-dimethylurea,
N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N-(2-hydroxyethyl)-N'-methylurea, N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)-N'- isopentyl-N,N'-dimethylurea,
N-[2-(l,3-dioxolan-2-yl)ethyl]-N,-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N,N'-dimethylurea,
N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N,N'-dimethy lurea,
N,N-diallyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N',N'-dipropylurea, N-butyl-N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methy lurea,
N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methyl-N-propy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isopropyl-N,N'-dimethylurea,
N'-cyclobutyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy ]methyl } pheny l)-N-methy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(tetrahydro-2-furanylmethyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-methoxyethyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-propylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxy- 1 -methylethy l)-N-methy lurea,
N'-(l-ethylpropyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2,2,2-trifluoroethyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-neopentylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- isobutyl-N-methylurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy Jmethy 1 } pheny 1)-N- methyl-N'-(2-methylbutyl)urea,
N,-(2-ethylhexyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy Jmethy 1 } pheny l)-N-methy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-propynyl)urea,
N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } pheny 1)-N'- (2-hydroxybutyl)-N-methylurea, N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy Jmethy 1 } pheny 1)-N'- (3-hydroxy-2,2-dimethylpropyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'- [2-(2-hydroxyethoxy)ethylJ-N-methylurea, N'-allyl-N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'- (2-methoxy- 1 -methy lethy l)-N-methy lurea,
N'-(cyanomethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy Jmethy 1 } pheny l)-N-methy lurea,
N'-cyclopropyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy Jmethy 1 } pheny l)-N-methy lurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'- isopropyl-N-methyl-N'-propylurea, N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'-
[( 1 R)- 1 -(hydroxymethyl)propylj -N-methy lurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxyJmethyl } pheny 1)-N- methyl-N'-(2-methyl-2-propenyl)urea,
N,-(2-fluoroethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lurea,
N'-ethyl-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxyJmethyl } pheny l)-N-methy lurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxypropyl)-N-methylurea, N'-(cyclopropylmethyl)-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy Jmethy 1 } pheny l)-N-methy lurea,
N'-(2-ethylbutyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lurea, N'-cyclopentyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxyJmethy 1 } pheny l)-N-methy lurea,
N'-(l,2-dimethylρropyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy Jmethy 1 } phenyl)-N-methy lurea, N'-sec-butyl-N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N'-[bicyclo[2.2.1]hept-2-ylJ-N-(4-{[3-fluoro-5-(4-methoxytetrahychO-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'- [2-(4-hydroxyphenyl)ethylJ-N-methylurea,
N'-(2-cyanoethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy Jmethy 1 } pheny l)-N-methy lurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-hydroxyethyl)-N-methylurea, N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
[l-(hydroxymethyl)cyclopentylJ-N-methylurea,
N'-(2,2-dimethylcyclopentyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy Jmethy 1 } pheny l)-N-methy lurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'- isopropyl-N-methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxyJmethyl}phenyl)-N'-methylurea,
N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxyJmethyl}phenyl)-N-(2-methoxyethyl)-N'-methylurea, N-butyl-N-(cyanomethyl)-N'-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-butyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N,N'-dimethy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxyJmethyl}phenyl)-N'- isopropyl-N'-(2-methoxyethyl)-N-methylurea,
N,N-diethyl-N'-(4- { [3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4- y l)phenoxyJmethy 1 } phenyl)-N'-methy lurea, N-(4-{[3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-
N,N',N'-trimethylurea,
N- [4-( { 3 -fluoro-5 - [4-(2-propyny loxy)tetrahydro-2H-pyran-4- yl]phenoxy}methyl)phenyl]-N,N',N'-trimethylurea,
N,N-diethyl-N,-(4-{[3-(4-ethyltetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- methy lurea, ethyl 4-[3-({4- [[(diethylamino)carbonylJ(methyl)aminoJbenzyl}oxy)phenyl]tetrahydro-2H-pyran-4- carboxylate,
N,N-diethyl-N'-(4-{[3-fluoro-5-(l-hydroxycyclohexyl)phenoxy]methyl}phenyl)-N'- methylurea,
N,N-diethyl-N'-{4-[(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl}-N'- methylurea, tert-butyl 4-[3-( { 4- [ [(diethy lamino)carbonyl] (methy l)aminoJbenzyl} oxy)-5- fluorophenylJ-4-hydroxy- 1 -piperidinecarboxylate, N-allyl-N'-(4-{[3-(trans-l,4-dimethoxycyclohexyl)-5-fluorophenoxyJmethyl}phenyl)-
N,N'-dimethylurea,
N-(4-{[3-(trans-l,4-dimethoxycyclohexyl)-5-fluorophenoxy]methyl}phenyl)-N',N'- diethyl-N-methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-moφholinyl)phenoxyJmethyl}phenyl)-N'- methylurea, and
N,N-diethyl-N'-[4-( { [6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2- pyridinylJoxy}methyl)phenylJ-N'-methylurea.
8. The method according to claim 1 wherein the compound is selected from those falling within formula I and
R, is lower alkyl;
R3 is selected from the group consisting of hydrogen and halogen; R4 is selected from the group consisting of hydrogen and halogen;
A is heterocycle;
B is NR^RJO wherein R, and R10 are independently selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl; X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
9. The method according to claim 1 wherein the compound is selected from those falling within formula I and R, is methyl;
R3 is selected from the group consisting of hydrogen and fluorine;
R4 is selected from the group consisting of hydrogen and chlorine;
A is pyrrolidinyl;
B is NRgR,,, wherein R<, and R10 are independently selected from the group consisting of hydrogen, alkoxyalkyl, and alkyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
10. The method according to claim 9 wherein the compound is selected from the group consisting of
N-[4-({3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl-1 -pyrrolidinecarboxamide and
N-[4-({3-[ethyl(2-methoxyethyl)aminoJ-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide.
11. The method according to claim 1 wherein the compound is selected from those falling within formula I and
R, is lower alkyl; R3 is selected from the group consisting of hydrogen and halogen; _4 is selected from the group consisting of hydrogen and halogen;
A is NR7R8 wherein R7 and R8 are independently selected from hydrogen, alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl; B is NRgR,,, wherein R, and R10 are independently selected from alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
12. The method according to claim 1 wherein the compound is selected from those falling within formula I and
R, is methyl;
R3 is selected from the group consisting of hydrogen and fluorine; R4 is selected from the group consisting of hydrogen and chlorine;
A is NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen and alkyl;
B is NRgRn, wherein R<, and R10 are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, and cycloalkyl; X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
13. The method according to claim 12 wherein the compound is selected from the group consisting of N-[4-({3-[bis(2-methoxyethyl)aminoJ-5-fluorophenoxy}methyl)phenylJ-N',N'- diethyl-N-methylurea,
N-(4-{[3-(cyclopentylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea, N-(4- { [3-(cyclohexylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea, and
N,N-diethyl-N'-[4-({3-[ethyl(2-methoxyethyl)amino]-5- fluorophenoxy } methy l)pheny 1] -N'-methy lurea.
14. The method according to claim 1 wherein the compound is selected from the group falling within formula I and
R, is lower alkyl;
R3 is selected from the group consisting of hydrogen and halogen;
R_4 is selected from the group consisting of hydrogen and halogen; A is selected from the group consisting of alkoxy, alkyl, and cycloalkyl;
B is heterocycle;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
15. The method according to claim 1 wherein the compound is selected from the group of those falling within formula I and
Rj is methyl;
R3 is selected from the group consisting of hydrogen and fluorine;
R4 is selected from the group consisting of hydrogen and chlorine; A is selected from the group consisting of alkoxy, alkyl, and cycloalkyl;
B is tetrahydro-2H-pyranyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
16. The method according to claim 15 wherein the compound is selected from the group consisting of
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,3 , 3 -trimethy lbutanamide, 2-ethyl-N-(4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methy 1 } pheny l)-N-methy lbutanamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,2-trimethylpropanamide,
N-(4- { [3 -fluoro-5 -(4-methoxy tetrahy dro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N- methylcyclopentanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopropanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethylpropanamide, isopropy 14- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl(methyl)carbamate, propyl 4-{ [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy]methy 1 } pheny l(methyl)carbamate, and tert-butyl 4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl(methyl)carbamate.
17. The method according to claim 1 wherein the compound is selected from those falling within formula II and
R, is lower alkyl; R2 is lower alkyl;
R3 is selected from the group consisting of hydrogen and halogen; R4 is selected from the group consisting of hydrogen and halogen; B is selected from the group consisting of cycloalkyl and heterocycle; X is selected from the group consisting of CH2 and O; and Y is selected from the group consisting of CH and N.
18. The method according to claim 1 wherein the compound is selected from those falling within formula II and R, is methyl;
R2 is methyl;
R3 is selected from the group consisting of hydrogen and fluorine; R4 is selected from the group consisting of hydrogen and chlorine; B is selected from the group consisting of cyclohexyl, piperdinyl, and tetrahydro-2H- pyranyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
19. The method according to claim 18 wherein the compound is selected from the gorup consisting of
5- { [3 -( 1 -benzyl-4-hydroxy-4-piperidinyl)-5-fluorophenoxy]methyl } - 1 ,3 -dimethyl- 1 ,3-dihydro-2H-benzimidazol-2-one,
5-{ [3-(trans- 1 ,4-dimethoxycyclohexyl)-5-fluorophenoxy]methyl } - 1 ,3-dimethyl- 1,3- dihydro-2H-benzimidazol-2-one, 5-{[3-fluoro-5-(8-hydroxy-l,4-dioxaspiro[4.5]dec-8-yl)phenoxy]methyl}-l,3- dimethyl-1 ,3-dihydro-2H-benzimidazol-2-one, and
5- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl} - 1 ,3-dimethyl- l,3-dihydro-2H-benzimidazol-2-one.
20. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds selected from the group of those falling within formula I
Figure imgf000160_0001
I, and formula II,
Figure imgf000160_0002
II, or mixtures thereof as well as their pharmaceutically acceptable salts in combination with a pharmaceutically acceptable carrier wherein, in formulas I and II, R, is selected from the group consisting of hydrogen and lower alkyl;
R2 is selected from the group consisting of hydrogen and lower alkyl;
R3 is selected from the group consisting of hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and
Figure imgf000160_0003
are independently selected from the • group consisting of hydrogen and alkyl; R, is selected from the group consisting of hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NR5R<;;
A is selected from the group consisting of alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR7R8 wherein R7 and R8 are independently selected from the group consisting of alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl; B is selected from the group consisting of cyclohexyl, heterocycle and
Figure imgf000161_0001
wherein R, and R10 are independently selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl; X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
21. A method of treating an allergic disease in a mammal comprising administering to a mammal in need of such treatment, a pharmaceutically effective amount of the pharmaceutical composition of claim 20.
22. The method according to claim 21 wherein the allergic disease is asthma.
23. A compound selected from the group of compounds consisting of those represented by formula I and formula II below
Figure imgf000161_0002
Figure imgf000161_0003
II, or their pharmaceutically acceptable salts, wherein, in formulas I and II,
R, is selected from the group consisting of hydrogen and lower alkyl; R2 is selected from the group consisting of hydrogen and lower alkyl;
R3 is selected from the group consisting of hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NRsR^ wherein R5 and R^ are independently selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydrogen, alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and -NRjR^;
A is selected from the group consisting of alkenyl, alkyl, alkynyl, alkoxy, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocyclealkyl, and NR7R8 wherein R7 and R8 are independently selected from the group consisting of alkenyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl;
B is selected from the group consisting of heterocycle and NRgR,,, wherein R, and R10 are independently selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle, and heterocyclealkyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N;
with the proviso that for compounds of formula I when R4 is hydrogen and A is piperdinyl, moφholinyl, thiomoφholinyl, piperazinyl, or NR7R8 and R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl then B is other than tetrahydro-2H-pyran-4-yl optionally substituted with 1 subsituent selected from the group consisting of hydroxy and alkoxy or cyclohexyl optionally substituted with 1 subsituent selected from the group consisting of hydroxy and alkoxy; and with the further proviso that for compounds of formula II when R3 is hydrogen and R^ is hydrogen then B is other than cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkyl, and hydroxy.
24. A compound according to claim 23 of formula I wherein
R, is selected from the group consisting of hydrogen and lower alkyl;
R3 is selected from the group consisting of hydrogen and halogen; R4 is selected from the group consisting of hydrogen and halogen;
A is selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocycle, and NR7R8 wherein R7 and R8 are independently selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkoxyalkyl, and hydroxyalkyl; B is selected from the group consisting of heterocycle and NI^R,,, wherein R, and R10 are independently selected from alkoxyalkyl, alkyl, and cycloalkyl;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
25. A compound according to claim 23 of formula I wherein
R] is methyl;
R3 is selected from the group consisting of hydrogen and fluorine;
R4 is selected from the group consisting of hydrogen and chlorine;
A is selected from the group consisting of azetidinyl, azepanyl, azocanyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, thiazolidinyl, and tetrahydropyridyl;
B is selected from the group consisting of moφholinyl, piperazinyl, piperdinyl, tetrahydro-2H-pyranyl, pyrrolidinyl, thiomoφholinyl, and NR^R^ wherein Re, and R10 are independently selected from the group consisting of alkoxyalkyl and alkyl;
X is selected from the group consisting of CH2 and O; and Y is CH.
26. A compound according to claim 25 selected from the group consisting of ethyl 4-{3-fluoro-5-[(4-{methyl[(2-methyl-l- pyrrolidinyl)carbonyl]amino}benzyl)oxy]phenyl}-l -piperazinecarboxylate,
N-[4-({3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4- { [3 -fluoro-5 -(4-thiomoφholiny l)phenoxy]methy 1 } pheny l)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-hydroxy-l-piperidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-(4-acetyl-l-piperazinyl)-5-fluorophenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5 -( 1 -piperidiny l)phenoxy]methy 1 } pheny l)-N,2-dimethy 1- 1 - pyrrolidinecarboxamide,
N- [4-( { 3 -fluoro-5 - [4-(2-hydroxy ethyl)- 1 -piperaziny 1 jphenoxy } methy l)pheny 1] -N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4- { [3 -fluoro-5-(4-methyl- 1 -piperidinyl)phenoxy]methyl } phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N- [4-( { 3 - [ethyl(2-methoxyethy l)amino] -5-fluorophenoxy } methy l)pheny 1] -N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3-fluoro-5-( 1 -pyrrolidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 - pyrrolidinecarboxamide,
N-(4-{[3-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-5-fluorophenoxy]methyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3-fluoro-5-(4-hydroxy-4-phenyl- 1 -piperidinyl)phenoxy]methyl } phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(3-hydroxy-l-pyrrolidinyl)phenoxy]methyl}phenyl)-N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-[4-({3-fluoro-5-[4-(2-methoxyethyl)-l-piperazinyl]phenoxy}methyl)phenyl]-N,2- dimethyl- 1 -pyrrolidinecarboxamide, N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azocanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-3- hydroxy-N-methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,5-trimethyl- 1 -pyrrolidinecarboxamide, (3R)-N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-3-hydroxy-N-methyl-l-pyrrolidinecarboxamide,
3 -ethyl-N-(4- { [3 -fluoro-5 -(4-methoxy tetrahy dro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N,2,4-trimethyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,5-trimethyl-2,5-dihydro-lH-pyrrole-l -carboxamide,
N-(4-{2-[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]ethyl}phenyl)-N,2- dimethyl- 1 -pyrrolidinecarboxamide,
N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N- methyl- 1 H-pyrrole- 1 -carboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-2,5-dihydro- 1 H-pyrrole- 1 -carboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 ,3 -thiazolidine-3 -carboxamide, N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } phenyl)-N- methyl-3 ,6-dihydro- 1 (2H)-pyridinecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl- 1 -azepanecarboxamide, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methy 1- 1 -azetidinecarboxamide,
(2R)-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-2-(hydroxymethy l)-N-methyl- 1 -pyrrolidinecarboxamide,
(2S)-N-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-2-(hydroxymethyl)-N-methyl- 1 -pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(4-hydroxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethyl- 1 -pyrrolidinecarboxamide,
N- { 4- [(3 -fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methy Ijphenyl } -N,2-dimethy 1- 1 ■ pyrrolidinecarboxamide, N-(4-{[3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
(-) N-(4-{[3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N,2-dimethyl-l- pyrrolidinecarboxamide,
(+) N-(4- { [3 -fluoro-5 -(4-moφholinyl)phenoxy jmethy 1 } pheny l)-N,2-dimethy 1- 1 - pyrrolidinecarboxamide,
N-(4-{[3-fluoro-5-(2-methyl-3-oxo-l-piperazinyl)phenoxy]methyl}phenyl)-N,2- dimethyl-1 -pyrrolidinecarboxamide, and
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-2-furamide.
27. A compound according to claim 23 of formula I wherein
R, is methyl;
R3 is selected from the group consisting of hydrogen and fluorine;
R,, is selected from the group consisting of hydrogen and chlorine; A is NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, 2- (l,3-dioxolan-2-yl)ethyl, tetrahydro-2-furanylmethyl, hydroxyalkoxyalkyl, and 2- phenylethyl; B is selected from the group consisting of tetrahy dro-2H-pyranyl and cyclohexyl;
X is selected from the group consisting of CH2 and O; and
Y is CH.
28. A compound according to claim 27 selected from the group consisting of N-allyl-N'-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]me yl}phenyl)-N,N'-dimethylurea,
N-(3 -chloro-4- { [3 -fluoro-5 -(4-methoxy tetrahy dro-2H-pyran-4- y l)phenoxy]methy 1 } pheny 1)-N,N' ,N'-trimethy lurea,
N-(cyclopropylmethyl)-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methy 1 } pheny l)-N'-methy 1-N-propy lurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,N'-dimethyl-N'-(2-propynyl)urea,
N-(2-cyanoethyl)-N-cyclopropyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran- 4-yl)phenoxy]methyl}phenyl)-N'-methylurea, N-allyl-N-ethyl-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N'-methy lurea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy] methyl } pheny 1)-N'- (2-methoxyethyl)-N,N'-dimethylurea,
N-[2-(l,3-dioxolan-2-yl)ethyl]-N'-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N,N'-dimethy lurea,
N,N-diallyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N'-cyclobutyl-N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy ] methyl } pheny l)-N-methy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(tetrahydro-2-furanylmethyl)urea,
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-yl)phenoxy]methy 1 } phenyl)-N'- (2-methoxyethyl)-N-methylurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-propynyl)urea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [2-(2-hydroxyethoxy)ethyl]-N-methylurea,
N'-allyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- (2-methoxy- 1 -methy lethyl)-N-methy lurea,
N'-(cyanomethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methy lurea, N'-cyclopropyl-N-(4- { [3-fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methyl-N'-(2-methyl-2-propenyl)urea,
N,-(cyclopropylmethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-methylurea,
N,-cyclopentyl-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl)-N-methylurea,
N'-[bicyclo[2.2.1]hept-2-yl]-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- y l)phenoxy Jmethy 1 } phenyl)-N-methy lurea, N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'-
[2-(4-hydroxyphenyl)ethyl]-N-methylurea,
N'-(2-cyanoethyl)-N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy ] methyl } pheny l)-N-methy lurea, N-(4-{[3-fluoro-5-(4-mefhoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- [ 1 -(hydroxymethyl)cyclopentyl]-N-methylurea,
N'-(2,2-dimethylcyclopentyl)-N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } pheny l)-N-methy lurea, N-ethyl-N'-(4- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N-(2-methoxyethyl)-N'-methylurea,
N-butyl-N-(cyanomethyl)-N'-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl}phenyl)-N'-methylurea,
N-[4-({3-fluoro-5-[4-(2-propynyloxy)tetrahydro-2H-pyran-4- yl]phenoxy}methyl)phenyl]-N,N',N'-trimethylurea,
N,N-diethyl-N'-(4-{[3-(4-ethyltetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N'- methylurea, ethyl 4-[3-({4- [[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)phenyl]tetrahydro-2H-pyran-4- carboxylate, and
N,N-diethyl-N'-{4-[(3-fluoro-5-tetrahydro-2H-pyran-4-ylphenoxy)methyl]phenyl}-N'- methylurea.
29. A compound according to claim 23 of formula I wherein R, is methyl;
R3 is selected from the group consisting of hydrogen and fluorine;
R4 is selected from the group consisting of hydrogen and chlorine;
A is NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of moφholinyl, piperazinyl, piperdinyl, pyrrolidinyl, thiomoφholinyl, and NRgR10 wherein R, and R10 are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, and cycloalkyl;
X is selected from the group consisting of CH2 and O; and
Y is CH.
30. A compound according to claim 29 selected from the group consisting of ethyl 4-[3-({4-[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)-5-fluorophenyl]- 1 -piperazinecarboxylate, N-[4-({3-[bis(2-methoxyethyl)amino]-5-fluorophenoxy}methyl)phenyl]-N',N'- diethyl-N-methylurea,
N-(4-{[3-(2,6-dimethyl-4-moφholinyl)-5-fluorophenoxy]methyl}phenyl)-N',N'- diethyl-N-methylurea,
N ,N-diethyl-N'-(4- { [3 -fluoro-5 -(4-thiomθφholinyl)phenoxy]methyl } pheny 1)-N'- methylurea,
N,N-diethyl-N'-(4-{[3-fluoro-5-(4-hydroxy-l-piperidinyl)phenoxy]methyl}phenyl)- N'-methylurea,
N-(4- { [3-(4-acetyl- 1 -piperazinyl)-5-fluorophenoxy]methyl } pheny l)-N',N'-diethyl-N- methylurea, N,N-diethy l-N'-(4- { [3 -fluoro-5-( 1 -piperidinyl)phenoxy]methyl } phenyl)-N'- methylurea,
N-(4-{[3-(cyclopentylamino)-5-fluorophenoxy]methyl}phenyl)-N',N'-diethyl-N- methylurea,
N-(4- { [3 -(cyclohexylamino)-5-fluorophenoxy]methyl } pheny l)-N',N'-diethy 1-N- methylurea,
N,N-diethyl-N'-[4-({3-fluoro-5-[4-(2-hydroxyethyl)-l- piperazinyl]phenoxy}methyl)phenyl]-N'-methylurea,
N,N-diethyl-N'-(4- { [3-fluoro-5-(4-methyl- 1 -piperidinyl)phenoxy]methyl } pheny 1)-N'- methylurea, N,N-diethyl-N'-[4-( { 3 -[ethyl(2-methoxyethyl)amino]-5 - fluorophenoxy}methyl)phenyl]-N'-methylurea,
N,N-diethyl-N'-(4- { [3 -fluoro-5-( 1 -pyrrolidinyl)phenoxy]methyl } phenyl)-N'- methylurea, N,N-diethyl-N,-(4-{[3-fluoro-5-(2-methyl-3-oxo-l- piperazinyl)phenoxy]methy 1 } phenyl)-N'-methy lurea, tert-butyl 4-[3-({4-[[(diethylamino)carbonyl](methyl)amino]benzyl}oxy)-5- fluorophenyl]-4-hydroxy- 1 -piperidinecarboxylate, and N,N-diethyl-N'-(4- { [3-fluoro-5-(4-moφholinyl)phenoxy]methyl}phenyl)-N'- methylurea.
31. A compound according to claim 23 of formula I wherein R4 is halogen.
32. A compound according to claim 23 of formula I wherein R4 is chlorine.
33. A compound according to claim 23 of formula I wherein R, is methyl;
R3 is selected from the group consisting of hydrogen and fluorine; _4 is chlorine;
A is NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; B is tetrahydro-2H-pyranyl;
X is O; and Y is CH.
34. A compound according to claim 33 that is N-(3-chloro-4-{ [3-fluoro-5-(4- methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N,N',N'-trimethylurea.
35. A compound according to claim 23 of formula I wherein
Y is N.
36. A compound according to claim 23 of formula I wherein
Rt is methyl;
R3 is hydrogen;
R4 is hydrogen;
A is selected from the group consisting of pyrrolidinyl and NR7R8 wherein R7 and R8 are independently selected from the group consisting of hydrogen and alkyl;
B is tetrahy dro-2H-pyranyl;
X is O; and
Y is N.
37. A compound according to claim 36 selected from the group consisting of (+) N-[4-({[6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy}methyl)phenyl]-
N,2-dimethy 1- 1 -pyrrolidinecarboxamide,
(-) N-[4-( { [6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-pyridinyl]oxy } methyl)phenyl]- N,2-dimethyl- 1 -pyrrolidinecarboxamide, and
N,N-diethyl-N'-[4-( { [6-(4-hydroxytetrahydro-2H-pyran-4-yl)-2- pyridinyl]oxy}methyl)phenyl]-N'-methylurea.
38. A compound according to claim 23 of formula I wherein R, is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of hydrogen and halogen;
R4 is selected from the group consisting of hydrogen and halogen;
A is selected from the group consisting of alkoxy, alkyl, and cycloalkyl;
X is O; and Y is CH.
39. A compound according to claim 23 of formula 1 wherein R, is methyl;
R3 is fluorine; R4 is hydrogen;
A is selected from the group consisting of alkoxy, alkyl, and cycloalkyl; B is tetrahy dro-2H-pyranyl; X is O; and Y is CH.
40. A compound according to claim 39 selected from the group consisting of
N-(4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4-y l)phenoxy]methy 1 } pheny 1)- N,3,3-trimethylbutanamide, 2-ethy l-N-(4- { [3 -fluoro-5-(4-methoxytetrahydro-2H-ρyran-4- yl)phenoxy]methyl}phenyl)-N-methylbutanamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2,2-trimethylpropanamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopentanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)-N- methylcyclopropanecarboxamide,
N-(4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl}phenyl)- N,2-dimethylpropanamide, isopropyl 4-{[3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4- yl)phenoxy]methyl } phenyl(methyl)carbamate, propyl 4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl(methyl)carbamate, and tert-butyl 4- { [3 -fluoro-5 -(4-methoxytetrahy dro-2H-pyran-4- yl)phenoxy]methyl}phenyl(methyl)carbamate.
41. A compound according to claim 23 of formula II wherein R, is methyl;
R2 is methyl; R3 is halogen;
R_4 is selected from the group consisting of hydrogen and halogen;
X is selected from the group consisting of CH2 and O; and
Y is selected from the group consisting of CH and N.
42. A compound according to claim 23 of formula II wherein R, is methyl;
R2 is methyl; R3 is fluorine; R4 is hydrogen;
B is selected from the group consisting of cyclohexyl, piperdinyl, and tetrahydro-2H- pyranyl;
X is O; and
Y is CH.
43. A compound according to claim 42 selected from the group consisting of 5-{[3-(l-benzyl-4-hydroxy-4-piperidinyl)-5-fluorophenoxy]methyl}-l,3-dimethyl- l,3-dihydro-2H-benzimidazol-2-one,
5-{[3-(trans-l,4-dimethoxycyclohexyl)-5-fluorophenoxy]methyl}-l,3-dimethyl-l,3- dihydro-2H-benzimidazol-2-one,
5-{[3-fluoro-5-(8-hydroxy-l,4-dioxaspiro[4.5]dec-8-yl)phenoxy]methyl}-l,3- dimethyl- 1 ,3-dihydro-2H-benzimidazol-2-one, and
5- { [3-fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenoxy]methyl } -1 ,3-dimethyl- 1 ,3-dihydro-2H-benzimidazol-2-one.
44. A method for treating asthma in a mammal which comprises administering to a mammal in need of such treatment, a pharmaceutically effective amount of a selective interleukin 5 gene expression inhibitor.
PCT/US2000/034229 1999-12-17 2000-12-15 Inhibitors of interleukin 5 gene expression WO2001044223A1 (en)

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