EP1250332A1 - Inhibitors of interleukin 5 gene expression - Google Patents

Inhibitors of interleukin 5 gene expression

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Publication number
EP1250332A1
EP1250332A1 EP00986489A EP00986489A EP1250332A1 EP 1250332 A1 EP1250332 A1 EP 1250332A1 EP 00986489 A EP00986489 A EP 00986489A EP 00986489 A EP00986489 A EP 00986489A EP 1250332 A1 EP1250332 A1 EP 1250332A1
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EP
European Patent Office
Prior art keywords
methyl
fluoro
phenyl
phenoxy
pyran
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP00986489A
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German (de)
English (en)
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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Abbott Laboratories
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Publication of EP1250332A1 publication Critical patent/EP1250332A1/en
Withdrawn legal-status Critical Current

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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
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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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
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    • 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
    • C07D295/205—Radicals derived from carbonic acid
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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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    • C07D309/02—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
    • C07D309/04—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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • C07D405/12—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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    • C07D417/02—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
    • 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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