WO2005023762A1 - Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv) - Google Patents

Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv) Download PDF

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WO2005023762A1
WO2005023762A1 PCT/US2004/028886 US2004028886W WO2005023762A1 WO 2005023762 A1 WO2005023762 A1 WO 2005023762A1 US 2004028886 W US2004028886 W US 2004028886W WO 2005023762 A1 WO2005023762 A1 WO 2005023762A1
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group
heteroaryl
alkylsulfonyl
aryl
carboxy
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PCT/US2004/028886
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English (en)
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Zhonghua Pei
Xiaofeng Li
Kenton L. Longenecker
Hing L. Sham
Paul E. Wiedeman
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • compositions As Inhibitors of Dipeptidyl Peptidase-IV (DPP-IV)
  • the present invention relates to compounds which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, ⁇ -cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.
  • DPP-IV dipeptidyl peptidase IV
  • Dipeptidyl peptidase IV (DPP-IV, CD26, EC 3.4.14.5) is a serine protease with specificity for cleaving Xaa-Pro and, to a lesser extent, Xaa-Ala dipeptides from the N-termini of polypeptides and proteins.
  • DPP-IV is a non-classical serine protease in that the catalytic triad of Ser-Asp-His, found in the C-terminal region of the enzyme, is in reverse order to that found in classical serine proteases.
  • DPP-IV is widely expressed in mammalian tissue as a type II integral membrane protein.
  • DPP- IV is expressed on the surface of differentiated epithelial cells of the intestine, liver, kidney proximal tubules, prostate, corpus luteum, and on leukocyte subsets such as lymphocytes and macrophages.
  • a soluble form of the enzyme is found in serum that has structure and function identical to the membrane-bound form of the enzyme but lacks the hydrophobic transmembrane domain.
  • DPP-IV has many physiologically relevant substrates such as chemokines, RANTES (regulated on activation normal T cell expressed and secreted), eotaxin, and macrophage-derived chemokine, neuropeptides such as NPY (neuropeptide Y) and substance P, vasoactive peptides, and incretins such as GLP-1 (glucagon-like peptide-
  • GLP-1 is a 30 amino acid peptide hormone produced in the L cells of the distal small intestine in response to ingested nutrients. GLP-1 binding to its receptor on various tissues stimulates insulin gene expression, biosynthesis and glucose-dependent insulin secretion, inhibits glucagon secretion, promotes satiety, slows gastric emptying and promotes growth of pancreatic beta cells. Based on this profile, GLP-1-based therapies are expected to be beneficial in the treatment of type II diabetes and obesity. Studies in which type II diabetic patients have been infused with GLP-1 have demonstrated efficacy in normalizing both fasted and prandial glycemia.
  • GLP-1 (7-36) amide is rapidly converted by DPP-IV to GLP-1 (9-36), which is inactive or is a receptor antagonist.
  • the short half-life of GLP-1 in the circulation (1- 1.5 minutes) is a major obstacle to its use as a therapeutic agent.
  • inhibitors of DPP-IV, the primary degradative enzyme of GLP-1 increase the level of active circulating GLP-1 (7-36) amide.
  • DPP-IV inhibitors have been demonstrated to improve glucose tolerance in type II diabetes. For a DPP-IV inhibitor to be optimally useful in a human therapeutic setting, it should ideally be delivered as a once-daily oral dose.
  • the compound in question must exhibit both potent inhibition of the enzyme and a desirable pharmacokinetic profile.
  • DPP-IV plays a critical role in controlling the degradation of GLP- 1 , and because the enzyme is ubiquitously expressed at high levels in a variety of tissues as well as within the vasculature, only a potent inhibitor will be capable of impacting circulating GLP-1 levels in a therapeutically relevant manner.
  • In vivo studies suggest that continuous inhibition of DPP ⁇ -IV leads to a maximal increase in circulating GLP-1, and thus to the greatest improvement in overall glucose control. These results suggest that an inhibitor with a long half-life is most therapeutically desirable.
  • DPP-IV inhibitor that is both highly potent and has an in vivo half-life consistent with once-daily dosing.
  • Many potent inhibitors contain a 2-cyanopyrrolidide functionality in the PI (catalytic binding site) position.
  • the cyano group of the 2-cyanopyrrolidide forms a covalent linkage with the enzyme through the catalytic Serine that confers increased potency to the inhibitors that contain it by slowing the release of inhibitor.
  • the 2-cyanopyrrolidide moiety has liabilities as well.
  • the cyano-group is found in close proximity to a P2-amine functionality that serves as a marker for the substrate ammo-terminus in the DPP-IV inhibitory pharmacophore. When these two groups are held in such proximity, they tend to react to form a cyclic amidine, destroying the pharmacophore.
  • cyanopyrrolidide-containing DPP-IV inhibitors tend to have limited chemical stability, which is reflected in poor pharmacokinetic profiles.
  • Intramolecular cyclization Active DPP-IV , ⁇ . Inhibitor lnact,ve Compounds of the instant invention are both highly potent and chemically stable, and thus provide unique therapeutic benefit and an improved dosing profile for the treatment of human diseases.
  • R is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RgR b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, cycloalkyl, cycloalkyl, arylalkyl, heteroary
  • ⁇ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RJR b N-, R a R b Ncarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxy, carb
  • R 12 and R 13 together with the carbon atoms to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, furan, imidazole, isothiazole, isoxazole, 1,3- dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine
  • R 21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy
  • R 22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyal
  • R 3 and R 24 together with the carbon atoms to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, furan, imidazole, isothiazole, isoxazole, 1,3-dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadia
  • R 2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl
  • R 3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio,
  • R 4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio,
  • R ⁇ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, RaR b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy
  • the present invention is directed to methods to improve glucose tolerance in type II diabetes comprising administering a therapeutically effective amount of a compound of formula (I).
  • a method for treating type 2 diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance, ⁇ -cell failure, obesity, satiety disorders, hypercholesterolemia, and hypertriglyceridemia comprising administering a therapeutically effective amount of a compound of formula (I).
  • the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
  • Rt is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, cycloalkyl, arylalkyl, heterocyclealkyl,
  • R 1 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, RaR b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxy, carb
  • R 3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyal
  • the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of R-u or R 44 is hydrogen.
  • Another embodiment of the present invention discloses compounds of formula
  • Ri is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfbnyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, cycloalkylalkyl, formyl, formylalkyl,
  • R! is selected from the group consisting of halo, haloalkyl, haloalkoxy, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, hydroxyalkyl, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl
  • R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl, alkenylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylalkylsulfonyl, arylsulfonyl, arylNHC(O), alkylsulfonyl, cycloalkylcarbonyl, heteroaryl, and heteroarylcarbonyl.
  • Another embodiment of the present invention discloses compounds of formula
  • Ri is selected from the group consisting of halo, alkoxy, cyano, alkyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylsulfonyl, heteroaryl and hydroxyalkyl, wherein the heteroaryl is pyrazolyl;
  • R 2 is selected from the group consisting of hydrogen, halo and alkylsulfonyl;
  • R 3 is selected from the group consisting of hydrogen, halo, haloalkyl, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, carboxy, carboxyalkoxy, alkylsulfonyl, heteroaryl and heterocycle, wherein the heteroaryl is tetrazolyl;
  • R 4 is selected from the group consisting of hydrogen, R a RbN-, alkoxycarbonyl, cyano, carboxy, alkylsulfonylNH and nitro; and R
  • R ⁇ and R 2 together with the carbon atoms to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, furan, imidazole, isothiazole, isoxazole, 1,3-dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyrimidine, pyrrole, thiazole, thiophene, triazine, 1,2,3-triazole or unsubstituted pyridine;
  • R 3 is selected from the group consisting of hydrogen, halo, haloalkyl, halo
  • R ⁇ and R 2 together with the carbon atoms to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, furan, imidazole, isothiazole, isoxazole, 1,3-dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyrimidine, pyrrole, thiazole, thiophene, triazine, 1,2,3-triazole or unsubstituted pyridine;
  • R 3 is selected from the group consisting of hydrogen, halo, haloalkyl, halo
  • R ⁇ and R 2 together with the carbon atoms to which they are attached, form a substituted or unsubstituted heterocycle or a substituted or unsubstituted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, thiophene or unsubstituted pyridine;
  • R 3 is selected from the group consisting of hydrogen, halo, haloalkyl, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, carboxy, carboxyalkoxy, alkylsulfonyl, heteroaryl, heterocycle, wherein the heteroaryl is tetrazolyl;
  • R 4 is selected from the group consisting of hydrogen, R a R b N-, alkoxycarbonyl, alkoxy cyano, alkylsulfonylNH and nitro; and
  • R a and R b are independently selected from the
  • R ⁇ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a RbN-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylalkyl, nitro, mercapto and mercaptoal
  • R ⁇ is selected from the group consisting of halo, haloalkyl, haloalkoxy, R a R b N-, RaR b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophen
  • R ⁇ is selected from the group consisting of halo, alkoxy, cyano and carboxy; R 12 and R 13 together with the carbon atoms to which they are attached, form a substituted or unsubstituted benzene; and R 1 is hydrogen.
  • R ⁇ is selected from the group consisting of halo, alkoxy, cyano and carboxy; R 12 and R 13 together with the carbon atoms to which they are attached, form a substituted or unsubstituted benzene; and R 1 is hydrogen.
  • R 21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, R a RbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylalkyl, nitro, mercapto and mercaptoalkyl, wherein the
  • R 21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thi
  • R 21 is selected from the group consisting of halo and carboxy; R is selected from the group consisting of hydrogen and halo; and R 3 and R 24 together with the carbon atoms to which they are attached, form 1,3-dioxolane.
  • Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
  • R 3 ⁇ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a RbN-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylalkyl, nitro, mercapto and mercap
  • R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylalkyl, nitro, mercapto and mercaptoalkyl, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazoly
  • R 31 is selected from the group consisting of halo, haloalkyl, haloalkoxy, R a R b N-,
  • RaR b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, aikenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
  • R 32 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkyl, arylalkyl, heterocyclealkyl, cycloalkyl, arylalkyl, heterocyclealkyl, cycloalkyl, arylalkyl, heterocyclealkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, heterocyclealkyl, cycloalkyl,
  • R 31 is halo; R 32 is hydrogen; R 3 is hydrogen; R 3 is hydrogen; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide.
  • Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
  • R ⁇ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylalkyl, nitro, mercapto and
  • R 41 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,
  • Rzu is selected from the group consisting of hydrogen, halo and carboxy;
  • R 42 is hydrogen;
  • R43 is selected from the group consisting of hydrogen, halo, alkoxycarbonyl and carboxy;
  • R 44 is hydrogen; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of Rzn or R 44 is hydrogen.
  • R 51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cyclo
  • R 51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, R a R b N-, R a R b Ncarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thi
  • R 51 and R 52 together with the carbon atoms to which they are attached, form a benzene; and R 53 is hydrogen.
  • Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
  • Rg 2 , Re, R ⁇ 4 and Res are each independently selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl, R a R b Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylal
  • Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is R 62 , R 63 , Re 4 and R ⁇ 5 are hydrogen.
  • Another embodiment of the present invention is directed toward a method of treating diabetes, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating type II diabetes, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating hyperglycemia, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating Syndrome X, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating hyperinsulinemia, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating ⁇ -cell failure, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating obesity, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating satiety disorders, comprising administering of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically suitable carrier.
  • Another embodiment of the present invention is directed toward a method of treating inflammatory bowel syndrome, including Crohn's disease and ulcerative colitis, comprising administration of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating short bowel disease, comprising administration of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of increasing bone ma ⁇ ow transplant efficiency, comprising administration of a therapeutically effective amount of a compound of formula (I).
  • Another embodiment of the present invention is directed toward a method of treating neurodegenerative and cognitive disorders, including Alzheimer's Disease, comprising administration of a therapeutically effective amount of a compound of formula (I).
  • 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.
  • alkenyl refers to C 2 -alkenyl, C 3 -alkenyl, C 4 - alkenyl, Cs-alkenyl, C 6 -alkenyl, C 7 -alkenyl, C 8 -alkenyl, C 9 -alkenyl or Cio-alkenyl.
  • alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2- methyl-1-heptenyl, and 3-decenyl.
  • alkenylcarbonyl refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • 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, and methoxymethyl.
  • alkoxyalkylcarbonyl refers to an alkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxyalkoxy refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
  • alkoxyalkoxycarbonyl refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxyalkoxyalkyl refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkoxyalkylcarbonyl refers to an alkoxyalkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • 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, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • 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, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkylsulfonyl refers to an alkyl group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkoxysulfonyl refers to an alkoxy group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.
  • 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.
  • alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl refers to a monocyclic-ring system, or a bicyclic- or a tricyclic-fused ring system wherein one or more of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • aryl groups of the present invention can be substituted with 0, 1, 2, or 3 substituents wherein each substitutent occu ⁇ ence is independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkylthio, aryl, arylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, halo, haloalkyl, haloalkoxy, haloalkylthio, heteroaryl, heterocycle, heteroarylalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, R a R b N-, RaR
  • 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, 3-phenylpropyl, and 2-naphth-2-ylethyl.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylalkylsulfonyl refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • arylsulfonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • carbonyl refers to a -C(O)- group.
  • carboxy refers to a HO 2 C- 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, and 3-carboxypropyl.
  • carboxyalkoxy refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • cyano refers to a NC- 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, and 3-cyanopropyl.
  • cycloalkyl refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.
  • monocyclic ring systems examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo(3.1. l)heptane, bicyclo(2.2.
  • Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo(3.3.1.0 3 ' 7 )nonane and tricyclo(3.3.1.1 3,7 )decane (adamantane).
  • cycloalkyl groups of this invention may be substituted with 0, 1, 2 or 3 substituents wherein each substitutent occurrence is selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkylthio, aryl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, halo, haloalkyl, haloalkoxy, haloalkylthio, heteroaryl, heterocycle, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, R a R b N-, R a R b Ncarbonyl, R a R b Ncarbonylalkyl and
  • cycloalkylalkyl refers to a 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.
  • cycloalkylcarbonyl refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • dialkylsulfonyl refers to two independent alkyl groups, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • formyl refers to a -C(O)H group.
  • formylalkyl refers to a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of formylalkyl include, but are not limited to, formylmethyl and 2-formylethyl.
  • halo refers to C1-, Br-, I- or F-.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3- fluoropentyl.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • haloalkylthio refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkylthio group, as defined herein.
  • heteroaryl means a monocyclic or a bicyclic ring. The monocyclic heteroaryl rings of the present invention may exist as a 5 or 6 membered ring.
  • the 5 membered heteroaryl ring has two double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S.
  • the 6 membered heteroaryl ring has three double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S.
  • the bicyclic heteroaryl ring consists of the 5 or 6 membered heteroaryl ring fused to a distal ring, wherein the distal ring is selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl, and a 5 or 6 membered heterocycle ring.
  • Nitrogen heteroatoms contained within the heteroaryl may be optionally oxidized to the N-oxide or optionally protected with a nitrogen protecting group known to those of skill in the art.
  • the heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • Representative examples of heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cinnolinyl, 5,6-dihydroisoquinolinyl,
  • heteroaryls of the present invention can be substituted with 0, 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkylthio, aryl, arylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, halo, haloalkyl, haloalkoxy, haloalkylthio, heteroaryl, heterocycle, heteroarylalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, R a R b N-, R a R b Ncarbonyl
  • R a R b Ncarbonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, and alkylcarbonyl.
  • heteroarylalkyl refers to a heteroaryl group as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic ring or a bicyclic ring or a tricyclic ring.
  • the monocyclic ring consists of a 3, 4, 5, 6 or 7 membered ring which contains at least one heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur.
  • the 3 or 4 membered ring contains 1 heteroatom.
  • the 5 membered ring contains zero or one double bond and one, two or three heteroatoms.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms.
  • monocyclic heterocyclic ring examples include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, mo ⁇ holinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, py ⁇ olinyl, py ⁇ olidinyl, tefrahydrofuranyl, tetrahydro
  • the bicyclic heterocyclic ring consists of the monocyclic heterocyclic ring fused to a distal ring, wherein the distal ring is selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and another monocyclic heterocyclic ring.
  • bicyclic heterocyclic ring examples include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 2,3-dihydro- lH-indolyl, and 1,2,3,4-tetrahydroquinolinyl.
  • the tricyclic heterocyclic ring consists of the bicyclic heterocyclic ring fused to a phenyl group or the bicyclic heterocyclic ring fused to a cycloalkyl group or the bicyclic heterocyclic ring fused to a cycloalkenyl group or the bicyclic heterocyclic ring fused to another monocyclic heterocyclic ring.
  • tricyclic heterocyclic ring include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-lH-carbazolyl, 5a,6,7,8,9,9a- hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.
  • heterocycles can be; substituted with 0, 1, 2 or 3 substituents wherein each substitutent occurrence is independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, halo, haloalkyl, haloalkoxy, haloalkylthio, heteroaryl, heterocycle, heteroarylalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, phenyl, R a R b N-, R a R
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyl and the like.
  • heterocyclecarbonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, pyridin-3-ylcarbonyl and 2-pyrimidin-2-ylcarbonyl 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, 2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl and the like.
  • mercapto refers to a -SH group.
  • mercaptoalkyl refers to a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • mercaptoalkyl include, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl.
  • nitro refers to a -NO 2 group.
  • sulfonyl refers to a -SO 2 - group.
  • R b N- refers to both R a and R , which are independently defined as a member selected from the group consisting of hydrogen, alkyl, aryl, alkenylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylalkylsulfonyl, arylsulfonyl, arylNHC(O), alkylsulfonyl, cycloalkylcarbonyl, heteroaryl, and heteroarylcarbonyl, appended to the parent molecular moiety through a nitrogen atom.
  • R a R b Ncarbonyl refers to R a R b N, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • R a R b Ncarbonylalkyl refers to R a R b Ncarbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • R a R b Nsulfonyl refers to R a R b N, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • the present invention is also directed to a method of treating disorders mediated by DPP-IV through inhibition of enzymatic activity.
  • Disorders known to be regulated through enzymatic activity are diabetes, especially type II diabetes, as well as hyperglycemia, Syndrome X, hyperinsulinemia, ⁇ -cell failure, obesity, atherosclerosis, and various immunomodulatory diseases. Therefore, according to an embodiment of the present invention there are provided compounds of formula (I), which are useful for the treatment of diabetes, especially type II diabetes, as well as hyperglycemia, Syndrome X, hyperinsulinemia, ⁇ -cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.
  • the present compounds can exist as therapeutically suitable salts.
  • terapéuticaally suitable salt refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like.
  • the amino groups of the compounds can also be quatemized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
  • the present invention contemplates pharmaceutically suitable salts formed at the nitrogen of formula (I-II).
  • Basic addition salts can be prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • the present compounds can also exist as therapeutically suitable prodrugs.
  • prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds that are rapidly transformed in vivo to the parent compounds of formula (I-II) for example, by hydrolysis in blood. Asymmetric centers can exist in the present compounds.
  • Stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting materials of particular stereochemistry are either commercially available or are made by the methods described herein and resolved by techniques well-known in the art.
  • Geometric isomers can exist in the present compounds.
  • the invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group.
  • compositions of the present compounds comprise an effective amount of the same formulated with one or more therapeutically suitable excipients.
  • therapeutically suitable excipient represents a non-toxic, solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.
  • therapeutically suitable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like.
  • Liquid dosage forms for oral administration of the present compounds comprise formulations of the same as emulsions, microemulsions, solutions, ' suspensions, syrups, and elixirs.
  • the liquid dosage forms can contain diluents and/or solubilizing or emulsifying agents.
  • the oral compositions can include wetting, emulsifying, sweetening, flavoring, and perfuming agents.
  • Injectable preparations of the present compounds comprise sterile, injectable, aqueous and oleaginous solutions, suspensions or emulsions, any of which can be optionally formulated with parenterally suitable diluents, dispersing, wetting, or suspending agents. These injectable preparations can be sterilized by filtration through a bacterial- retaining filter or formulated with sterilizing agents that dissolve or disperse in the injectable media. Inhibition of DPP-IV by the compounds of the present invention can be delayed by using a liquid suspension of crystalline or amo ⁇ hous material with poor water solubility. The rate of abso ⁇ tion of the compounds depends upon their rate of dissolution which, in turn, depends on their crystallinity.
  • Delayed abso ⁇ tion of a parenterally administered compound can be accomplished by dissolving or suspending the compound in oil.
  • Injectable depot forms of the compounds can also be prepared by microencapsulating the same in biodegradable polymers. Depending upon the ratio of compound to polymer and the nature of the polymer employed, the rate of release can be controlled. Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions that are compatible with body tissues.
  • Solid dosage forms for oral administration of the present compounds include capsules, tablets, pills, powders, and granules.
  • the compound is mixed with at least one inert, therapeutically suitable excipient such as a carrier, filler, extender, disintegrating agent, solution retarding agent, wetting agent, absorbent, or lubricant.
  • excipient can also contain buffering agents.
  • Suppositories for rectal administration can be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperature but fluid in the rectum.
  • the present compounds can be micro-encapsulated with one or more of the excipients discussed previously.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric and release-controlling.
  • the compounds can be mixed with at least one inert diluent and can optionally comprise tableting lubricants and aids. Capsules can also optionally contain opacifying agents that delay release of the compounds in a desired part of the intestinal tract. Transdermal patches have the added advantage of providing controlled delivery of the present compounds to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux of the compounds across the skin, and the rate of abso ⁇ tion can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel.
  • a therapeutically effective amount refers to a sufficient amount of a compound of formula (I) to effectively ameliorate disorders by inhibiting DPP-IV at a reasonable benefit/risk ratio applicable to any medical treatment.
  • 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; the activity of the 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, rate of excretion; the duration of the treatment; and drugs used in combination or coincidental therapy.
  • the total daily dose of the compounds of the present invention necessary to inhibit the action of DPP-IV in single or divided doses can be in amounts, for example, from about 0.01 to 50 mg kg body weight. In a more prefe ⁇ ed range, compounds of the present invention inhibit the action of DPP-IV in a single or divided doses from about 0.05 to 25 mg/kg body weight.
  • Single dose compositions can contain such amounts or submultiple doses thereof of the compounds of the present invention to make up the daily dose.
  • treatment regimens comprise administration to a patient in need of such treatment from about 1 mg to about 1000 mg of the compounds per day in single or multiple doses.
  • rat DPP-IV Isolation of rat DPP-IV DPP-IV was purified to homogeneity (electrophoretic) from rat kidney as described in Arch. Biochem. Biophy. 1995, 323, 148-154.
  • Rat kidney 120 g was homogenized in 4 volumes of water and the homogenate centrifuged for 15 minutes at lOOOg. The pH of the supernatant was adjusted to 3.9 with 1 M HC1 and the enzyme solubilized by autolysis for 18 hours at 37 °C. The pH of the supernatant collected after centrifugation was adjusted to 7.2 with 1 M Trizma base and the enzyme was precipitated with (NH 4 ) 2 SO at 90% saturation (662 g solid ammonium sulfate per liter of solution). The solubilized precipitate was chromatographed on Sephadex G-
  • DPP-IV was then resolved from other brush border peptidases by chromatography on a phenyl Sepharose column (12 x 2 cm) equilibrated with 25% (NH ) 2 SO 4 at saturation (144 g ammonium sulfate per liter of 0.05 M Tris-HCl, pH 7.5). The enzyme was eluted in a homogeneous form with a 200-mL linear gradient of 25-0% (NH 4 ) 2 SO 4 , prepared in 0.05 M Tris HC1 buffer . Partial Purification of Human DPP-IV Caco-2 cells were obtained from American Type Culture Collection (P.O.
  • the assay is carried out at room temperature in black 96 well polypropylene or polyethylene plates in a total volume of 100 ⁇ L per well. Appropriate dilutions of the compounds are made in DMSO and then diluted ten fold into water. 10 ⁇ L of 5 concentrations of the compound of formula (I) (inhibitor) or 10% DMSO in water are added to individual wells containing 80 ⁇ L of DPP-IV diluted in assay buffer containing 25 mM HEPES (pH 7.5), 150 mM NaCl and 0.12 mg/mL BSA. After 10 minutes at room temperature, the reaction is initiated by adding 10 ⁇ L of either 280, 700, 1750, or 3500 ⁇ M Gly-Pro-AMC in water.
  • the DPP- IV activity results in the formation of the fluorescent product amido-methylcoumarin (AMC) which is continuously monitored by excitation at 350 nm and measurement of fluorescent emission at 460 nm every 112 seconds for 37 minutes using an appropriate plate reader.
  • the fluorescence at 460 nm is converted to nanomoles of AMC using a standard curve and the initial rate of AMC formation is calculated.
  • the initial rates are used to fit the rectangular hyperbola of Michaelis-Menten by nonlinear regression analysis (GraphPad Software Prism 3.0).
  • the ratio of the apparent Km/Vmax vs. inhibitor concentration is plotted and the competitive Ki is calculated by linear regression to be the negative x-intercept.
  • the uncompetitve Ki is similarly calculated from the x-intercept of the plot of the reciprocal of the apparent Vmax versus the inhibitor concentration (Cornish-Bowden , A. 1995. Fundamentals of Enzyme Kinetics. Revised edition. Portland Press, Ltd., London, U.K.).
  • the compounds of the present invention were found to inhibit DPP-IV induced fluorescence with inhibitory constants in a range of about 0.0003 ⁇ M to about 0.03 ⁇ M.
  • compounds of the present invention are assayed using the following protocol:
  • the filtrate was transfe ⁇ ed to amber HPLC vials and placed in an autosampler at 37°C.
  • the first sample was immediately injected and counted as the time zero sample.
  • the solution concentration was measured at various timepoints using an appropriate HPLC method.
  • the chromatograms were processed for each compound. The rate and half-life were determined from a plot of log 10 peak area remaining/peak area at zero time vs. exposure time @ 37 °C using Microsoft® Excel 2000. Rates of reaction and half-lives were calculated using a pseudo-first order kinetic model.
  • Comparative compound ⁇ Comparative compound ⁇ Comparative compound ⁇ Representative potency and chemical stability data of both the Comparative compounds and the compounds of the present invention are shown below in Table I. Compounds of the present invention are both potent and stable, as indicated for Compounds listed below.
  • the compounds of the present invention are useful in treating disorders that are mediated by DPP-IV.
  • Disorders that are mediated by DPP-IV include diabetes, type II diabetes, hyperglycemia, Syndrome X, hyperinsulinemia, ⁇ -cell failure and obesity. Therefore the compounds of the present invention are useful in treating the disorder of diabetes, type II diabetes, hyperglycemia, Syndrome X, hyperinsulinemia, ⁇ -cell failure and obesity.
  • Compounds of the present invention are evaluated for the ability to treat diabetes using an acute oral glucose tolerance test (OGTT) as follows: Insulin resistant female ZDF rats, 11 weeks of age, on a normal chow diet, are fasted overnight.
  • OGTT acute oral glucose tolerance test
  • a baseline tail snip blood sample is taken to measure glucose levels (Precision PCx glucose meter, Abbott Laboratories, Abbott Park, IL) at the beginning of the experiment. Immediately after this baseline sample, compounds of the present invention (or placebo) are dosed orally. Four hours later, a tail snip blood glucose measurement is taken, immediately followed by an oral glucose dose (OGTT, 2 gm/kg). The glucose excursion is followed for 2 hr with samples taken at 10, 20, 30, 60 and 120 min post OGTT. These timed glucose data are used to construct a glucose excursion curve, from which an area under the glucose curve (AUGC) is determined. Data are reported as the baseline-adjusted area under the glucose curve (deltaAUGC) for drug and control groups.
  • AUGC area under the glucose curve
  • Dipeptidyl-peptidase IV (DPP-IV, EC 3.4.14.5; CD26) is a post-proline cleaving serine protease with significant homology to other alpha-beta hydroxylases (e.g. prolyl oligopeptidase).
  • DPP-IV is found throughout the body, both circulating in plasma and as a type II membrane protein produced by a variety of tissues, including kidney, liver and intestine. DPP-IV plays a role in the cleavage of specific substrates with accessible amino-terminal Xaa-Pro- or Xaa-Ala- dipeptide sequences, resulting in their inactivation or alteration in their biological activities.
  • DPP-IV substrates include growth hormone releasing hormone, glucagon-like peptides (GLP)- 1 and 2, gastric inhibitory polypeptide (GIP) and certain chemokines like RANTES (regulated on activation, normal T cell expressed and secreted), stromal cell-derived factor, eotaxin, and macrophage-derived chemokine (Mentlein, R. Regulatory Peptides, 1999, 85, 9-24).
  • GLP gastric inhibitory polypeptide
  • chemokines like RANTES (regulated on activation, normal T cell expressed and secreted)
  • stromal cell-derived factor stromal cell-derived factor
  • eotaxin eotaxin
  • macrophage-derived chemokine Mentlein, R. Regulatory Peptides, 1999, 85, 9-24.
  • the DPP-TV substrate, glucagon-like peptide (GLP)-l is released from L cells in the distal small intestine and colon after oral ingestion of nutrients.
  • GLP-1 (7- 36) amide Other activities attributed to GLP-1 (7- 36) amide include stimulation of insulin gene expression, trophic effects on pancreatic beta cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and slowing of gastric emptying (Drucker, D. J. Diabetes, 1998, 47, 159-169). These effects of GLP-1 (7-36) amide contribute to glucose homeostasis and the normalization of blood glucose levels in conditions of impaired glucose tolerance.
  • GLP-1 (7-36) amide has been demonstrated to reduce postprandial and fasting glycemia in patients with insulin-dependent and non-insulin-dependent diabetes mellitus (Nauck, et al., Hormone Metab. Res. 2002, 29, 411-416; Gutniak et al., J. Internal Medicine, 2001, 250, 81-87; Rauchman, et al., Diabetologia. 1997, 40,
  • GLP-1 based therapy has therapeutic potential for the treatment of type 2 diabetes.
  • active GLP-1 (7-36) amide is rapidly converted to GLP-1 (9-36) amide by DPP-IV cleavage of the amino-terminal His-Ala- dipeptide of GLP-1 (7-36) amide (Mentlein, et al., Eur. J. Biochem. 1993, 214, 829-835).
  • the resulting GLP-1 (9-36) amide is inactive and is an antagonist of the GLP-1 receptor (Knudson, et al., Eur. J. Pharmacol. 1996, 318, 429-35).
  • GLP-1 (7-36) amide in the circulation (1-1.5 minutes) makes it impractical as a therapeutic agent and has led to the development of alternative strategies to enhance the anti-diabetogenic activity of GLP-1.
  • One strategy is to increase the circulating half-life of GLP-1, by inhibiting DPP-IV activity (Deacon, et al., Diabetes 1995, 44 1126-31). Inhibition of DPP-IV in vivo increases the level of circulating GLP-1 (7-36) amide with a concomitant increase in its insulinotropic effect (Deacon, et al., Diabetes. 1998, 47, 764-9).
  • a DPP-IV inhibitor has been demonstrated to improve glucose tolerance in non-insulin-dependent diabetes mellitus (Ahren B, et al., Diabetes Care 2002, 25, 869-875). Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used in the treatment of conditions caused by or associated with impaired glucose tolerance including the prevention or treatment of diabetes, especially non-insulin- dependent diabetes mellitus, hyperglycemia, hyperinsulinemia and metabolic syndrome (Johannsson, et al., J. Endocrinol. Invest. 1999, 22(5 Suppl), 41-6). Striking similarities exist between the metabolic syndrome (syndrome X) and untreated growth hormone deficiency.
  • compounds of the present invention may be used alone, or in combination with any existing anti-diabetic agent.
  • Agents which may be used in combination with the compounds of the present invention include, but are not limited to insulin, an insulin analog such as mecasermin and the like, an insulin secretagogue such as nateglinide and the like, a biguanide such as metformin and the like, a sulfonylurea such as chlo ⁇ ropamide, glipizide, glyburide, and the like, an insulin sensitizing agent such as a PPAR ⁇ agonist such as froglitazone, pioglitazone, rosiglitazone, and the like, an ⁇ -glucosidase inhibitor such as acarbose, voglibose, miglitol and the like, an aldose reductase inhibitor such as zopolrestat and the like, a metiglinide such as repaglinide and the like, a glycogen phosphorylase inhibitor, GLP-1 or a mimetic of GLP-1 such as exendin
  • DPP-IV-mediated proteolysis has been established as a major route of growth hormone releasing hormone (GHRH) degradation and inactivation (Kubiak, et al., Drug Metab. Dispos. 1989, 17, 393-7). GHRH-derivatives that are resistant to DPP- IV cleavage are more potent in increasing serum growth hormone levels when administered i.v.
  • the compounds of the present invention can be used in the treatment of conditions associated with deficiency in growth hormone including metabolic disorders (central obesity, dyslipidemia), osteoporosis and frailty of aging.
  • Diabetic dyslipidemia is characterized by multiple lipoprotein defects including moderately high serum levels of cholesterol and triglycerides, small LDL particles and low levels of HDL cholesterol.
  • the dyslipidemia associated with non- insulin-dependent diabetes mellitus is improved in conjunction with improved diabetic condition following treatment with GLP-1 (Junti-Berggren, et al., Diabetes Care 1996, 19, 1200-6).
  • DPP-IV inhibition is predicted to increase the level of circulating GLP-1 (7-36) amide and thereby would be effective in the treatment of diabetic dyslipidemia and associated complications. Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used in the treatment hypercholesterolemia, hypertriglyceridemia and associated cardiovascular disease.
  • Parenteral injection of GLP-1 (7-36) amide in healthy men, obese men or patients with non-insulin-dependent diabetes mellitus has been reported to promote satiety and to suppress food intake (Flint, et al., J. Clin. Invest. 1998, 101, 515-520; Naslund, et al., Am. J. Clin. Nutr.
  • the compounds of the present invention including but not limited to those specified in the examples can be used in the treatment of obesity.
  • compounds of the present invention may be used alone, or in combination with any existing anti-obesity agent as described by Flint, A.; Raben, A.; Astrup, A.; Hoist, J. J. in J. Clin. Invest. 1998, 101, 515-520 or by Toft-
  • Agents which may be used in combination with the compounds of the present invention include, but are not limited to fatty acid uptake inhibitors such as orlistat and the like, monoamine reuptake inhibitors such as sibutramine and the like, anorectic agents such as dexfenfluramine, bromocryptine, and the like, sympathomimetics such as phentermine, phendimetrazine, mazindol, and the like, thyromimetic agents, or other such anti-obesity agents that are known to one skilled in the art.
  • fatty acid uptake inhibitors such as orlistat and the like
  • monoamine reuptake inhibitors such as sibutramine and the like
  • anorectic agents such as dexfenfluramine, bromocryptine, and the like
  • sympathomimetics such as phentermine, phendimetrazine, mazindol, and the like
  • thyromimetic agents or other such anti-obesity agents that are known
  • DPP- IV is expressed on a fraction of resting T cells at low density but is strongly upregulated following T-cell activation. DPP-IV may have important functions on T cells and in the immune system. Synthetic inhibitors of the enzymatic activity of CD26 have been shown to suppress certain immune reactions in vitro and in vivo. In vitro recombinant soluble DPP-IV enhances proliferative responses of peripheral blood lymphocytes to stimulation with soluble tetanus toxoid antigen. In addition, the enhancing effect requires DPP-IV enzyme activity (Tanaka, et al., Proc.
  • Soluble DPP-IV up-regulates the expression of the costimulatory molecule CD86 on monocytes through its dipeptidyl peptidase IV activity suggesting that ⁇ soluble DPP-IV enhances T cell immune response to recall antigen via its direct effect on antigen presenting cells (Ohnuma, et al, J. Immunol. 2001, 757(12), 6745-55).
  • the compounds of the present invention including but not limited to those specified in the examples can be used in the treatment of rheumatoid arthritis, multiple sclerosis, scleraderma, chronic inflammatory bowel disease or syndrome and allograft rejection in transplantation.
  • enteroendocrine L cells secrete glucagon-like peptide 2 (GLP-2) in response to food intake.
  • GLP-2 has trophic effects on intestinal epithelium and has been demonstrated to promote nutrient abso ⁇ tion in rodents (Drucker, DJ in Gastroenterology 2002, 122, 531-544) and to promote intestinal mucosal wound healing (Bulut, K., et. al, in Regulatory Peptides, 2004, 121, 137- 143).
  • GLP-2 is a likely in vivo substrate for DPP-IV and inhibitors of DPP-IV are predicted to potentiate the action of endogenous GLP-2. Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used in the treatment of inflammatory bowel syndrome, Crohn's disease and short bowel disease and other malabso ⁇ tion disorders.
  • Chemokine receptors, especially CCR5 and CXCR4 act as cofactors for HIV-
  • the CXC chemokine, stromal cell derived factor- 1 (SDF-1) is a chemokine for resting T-lymphocytes and monocytes.
  • SDF-1 exists as two splice variants, SDF-lalpha and SDF-lbeta that differ by four additional C-terminal residues in SDF-lbeta. Truncation of the N-terminal Lys-Pro- residues from both SDF-1 alpha and SDF-1 beta results in the loss of their chemotactic and antiviral activities in vitro (Ohtsuki, et al, FEBSLett.
  • DPP-IV inactivates SDF-1 alpha as a ligand for CXCR4 that is a T cell chemotactic receptor as well as the major co-receptor for T-tropic HIV-1 strains. DPP-IV inhibition would be predicted to increase full-length SDF-1 levels and thereby suppress HTV-1 entry into CXCR4+ cells. Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used in the treatment of HIV infection (AIDS).
  • DPP-IV inhibition may be useful in hematopoeitic stem cell (HSC) transplantation (Christopherson, KW, et.al, in Science, 2004, 305, 1000-10002).
  • HSC hematopoeitic stem cell
  • Expression of DPP-IV on the surface of HSC decreases homing and engraftment to bone ma ⁇ ow niches.
  • DPP-IV inhibition greatly increases the efficiency of transplantation. Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used to improve bone ma ⁇ ow transplant efficiency.
  • Mice deficient in GLP-1 receptor signaling have learning deficits and increased neural injury after kainite administration (During, MJ, et.al., in Nature Medicine, 2003, 9, 1173-1179).
  • GLP-1 receptor agonists prevent kainite- induced neuronal apoptosis in normal animals.
  • DPP-IV inhibitors would be predicted to increase active GLP-1 and show similar effects. Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used for the treatment of Alzheimer's Disease and other neurodegenerative and cognitive disorders.
  • compounds of the general formula 1 which may either be purchased directly or may be obtained by modifying commercially available starting material through methods commonly known to those skilled in the art, may be treated with compounds of general formula 2 along with reagents such as but not limited to benzotriazol- 1 -yl-oxy-tris-py ⁇ olidino-phpsphoniumhexafluorophosphate (PyBOP), l-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI), 2-(lH-benzotriazol-lyl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) in the presence of a base such as but not limited to N-methylmo ⁇ holine or diisopropylethylamine in solvents such as but not limited to dichloromethane to provide compounds of general formula 3.
  • reagents such as but not limited to benzotriazol- 1 -yl-oxy
  • Compounds of formula 3 may be treated trifluoroacetic acid in dichloromethane or with reagents known to deprotect the nitrogen protecting group as known to those skilled in the art or demonstrated in Greene, T.W. and Wuts, G.M. "Protective groups in Organic Synthesis", third ed. John Wiley & Sons, 1999, to provide compounds of general formula 4, which are representative of compounds of formula (I).
  • ethyl (S)-(+)-2-py ⁇ olidone-5-carboxylate 5 can be treated with di-tert-butyl dicarbonate ((Boc) 2 O) in solvents such as but not limited to THF, dioxane or acetonitrile followed by treatment with Grignard reagents of general formula R ⁇ BAMgBr, wherein R l5 B and A are as defined in formula (I) in solvents such as but not limited to THF and diethyl ether to provide compounds of general formula 6.
  • the treatment of compounds of general formula 6 with reagents that deprotect a nitrogen protecting group such as the removal of the Boc protecting group with TFA will provide compounds of general formula 7.
  • compounds of general formula 17 which were described in Scheme 3, can be treated with sodium borohydride in solvents such as but not limited to THF and dioxane to provide compounds of general formula 20.
  • Compounds of general formula 20 can be treated with compounds of general formula R ⁇ -halogen and abase, wherein R ⁇ is alkyl, alkylcarbonyl, arylalkyl, arylcarbonyl, cycloalkylalkyl, heterocyclealkyl, heterocyclecarbonyl and hydroxyalkyl and halogen is chloro, bromo, or iodo to provide compounds of general formula 21.
  • Typical bases for this transformation include but are not limited to triethylamine, diisopropylethylamine, sodium methoxide, sodium hydride but may include others depending upon R 2 -halogen or as known to those skilled in the art.
  • the transformation of compounds of general formula 21 to compounds of general formula 22 can be accomplished using trifluoroacetic acid or other methods known to remove Boc protecting groups from nitrogen atoms.
  • Compounds of general formula 20 can be treated with compounds of formula R t OH, diethylazodicarboxylate and triphenylphosphine in solvents such as but not limited to tefrahydrofuran to provide compounds of general formula 21.
  • Compounds of general formula 21 can be converted into compounds of general formula 22 using conditions described in Scheme 4.
  • compounds of general formula 20 may be converted to a mesylate of general formula 23 upon treatment of compounds of formula 20 with methanesulfonyl chloride and triethylamine in dichloromethane.
  • Mesylates of general formula 23 when treated with a nucleophile RpBH which may be a heterocycle or aryl or heteroaryl or other group, will provide a compound of general formula 24.
  • Typical conditions for this reaction include but are not limited to the treatment of compounds of general formula 23 with a nucleophile and a base such as sodium hydride in tefrahydrofuran or cesium carbonate in DMF will provide compounds of general formula 24.
  • nucleophiles may also be treated with sodium hydride in tefrahydrofuran followed by treatment with compounds of general formula 23 to provide compounds of general formula 24.
  • the conversion of compounds of general formula 24 to compounds of general formula 25 can be effected through conditions described above or are known to those skilled in the art.
  • Scheme 7 As shown in Scheme 7, compounds of general formula 28 can be oxidized through conditions such as but not limited to oxalyl chloride, DMSO and triethyl amine; pyndmium chlorochromate; pyridinium dichromate and the like followed the treatment with (diethylamino)sulfur trifluoride (DAST) to provide compounds of general formula 29.
  • DAST diethylamino)sulfur trifluoride
  • the ester functionality of compounds of general formula 29 can be hydrolyzed upon treatment with lithium hydroxide in aqueous methanol or through methods know to those skilled in the art, followed by first treatment with isobutyl chloroformate followed by addition of aqueous ammonia to the reaction mixture to provide compounds of general formula 30.
  • Compounds of general formula 30 can be treated with trifluoroacetic acid to remove the Boc protecting group to provide compounds of general formula 31.
  • Compounds of general formula 31 can be treated with compounds of general formula 1 and TBTU to provide compounds of general formula 32.
  • Compounds of general formula 32 can be treated with phosphorous oxychloride, pyridine and DMAP followed by treatment with trifluoroacetic acid to provide compounds of general formula 33.
  • compounds of general formula 17 can be treated with reagents such as but not limited to KMnO to provide compounds of general formula 34.
  • the acid functionality of compounds of general formula 34 can be activated with TBTU in the presence of an amine of formula R 1 NH 2 to provide compounds of general formula 35.
  • Compounds of general formula 35 can be treated with TFA to provide compounds of general formula 36.
  • the required tert-butyl ester phenol of general formula 40 can be synthesized form bromophenols of general formula 37.
  • Bromophenols 37 can be carbonylated under carbon monoxide atmosphere in the presence of proper palladium catalyst.
  • the resulting esters 38 can be hydrolyzed with proper base such as LiOH to afford the co ⁇ esponding acids 39.
  • Acids 39 can be treated with either N,N- dimethylformaldehyde di(tert-butyl)acetal or a proper coupling reagent such as DCC to afford tert-butyl ester phenol 40.
  • the nitrogen atom of the pyridinyl group in general structure 41 can be oxidized with a proper reagent such as /weta-chloroperoxybenzoic acid (mCPBA). Removal of the Boc group with a proper reagent such as trifluoroacetic acid (TFA) affords the desired N-oxides of general structure 42.
  • a proper reagent such as /weta-chloroperoxybenzoic acid (mCPBA).
  • TFA trifluoroacetic acid
  • Example 1A 2S-tert-butoxycarbonylamino-5-oxo-heptanoic acid ethyl ester Ethyl N-Boc (S)-pyroglutamate (2.33 g, 9.06 mmol) prepared as described by:
  • Example IB 5-ethyl-3,4-dihydro-2H-py ⁇ ole- (2S)-carboxylic acid ethyl ester
  • the ester from Example 1A was dissolved in 3 mL of CH C1 2 and treated with 3 mL of trifluoroacetic acid at room temperature. After 3 hours, the volatiles were evaporated to provide the titled compound.
  • MS (ESI) m/z 170 (M+H) + .
  • Example IE 5S-Ethyl-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester The material from Example ID (3.69 g, 14.34 mmol) in 15 mL of EtOH was treated with 14.3 mL of 1.7 N LiOH. After 4 hours, the mixture was concentrated in vacuo, acidified with IN HC1 and extracted with ethyl acetate. The organic extracts were dried with Na 2 SO and concentrated to provide the title compound which was used without further purification in the next step.
  • the material prepared in Example IE (201 mg, 0.88 mmol), 2S- cyanopy ⁇ olidine hydrochloride (1.1 mol) and PyBOP (641 mg, 1.23 mmol) were mixed in 3.5 mL of CH 2 C1 2 followed by addition of 422 ⁇ L of dusopropylethylamine
  • Example 1G (2S)- 1 -((5S)-5 -ethyl-L-prolyl)py ⁇ olidine-2-carbonitrile
  • the sample of Example IF (180 mg) dissolved in 1 mL of CH 2 C1 2 was treated with 1.5 mL of TFA. After 4 hours, the mixture was concentrated and the residue dissolved in 3 mL of MeOH, then purified by reverse-phase HPLC (0% to 70% CH 3 CN H 2 O contained 0.1% TFA.) to provide the title compound as the co ⁇ esponding trifluoroacetic acid salt (147 mg).
  • Example 2 (2S)- 1 -((5ig)-5-phenyl-L-prolyl)py ⁇ olidine-2-carboni ⁇ rile
  • the title compound was synthesized by substituting 5S-ethyl-N-Boc-2S- proline in Example 1 with 5R- ⁇ henyl-N-Boc-2S- ⁇ roline.
  • H NMR MeOH-d 4 , 500 MHz
  • ⁇ 2.29 (m, 6 H) 2.48 (m, 1 H) 2.64 (m, 1 H) 3.69 (m, 2 H) 4.74 (m, 2 H) 4.86 (dd, J 7.80, 4.37 Hz, 1 H) 7.48 (m, 3 H) 7.61 (m, 2 H) ppm.
  • MS (ESI) m/z 270 (M+H) + .
  • Example 3A 4-Oxo-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • Oxalyl chloride (1.30 mL, 14.96 mmol) was added to 10 mL of CH 2 C1 2 and cooled to -78 °C.
  • DMSO (1.33 mL, 18.70 mmol) was added via syringe.
  • 4R-hydroxy-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.83 g, 7.48 mmol) in 12 mL of CH 2 C1 2 was added.
  • Et 3 N (3.64 mL) was added.
  • Example 3B 4,4-Difluoro-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • the compound from Example 3 A (2.20 g) in 15 mL of CH 2 C1 2 was cooled to - 50 °C, then Et 2 NSF 3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was sti ⁇ ed overnight. NaHCO 3 solution was added slowly to the mixture and the mixture was extracted with dichloromethane
  • Example 3C 4,4-Difluoro-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester
  • the compound from Example 3B (1.80 g, 6.78 mmol) was dissolved in 3 mL each of MeOH and THF, then 6.8 mL of 1.7 N LiOH was added. After stirring for 2 hours, the mixture was concentrated in vacuo, and ethyl acetate and IN HC1 were added.
  • Example 3D 2S-Carbamoyl-4,4-difluoro-py ⁇ olidine-l -carboxylic acid tert-butyl ester
  • the compound from Example 3C and triethylamine (1.7 mL) were mixed with 15 mL of THF and cooled to 0 °C.
  • Isobutyl chloroformate (1.14 mL) was added via syringe. After 30 minutes, 27.1 mL of 0.5 N NH 3 in dioxane were added. After stirring overnight, the mixture was concentrated in vacuo and extracted with ethyl acetate.
  • Example 3E 4,4-Difluoro-pyrrolidine-2S-carboxylic acid amide
  • the compound from Example 3D (802 mg, 3.2 mmol) in 1.5 mL of CH 2 C1 2 was treated with 2.0 mL of TFA. After 4 hours, the mixture was concentrated to provide the crude amino amide (1.05g).
  • Example 3F 2S-(2S-Carbamoyl-4,4-difluoro-py ⁇ olidine- 1 -carbonyl)-5S-methyl-py ⁇ olidine- 1 - carboxylic acid tert-butyl ester
  • the compound from Example 3E (303 mg, 0.93 mmol), 5S-methyl- py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester ( leq, prepared as described in Example 5) and 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1.4 eq.) were mixed in 2 mL of DMF, then Et 3 N was added until the pH of the mixture reached 6-7 (wet pH paper). The mixture was sti ⁇ ed overnight and purified by reverse-phase HPLC to provide the titled compound. (170 mg, 56%).
  • Example 3G 2S-(2S-Cyano-4,4-difluoro-py ⁇ olidine- 1 -carbonyl)- 5S-methyl-py ⁇ olidine-l -carboxylic acid tert-butyl ester
  • the compound of Example 3F 160 mg, 0.44 mmol
  • imidazole (1.25 eq.) was mixed in 3 mL of pyridine and cooled to -30 °C, then POCl 3 (2.5 eq.) was added via syringe. The mixture was then placed in a freezer (-20 °C) overnight. Saturated NH 4 C1 solution was added, and the mixture was concentrated in vacuo. The mixture was taken up in ethyl acetate and washed with IN HC1 and then brine. The organic layer was dried with Na 2 SO 4 and concentrated to provide the title compound (147 mg).
  • Example 3H (2S)-4,4-difluoro- 1 -((5S)-5-methyl-L-prol ⁇ l)py ⁇ olidine-2-carbonitrile
  • the Boc group of Example 3G was removed as described in Example 1G to provide the title compound.
  • Example 1 with thiazolidine and using the methyl py ⁇ olidine prepared as described in Example 5.
  • MS (ESI) m/z 201 (M+H) + .
  • Example 5 (2S)- 1 -((5 S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile The title compound was synthesized by substituting EtMgBr in Example 1 with MeMgBr.
  • Example 6 (2S)- 1 -((5S)-5-ethyl-L-prolyl)-4,4-difluoropy ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 5S-methyl-N-Boc-2S- proline in Example 3 with 5S-ethyl-N-Boc-2S-proline prepared as described in Example 1.
  • Example 7A 5R-ethyl-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 5S-Vinyl-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • Example 22B lg and 10% Pd/C (200 mg) were sti ⁇ ed in ethanol (20mL) under an atmosphere of hydrogen at room temperature for 16 hours. The catalyst was removed by filtration, and the filtrate concentrated under reduced pressure to provide the title compound (lg, 99 %). MS (DCI) m/z 258 (M+H) + .
  • Example 7B (2S)-l- ⁇ (5S)-5-((4-bromophenoxy)methyl)-L-prolyl ⁇ py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 5S-ethyl-py ⁇ olidine-l,2S- dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in Example 1 with 5R-ethyl- py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester prepared in Example 7A.
  • Example 8 (2S)- 1 -((5R)-5-isopropyl-L-prolyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting EtMgBr in Example 1 with i-PrMgBr.
  • Example 9 (2S)- 1 -((5R)-5- ⁇ ((4-methoxyphenyl)amino)methyl) -L-prolyl)py ⁇ olidine-2- carbonitrile
  • Example 9A dimethyl (2S)-5-oxopy ⁇ olidine- 1 ,2-dicarboxylate In a procedure adapted from Li, H.; Sakamoto, T.; Kato, M.; Kikugawa, Y. Synth. Commun.
  • the resulting slurry was sti ⁇ ed at -78 °C for 1 hour after which the reaction was quenched with 1 MHO (50 mL). The mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and 1 HC1 (200 mL). The aqueous layer was extracted with ethyl acetate (2 X 200 mL), and the combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound (5.85 g, 86% yield).
  • Example 9B dimethyl (2S)-5-methoxypy ⁇ olidine- 1 ,2-dicarboxylate
  • a cold solution (-78 °C) of dimethyl (2S)-5-oxo ⁇ y ⁇ olidine-l,2- dicarboxylate (.80 g, 28.8 mmol) in tetrahydrofuran (100 mL) was added a solution of lithium triethylborohydride (1 Min THF, 35 mL, 35 mmol) dropwise via syringe over 10 minutes.
  • the resulting solution was sti ⁇ ed at -78 °C for 30 minutes and then quenched by the careful addition of saturated sodium bicarbonate solution (50 mL).
  • the reaction was diluted with aqueous sodium bicarbonate solution (40 mL), the volatile solvents were removed under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and brine (200 mL). The aqueous layer was further extracted with ethyl acetate (200 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to an oil which was purified by flash chromatography using 60% hexane/40% ethyl acetate as eluent to provide the titled compound (3.80 g, 61 % yield) as a mixture of diastereomers.
  • Example 9C dimethyl (2S,5i?)-5-((trimethylsilyl)ethynyl)py ⁇ olidine- 1 ,2-dicarboxylate and dimethyl (2S,5S)-5-((trimethylsilyl)ethynyl)py ⁇ olidine- 1 ,2-dicarboxylate Using a procedure adapted from Beal, L.M.; Liu,B.; Chu, W.; Moeller, K.D.
  • Iodotrimethylsilane (6.4 mL, 42.9mmol) was added to the solution of the 2S5i?-isomer of Example 9C (10.15 g, 35.8 mmol) in chloroform (20 mL). The mixture was sti ⁇ ed for 1.5 hours at 65 °C. The mixture was concentrated under reduced pressure, purified by chromatography (50%-60% EtOAc/Hexane) to give the title amine (7.4 g, 93%). MS (DCI) m/z 226 (M+H) + .
  • Example 9E 5i?-Ethynyl-py ⁇ olidine-l, 2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The compound of Example 9D (7.4 g, 32.9 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.8 mmol) were dissolved in dichloromethane (20 mL) then triethylamine (7.2 mL) was added. After the reaction was over, the mixture was concentrated xmder reduced pressure to give the crude Boc-protected py ⁇ olidine (10.5 g), which was used in the next step without purification. MS (DCI) m/z 326 (M+H) + .
  • Example 9F 5R-Ethenyl-py ⁇ olidine-l, 2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • Boc-protected amine (6.9 g, 27.2 mmol) was dissolved in ethyl acetate (130 mL).
  • 5% Pd/BaSO 4 260 mg
  • quinoline 6.5 mL
  • the mixture was sti ⁇ ed under H (20 psi ) at room temperature for 4-5 minutes.
  • Example 9G 2S-(2S-Cyano-py ⁇ olidine- 1 -carbonyl)-5i.- vinyl-py ⁇ olidine- 1 -carboxylic acid tert- butyl ester
  • Example 9H 2S-(2S-Cyano-py ⁇ olidine- 1 -carbonyl)-5R- formyl-py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the compound of Example 9G (0.34 g, 1.06mmol) in 2 mL each of CH 2 C1 2 and MeOH was cooled to -78 °C, and O 3 was bubbled into the mixture for 30 minutes. Then O 2 was bubbled for 5 minutes followed by the addition of Me 2 S (2 mL). The cooling bath was then removed allowing the mixture to slowly warm over 1.5 hours. The mixture was concentrated in vacuo, and the resulting oil purified by column chromatography to provide the aldehyde product (270 mg, 78%).
  • Example 91 2S-(2S-Cyano- ⁇ y ⁇ olidine- 1 -carbonyp-5 i ⁇ - ⁇ ((4-methoxy-phenyl)-methyl-amino)- methyl ⁇ -py ⁇ olidine-l -carboxylic acid tert-butyl ester
  • the compound from Example 9H 50 mg, 0.155 mmol
  • Example 9J (2S)-l-((5R)-5- ⁇ ((4-methoxyphenyl)amino)methyl ⁇ -L-prolyl)py ⁇ olidine-2- carbonitrile
  • the Boc group of Example 91 was removed as described in Example 1G to provide the title compound.
  • Example 10 (2S)- 1 -((5R)-5- ⁇ ((4-memylphenyl)amino)methyl ⁇ -L-prolyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 4-methoxyaniline in Example 9 with 4-methylaniline.
  • Example 11 6-((5-(2-cyano-py ⁇ olidme-l-carbonyl)-py ⁇ olidin-2-ylmethyl -amino)-nicotinonitrile
  • the title compound was synthesized by substituting 4-methoxyaniline in Example 9 with 6-aminonicotinonitrile.
  • Example 13 (2S)-l-((5R)-5- ⁇ ((phenyl)amino)methyl ⁇ -L-prolyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 4-methoxyaniline in Example 9 with aniline.
  • Example 14A 2S-(2S-Cyano-py ⁇ olidine- 1 -carbonyl)-5R- hydroxymethyl-py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the compound of Example 9G (3.0 g, 9.3 mmol) in 6 mL each of CH 2 C1 2 and MeOH were cooled to -78 °C, and O 3 was bubbled into the mixture for 30 minutes. Then O was bubbled for 5 minutes followed by the addition of Me S (5 mL). The cooling bath was then removed, and the mixture was allowed to warm with stirring over 1.5 hours. The mixture was then concentrated in vacuo.
  • Example 14B (2S)- 1 -((5- ⁇ )-5-(hydroxymethyl)-L-prolyl)py ⁇ olidine-2-carbonitrile
  • the compound of Example 14A was treated as described in Example 1G to provide the title compound.
  • Example 15 (2S)-l- ⁇ (5i?)-5-((4-bromophenoxy)methyl)-L-prolyl ⁇ py ⁇ olidine-2-carbonitrile
  • the compound of Example 14A 50 mg, 0.154 mmol
  • triphenylphosphine 53 mg, 0.200 mmol
  • 4-bromophenol (0.17 mmol) were mixed in 1 mL of dry THF.
  • diethyl azodicarboxylate 50% in toluene, 0.093 mL, 0.21 mmol
  • the reaction was heated at 50 °C overnight and purified by reverse phase HPLC. This intermediate was treated as described in Example 1G to provide the title compound.
  • Example 16 (2S)- 1 - ⁇ (5S)-5-((4-bromophenoxy)meth.yl)-L-prolyl ⁇ pyrrolidine-2-carbonitrile
  • the trans alcohol was synthesized by substituting the co ⁇ esponding cis olefin in Example 14 with the co ⁇ esponding trans olefin.
  • the title compound was synthesized by substituting the 5R alcohol in Example 15 with the co ⁇ esponding 5S isomer.
  • Example 19 3- ⁇ (5i?)-5-((4-bromophenoxy)methyl)-L-prolyl ⁇ - 1 ,3-thiazolidine
  • the title compound was synthesized by substituting 2S-cyanopy ⁇ olidine in Example 15 with thiazolidine.
  • 1H NMR (MeOH-d ⁇ , 500 MHz) ⁇ 1.98 (m, 1 H), 2.22 (m, 1 H), 2.32 (m, 1 H), 2.56 (m, 1 H), 3.10 (m, 1 H), 3.18 (m, 1 H), 3.77 (m, 1 H),
  • Example 21 (2S)- 1 - ⁇ (5ig)-5-((2-chlorophenoxy)methyl)-L-prolyl ⁇ py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 4-bromophenol in Example 15 with 2-chlorophenol.
  • Example 22A 5S-Ethynyl-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Iodotrimethylsilane (6.17 mL, 43.2 mmol) was added to the solution of dimethyl (2S,5S)-5-((trimethylsilyl)ethynyl)py ⁇ olidine-l,2-dicarboxylate (10.2 g, 36 mmol, Example 9C) in chloroform (20 mL). The mixture was sti ⁇ ed for 2 hours at 65 °C. The mixture was concentrated under reduced pressure.
  • Example 22B 5S-Vinyl-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • Boc-protected amine 6.2 g, 24.5 mmol
  • ethyl acetate 124 mL
  • 5% Pd/BaSO 4 248 mg
  • quinoline 6.2 mL
  • the mixture was sti ⁇ ed under 20 psi H 2 at room temperature for 4-5 minutes.
  • the mixture was filtered, washed with 1 N HC1 and concentrated to provide the vinyl product (6.2 g 100%).
  • Example 22C 5S-Vinyl- ⁇ y ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester
  • Example 22D 2S-(2S-Cyano-py ⁇ olidine- 1 -carbonyl -5S- vinyl-py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • Example 22C (1.01 g, 4.14 mmol), 2S-cyano ⁇ y ⁇ olidine HC1 salt (4.97 mmol) and 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethylxrronium tetrafluoroborate (TBTU, 1.60 g, 4.97 mmol) were mixed in 4 mL each of CH 2 C1 2 and DMF, and then Et 3 N (approx.
  • Example 22E (2S)-l-((5S)-5-vinyl-L-prolyl)py ⁇ olidine-2-carbonitrile
  • the Boc group of Example 22D was removed as described in Example 1G to provide the title compound.
  • Example 23 (2S)-l- ⁇ (5iyS)-5-((E)-2-(3-methylphenyl)vinyl)-L-prolyl ⁇ py ⁇ olidine-2-carbonitrile
  • a 5 mL microwave tube was charged with a magnetic stirring bar, DMF (2mL), Example 22D (150 mg, 0.59 mmol), palladium acetate (5.6 mg, 0.03 mmol), tri-o-tolyphosphine (15 mg, 0.06 mmol), diisopropylethylamine(0.18 mL, 118 mmol) and 3-methyliodobenzene (0.6 mmol).
  • the tube was flushed with nitrogen and placed in the microwave reaction vessel.
  • Example 24 (2S)-l- ⁇ (5R/S)-5-((E)-2- ⁇ henylvinyl)-L-prolyl>py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with iodobenzene.
  • Example 25 (2S)-l-((5S/R)-5-((E)-2-(4-methylphenyl)vinyl)-L- ⁇ rolyl ⁇ py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-methyliodobenzene.
  • Example 26 (2S)-l- ⁇ (5S/R)-5-((E)-2-(2-bromo ⁇ henyl)vinyl)-L-prolyl ⁇ y ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 2-bromoiodobenzene.
  • Example 27 (2S)-l- ⁇ (5S/i-)-5-((E)-2-(2-methylphenyl)vinyl)-L-prolyl ⁇ y ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 2-methyliodobenzene.
  • Example 29 (2S)-l-((5R S)-5- ⁇ (E)-2-(4-(trifluoromethyl)phenyl)vinvU -L-prolyl)pyHolidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-trifluoromethyliodobenzene.
  • Example 31 (2S)- 1 - ⁇ (5R/S)-5-((E)-2-(4-chloro ⁇ henyl)vinyl)-L-prolyl ⁇ py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-chloroiodobenzene.
  • Example 32 (2S)-l- ⁇ (5ig/S)-5-((E)-2-(l,3-benzodioxol-5-yl)vinyl)-L- ⁇ rolyl> ⁇ v ⁇ olidine-2- carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 5-iodo-benzo(l,3)dioxole. !
  • Example 33 (2S)-l- ⁇ (5R/S)-5-((E)-2-(4-hydroxyphenyl)vinyl)-L-prolyl ⁇ py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-hydroxyiodobenzene.
  • Example 34 (2S)-l- ⁇ (5S/i?)-5-((E)-2-(4-methoxyphenyl)vinyl)-L- ⁇ rolyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-methoxyiodobenzene.
  • 1H NMR 400 MHz, MeOH-d 4 ) ⁇ 2.18 (m, 7 H), 2.65 (m, 1 H), 3.65 (m, 2 H), 3.80 (s, 3 H), 4.34 and 4.44 (m, 1 H), 4.63 (dd,
  • Example 35 (2S)-l- ⁇ (5S/ig -5-((E)-2-(3,4-dimethylphenyl)vinyl)-L-prolyl>py ⁇ olidine-2- carbonitrile
  • the title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 3,4-dimethyliodobenzene.
  • Example 36 (2S)-l- ⁇ (5i ⁇ S)-5-(2-(3-memylphenyl)ethyl)-L-prolyllpy ⁇ olidine-2-carbonit ⁇ ile
  • the catalyst was removed by filtration, and the filtrate was concentrated to provide the desired product.
  • Example 37 (2S)-l- ⁇ (5ig/S)-5-(2-(4-chlorophenyl)ethyl)-L- ⁇ rolyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 2-(2-(S)-cyano- py ⁇ olidine-l-carbonyl)-5-(R/S)-(2-m-tolyl-vinyl)-py ⁇ olidine-l -carboxylic acid tert- butyl ester in Example 36 with 2-(2-(S)-cyano-py ⁇ olidine-l-carbonyl)-5-(R/S)-(2-p- chlorophenyl-vinyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester.
  • Example 38 (2S)- 1 -((5R/S)-5-(2- ⁇ henylethyl)-L-prolyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 2-(2-(S)-cyano- py ⁇ olidine- 1 -carbonyl)-5-(R S)-(2-m-tolyl-vinyl)-py ⁇ olidine- 1 -carboxylic acid tert- butyl ester in Example 36 with 2-(2-(S)-cyano-py ⁇ olidine-l-carbonyl)-5-(R/S)-(2- phenyl-vinyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester.
  • Example 39A 2S-(4-Carboxy-phenylcarbamoyl)-5R-(2S-cyano-pyrrolidine- 1 -carbonyl) -py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • 2S-(2S-cyano-py ⁇ olidine-l-carbonyl)-5R-formyl-py ⁇ olidine- 1-carboxylic acid tert-butyl ester (278 mg, 0.865 mmol, Example 9H) in 2ml:3.2 mL of MeCN:t-BuOH was added 3.5 mL of 5% NaH 2 PO 4 solution followed by 5.2 mL of IM KMnO 4 solution (5.2 mmol) at room temperature.
  • Example 39B (2ig,5S)-5- ⁇ ((2S)-2-cyanopy ⁇ olidin-l-yl)carbonyl> -N-(3-carboxy)phenylpy ⁇ olidine-2-carboxamide
  • the crude acid from Step A was coupled to t-butyl 4-aminobenzoate in the presence of TBTU in a similar fashion as described in Example 3.
  • the deprotection was done in the same method as described in Example 1G to provide the title compound.
  • Example 41 (2S)- 1 - ⁇ (5R)-5-(naphthalen- 1 -yloxymethyl)-L-prolyl) -py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 4-bromophenol in Example 15 with 1-naphthol.
  • Example 42 (2S)-l- ⁇ (5R)-5-((4-cyano-2-methoxyphenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the compound of example 14A (0.167 mmol), 2-methoxy-4-cyanophenol (0.3 mmol) and triethylamine (0.334 mmol) were mixed in 2 mL of benzene. Cyanomethylenetri-n-butylphosphorane (CMBP, 0.334 mmol) was added and the mixture was heated to 55 °C. After the reaction was over, the mixture was purified by reverse-phase HPLC to give the title compound (40% yield). MS (ESI) m/z 455 (M+H) + . The Boc group was removed according to Example 1G to give the title compound. 1H NMR (500 MHz, MeOH-d 4 ) ⁇ 1.98 - 2.09 (m, 1 H), 2.10 - 2.46 (m, 5
  • Example 44 (2S)- 1 - ⁇ (5R)-5-((2-chloro-4-cyanophenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • Example 45 (2S)- 1 - ⁇ (5i?)-5-((2-chloropyridyl-3-oxy)-methyl)-L-prolyl> -py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with 2-chloro- ⁇ yridin-3-ol.
  • Example 46A 4-Hydroxy-3-methoxy-benzoic acid tert-butyl ester 4-Hydroxy-3-methoxy-benzoic acid (1.0 g, 5.95 mmol), 1,3- dicyclohexycarbodiimide (1.5 g, 7.14 mmol) and 4-dimethylaminopyridine (72.7 mg, 0.6 mmol) were mixed in t-butanol (10 mL) and sti ⁇ ed at room temperature for 4 hours. The reaction was filtered and purified by column chromatography to provide the title compoiind (1.0 g, 75%).
  • Example 46B (2S)-l- ⁇ (5i ⁇ )-5-((4-carboxy-2-methoxyphenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with the compound of Example 46A.
  • Example 47A 4-Bromo-2-tert-butyl-phenol 2-tert-Butylphenol (2.03 g, 13.51 mmol) was dissolved in the mixture of 60 mL of CH 2 C1 and 40 mL of MeOH, then tetrabutylamonium tribromide (7.82 g,
  • Example 47B 1 -B enzyloxy-4-bromo-2-tert-butyl-benzene
  • the compound of Example 47A (2.24 g, 9.77 mmol), benzyl bromide (1.4 mL, 11.72 mmol) and cesium carbonate (4.77 g, 14.65 mmol) were mixed in 10 mL of acetonitrile. The mixture was heated to 63 °C. After 5 hours, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (100% hexane) to provide the title compound (2.49 g, 80%).
  • Example 47C 4-Benzyloxy-3-tert-butyl-benzoic acid methyl ester
  • the compound of Example 47B (778 mg), PdCl 2 (d ⁇ f CH 2 Cl 2 (200mg), and triethyl amine (1.02 mL) were mixed in 15 mL of methanol in a pressure vessel.
  • the reaction vessel was charged with CO (500 psi) and then heated to 120 °C for 16 hours.
  • the reaction was cooled to ambient temperature and the mixture was filtered.
  • the filtrate was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0% then 10% EtOAc/Hexane) to provide the title compound (670 mg, 92%).
  • Example 47D 4-Benzyloxy-3-tert-butyl-benzoic acid tert-butyl ester
  • the compound of Example 47C (630 mg, 2.11 mmol) in 4 mL of THF was treated with 4 mL of IN NaOH aq. solution at ambient temperature. After stirring overnight, another 2 mL of 1.7 N LiOH aq. solution was added. After all the starting material had disappeared, the mixture was concentrated in vacuo and EtOAc was added to the resulting residue followed by 2N HC1 solution.
  • Example 47E 3-tert-Butyl-4-hydrox ⁇ -benzoic acid tert-butyl ester
  • the compound of Example 47D 400 mg, 1.17 mmol
  • 100 mg of 10% Pd/C were mixed in 3 mL each of EtOAc and EtOH in a flask and purged with nitrogen.
  • a hydrogen balloon was connected to the flask. After all the starting material disappeared, the mixture was filtered. The filtrate was concentrated in vacuo to give the free phenol (322 mg).
  • MS (DCI) m/z 251 (M+H) + .
  • Example 47F 2-(4-tert-Butoxycarbonyl-2-tert-butyl-phenoxymethyl)-5-(2-cyano-py ⁇ olidine-l- carbonyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester
  • the compound of example 14A (305 mg, 0.943 mmol), 3-tert-butyl-4- hydroxy-benzoic acid tert-butyl ester (283 mg, 1.13 mmol), and triphenyl phosphine (396 mg, 1.51 mmol) were mixed in 5 mL of toluene.
  • di-tert-butyl azodicarbonate DBAD, 265 mg, 1.51 mmol
  • Example 47G (2S)-l- ⁇ (5i-)-5-((4-carboxy-2-tert-butylphenoxy)-methyl)-L- ⁇ rolyl>-py ⁇ olidine-2- carbonitrile
  • the compound of Example 47F was deprotected according to the procedures of Example 1G to give the title compound.
  • Example 48 (2S)-l- ⁇ (5i-)-5-((4-carboxy-2-chlorophenoxy)-methyl)-L- ⁇ rolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 2-chlorophenol.
  • Example 49 (2S)- 1 - ⁇ (5i-)-5-((4-carboxy-2- ⁇ Q-propylphenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 2-iso-propylphenol.
  • Example 50 (2S)- 1 - ⁇ (5i-)-5-(r4-(tetrazol-5-yl)-2-chloro ⁇ henoxyl-methyl)-L- ⁇ rolyl) -py ⁇ olidine-2- carbonitrile
  • Example 50A 5R-Hydroxymethyl-py ⁇ olidine-l, 2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • the compound of Example 9F was reacted according to the procedures of
  • Example 5 OB 5R-(2-chloro-4-cyano-phenoxymethyl)-py ⁇ olidine-l ,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
  • the compound of Example 50A was reacted according the procedure of Example 42 to give the title compound.
  • Example 5 PC ' 5R-r2-Chloro-4-(lH-tetrazol-5-yl)-phenoxymethyl1-py ⁇ olidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester NaN 3 (145 mg, 0.17 mmol) and NH 4 C1 (91.8 mg, 0.17 mmol) were added to the compound of Example 50B (520 mg, 0.13 mmol) in DMF (2mL) under N 2 . The reaction was heated to 110 °C for 48 hours. Saturated NaHCO 3 was added and the mixture was extracted with EtOAc (3X). The combined extracts were dried (Na SO 4 ), concentrated and purified by column chromatography to give the product (520 mg, 90 %). MS (ESI) m/z 438, 440 (M+H 1" ).
  • Example 50D Example 5R-r2-Chloro-4-(lH-tetrazol-5-yl)-phenoxymethyl1-py ⁇ o
  • Example 51 (2S)-l- ⁇ (5i-)-5-((5-carboxy-2-chlorophenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the title compound was synthesized by substituting 4-bromo-2-tert-butyl- phenol in Example 47 with 2-chloro-5-bromophenol.
  • Example 52A 5-Hydroxy-nicotinic acid tert-butyl ester 5-Hydroxy-nicotinic acid methyl ester (lg, 5.99 mmol) and potassium t- butoxide (4g, 36 mmol) was sti ⁇ ed in THF (10 mL) and t-butanol (10 mL) at room temperature overnight. IN HC1 was added to adjust pH ⁇ 7 and the mixture was extracted with EtOAc (3X). The combined extracts were dried (Na 2 SO 4 ), concenfrated and purified by column chromatography to give the product (400 mg, 34 %). MS (DCI) m z 196 (M+H) + .
  • Example 52B 6-Chloro-5-hydroxy-nicotinic acid tert-butyl ester
  • the compound of Example 52A 400mg, 2.05 mmol was dissolved in DMF ⁇ (2 mL) and N-chlorosuccinimide (328 mg, 2.46 mmol) was added. The mixture was heated to 80 °C overnight, concentrated and purified by column chromatography to give the chloro pyridine (234 mg, 50 %). MS (DCI) m/z 230, 232 (M+H 1" ).
  • Example 52C (2S)-l- ⁇ (5R)-5-((5-carboxy-2-chloropyridyl-3-oxy)-methyl)-N-Boc-L- ⁇ rolyl ⁇ - py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47 with the compound of Example 52B.
  • MS (ESI) m/z 479, 481 (M+H) + .
  • Example 52D (2S)-l- ⁇ (5R)-5-((5-carboxy-2-chloropyridyl-3-oxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the Boc group was removed using procedure as described in Example 1G to give the title compound.
  • Example 53A 5-Hydroxy-naphthalene-l -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 4-benzyloxy-3-tert-butyl- benzoic acid in Example 47D with 5-hydroxy-naphthalene-l -carboxylic acid (Girardet, Lo Russo. Helv.Chim.Acta; , 49, 471-478, 1966).
  • MS (DCI) m/z 245 (M+H) + .
  • Example 53B (2S) ⁇ 1 - ⁇ (5i?)-5-(5-carboxynaphthalen- 1 -yloxymethyl)-L-prolyl> -py ⁇ olidine-2- carbonixrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47 with the compound of Example 53 A. !
  • Example 54 (2S)- 1 -
  • the title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 1 -naphthol.
  • 1H NMR 500 MHz, MeOH-d ⁇ 2.21 (m, 7 H), 2.55
  • Example 55 (2S)-l- ⁇ (5i-)-5-((5-carboxy-3-chloropyridyl-2-oxy)-methyl)-L-prolyl ⁇ -pyrrolidine-2- carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47 with 5-chloro-6-hydroxy-nicotinic acid tert-butyl ester (CIBA-GEIGY AG; FR 2218101; 1974; DE 2406930; 1976;
  • Example 56 (2S)-l- ⁇ (5J-)-5-((5-carboxy-2-bromophenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • Example 56A 4-Bromo-3-hydroxy-benzoic acid Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxy-benzoic acid (500 mg, 3.6 mmol) in ethanol (2 mL) and acetic acid (1 mL). The mixture was sti ⁇ ed at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40 %). MS (DCI) m/z 234 (M+NE ) + .
  • Example 56B 4-Bromo-3-hydroxy-benzoic acid tert-butyl ester
  • the title compound was synthesized by substituting 4-benzyloxy-3-tert-butyl- benzoic acid in 47D with the compound of Example 56A.
  • Example 56C (2S)- 1 - ⁇ (5i?)-5-((5-carboxy-2-bromophenoxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2- carbonitrile
  • the title compoxrnd was synthesized by substituting 3-tert-butyl-4-hydroxy ⁇ benzoic acid tert-butyl ester in Example 47 with the compound of Example 56B.
  • Example 57 (2S)-l-( ⁇ (2S,5R)-5-r(2-methylphenoxy)methynpy ⁇ olidin-2-yl ⁇ carbonyl)py ⁇ olidine- 2-carbonitrile
  • the title compound was synthesized by substituting 4-bromophenol in - Example 15 with 2-methylphenol followed by removal of the Boc group as described in Example 1G.
  • Example 58 (2S)- 1 -( ⁇ (2S,5R)-5-r(2-methoxyphenoxy)methyllpy ⁇ olidin-2- yl ⁇ carbonyl)pyrrolidine-2-carbonitrile
  • the title compound was synthesized by substituting 4-bromophenol in Example 15 with 2-methoxyphenol followed by removal of the Boc group as described in Example 1G.
  • Example 59 (2S)-l-( ⁇ (2S,5R)-5-r(2,4-dichlorophenoxy)methyll ⁇ y ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 4-bromophenol in Example 15 with 2,4-dichlorophenol followed by removal of the Boc group as described in Example 1G.
  • Example 60 (2S)-l-r((2S,5R)-5- ⁇ r2-bromo-4-(trifluoromethyl)phenoxy1methyl>py ⁇ olidin-2- yl)carbonyllpyrrolidine-2-carbonitrile
  • the compound of Example 14A 50 mg, 0.15 mmol
  • 3-bromo-4- fluorobenzotrifluoride 30 ⁇ L, 0.2 mmol
  • NaH 13 mg, 0.3 mmol
  • Example 61 (2S)-l-( ⁇ (2S,5R)-5-r(4-bromo-2-methoxy ⁇ henoxy)methynpy ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonixrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 2-methoxy-4-bromophenol followed by removal of the Boc group described in Example IG.
  • Example 62 (2S)-l-( ⁇ (2S,5R)-5-r(2-chloro-4-methoxy ⁇ henoxy)methyllpy ⁇ olidin-2- yl> carbonyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 2-chloro-4-methoxyphenol followed by removal of the Boc group described in Example IG.
  • Example 63A 2R-(4-Bromo-2-chloro-phenoxymethyl)-5S-(2S-cyano-py ⁇ olidine-l-carbonyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 2-chloro-4-bromophenol.
  • MS (ESI) m z 512, 514 (M+H) + .
  • Example 63B (2S)-l-( ⁇ (2S,5R)-5-r(4-bromo-2-chlorophenoxy)methynpy ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonifrile
  • the title compound was synthesized after removal of the Boc group described in Example IG.
  • Example 64 (2S)-l-r((2S,5R)-5- ⁇ r(4-chloro-l-na ⁇ hthyl)oxylmethyl
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 4-chloro-naphthalen-l-ol followed by removal of the Boc group described in Example IG.
  • Example 65 (2S)-1 -( ⁇ (2S,5R)-5-r(quinolin-4-yloxy)methyllpy ⁇ olidin-2-yl ⁇ carbonyl)py ⁇ olidine- 2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 1-hydroxylquinoline followed by removal of the Boc group described in Example IG.
  • Example 66 (2S)- 1 -( ⁇ (2S,5R)-5-r(quinolin-5-yloxy)methyl1py ⁇ olidin-2-yl ⁇ carbonyl)py ⁇ olidine- 2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 5-hydroxylquinoline followed by removal of the Boc group described in Example IG.
  • Example 68 (2S)-l-( ⁇ (2S,5R)-5-r(2-tert-butylphenoxy)methvnpy ⁇ olidin-2- yl) carbonyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 2-tert-butyl-phenol followed by removal of the Boc group described in Example IG.
  • Example 69 (2S)- 1 -( ⁇ (2S,5R)-5-r(2-tert-butyl-4-cyano ⁇ henoxy)methyl1py ⁇ olidin-2- yl ⁇ carbonyl)pyrrolidine-2-carbonitrile
  • Example 69A l-Benzyloxy-4-cyano-2-tert-butyl-benzene l-Benzyloxy-4-bromo-2-tert-butyl-benzene made in example 47B (319mg, 1 mmol), zinc cyanide (129 mg, 1.1 mmol) and Pd(PPh 3 ) 4 ( 34.5 mg, 0.03 mmol) were mixed in 4 mL of DMF then the mixture was heated to 175 °C in a microwave reactor (Emrys Optimizer by Personal Chemistry) for 5 minutes.
  • Example 69B 4-cyano-2-tert-butylphenol
  • the benzyl group of Example 69A was removed according the procedure described in example 47E to give the desired phenol.
  • Example 69C (2S)-l-( ⁇ (2S,5R)-5-r(2-tert-butyl-4-cyano ⁇ henoxy)methyllpy ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 4-cyano-2-tert-butylphenol followed by removal of the Boc group described in Example IG.
  • Example 70 (2S -l-( ⁇ (2S,5R)-5-r(4-bromo-2-tert-butylphenoxy methyll ⁇ y ⁇ olidin-2- yl) carbonyl)py ⁇ olidine-2-carbonitrile
  • Example 70A 4-bromo-2-tert-butyl-phenol l-Benzyloxy-4-bromo-2-tert-butyl-benzene made in Example 47B was hydgrogenated using the procedure as described in example 47E to provide the titled phenol.
  • Example 70B (2S)-l-( ⁇ (2S,5R)-5-[(4-bromo-2-tert-butylphenoxy)methyllpy ⁇ olidin-2- yl ⁇ carbonyl)p ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 4-bromo-2-tert-butyl-phenol followed by removal of the Boc group described in Example IG.
  • Example 71 (2S)-l-( ⁇ (2S,5R)-5-f(2-isopro ⁇ ylphenoxy)methyl1 ⁇ y ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 2-iso-propyl-phenol followed by removal of the Boc group described in Example IG.
  • Example 72A 3-tert-Butyl-4-hydroxy-benzoic acid ethyl ester
  • the compound of Example 47A (2.3 g), PdCl 2 (dppf) «CH 2 Cl 2 (820 mg), and triethyl amine (4.2 mL) were mixed in 40 mL of ethanol in a pressure vessel.
  • the reaction vessel was charged with CO (500 psi) and then heated to 120 °C for 16 hours.
  • the reaction was cooled to ambient temperature and the mixture was filtered.
  • the filtrate was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0% then 10% EtOAc/Hexane) to provide the title compound (1.9 g, 83%).
  • Example 72B ethyl 3-tert-butyl-4-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin- 1 -yncarbonyl ⁇ olidin-2- yl)methoxylbenzoate
  • the title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 3-tert-butyl-4-hydroxy-benzoic acid ethyl ester followed by removal of the Boc group as described in Example IG.
  • Example 73A (3-tert-Butyl-4-hydroxy-phenoxy)-acetic acid tert-butyl ester tert-Butyl-hydroquinone (500 mg, 3.0 mmol) and K 2 CO 3 (1.11 g, 8.0 mmol) were mixed in acetonitrile (4 mL).
  • t-Butyl bromoacetate (0.53 mL, 3.6 mmol) was added and the mixture was heated to reflux. After the reaction was over, it was concentrated and purified by silica gel chromatography (10% - 25% EtOAc/Hexane) to give the title phenol (230 mg, 40%).
  • Example 73B ⁇ 3-tert-butyl-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxy1phenoxy ⁇ acetic acid
  • the title compound was synthesized by substituting 4-bromophenol in Example 15 with (3-tert-butyl-4-hydroxy-phenoxy)-acetic acid tert-butyl ester followed by removal of the Boc and tert-butyl groups as described in Example IG.
  • Example 74 (2S)-l-r((2S,5R)-5- ⁇ r2-methoxy-4-(lH-tetraazol-5-yl)phenoxylmethyl ⁇ y ⁇ olidin-2- yl)carbonyl1py ⁇ olidine-2 -carbonitrile
  • the title compound was synthesized using the same reaction sequence of Example 50 by substituting 4-hydroxy-3-chlorobenzonitrile in Example 50A with 4- hydroxy-3-methoxybenzonitrile.
  • Example 75A 3 -tert-Butyl-4-hydroxy-benzamide
  • DCC 856 mg, 5.4mmol
  • HOBt 540 mg, 5.4 mmol
  • Ammonium hydroxide 28 %, 22mL
  • the reaction was sti ⁇ ed over night and purified by silica gel chromatography (70% - 90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5 %).
  • Example 75B 3-tert-butyl-4-r((2R,5S)-5- ⁇ r(2S)-2-cvano ⁇ v ⁇ olidin-l-yncarbonyl ⁇ y ⁇ olidin-2- yl)methoxylbenzamide
  • the title compound was synthesized by substituting 4-bromophenol in Example 15 with the above benzamide followed by removal of the Boc group as described in Example IG.
  • Example 76A 4-Bromo-2-isopropyl-phenol The title compound was synthesized by substituting 2-tert-butylphenol in Example 47A with 2-iso ⁇ ropyl ⁇ henol. MS (DCI) m/z 215, 217 (M+H) + .
  • Example 76B 4-cyano-2-isopropyl-phenol 4-Bromo-2-iso ⁇ ro ⁇ yl- ⁇ henol (500 mg, 2.3 mmol), Zn(CN) 2 (270 mg, 2.3 mmol) and tetrakis(triphenylphosophine)palladium (237 mg) were mixed in DMF (ImL) in a microwave reaction tube. It was reacted under microwave condition at 180 °C for 20 minutes. The mixture was filted and purified by by silica gel chromatography (40% - 60% EtOAc/Hexane) to provide the title compound (220 mg, 60 %). MS (DCI) m/z 162 (M+H) + .
  • Example 76C 2S-(2S-Cyano-py ⁇ olidine-l-carbonyl)-5R-r2-isopropyl-4-(lH-tet ⁇ azol-5-yl)- phenoxymethyll-py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 4-hydroxy-3- chlorobenzonitrile in Example 50A with 4-hydroxy-3-isopropylbenzonitrile.
  • Example 76D (2S -l-r(f2S,5R)-5- ⁇ F2-iso ⁇ ro ⁇ yl-4-(lH-tetraazol-5-yl)phenoxylmethyl>py ⁇ olidin-2- yl)carbonyllpyrrolidine-2-carbonitrile
  • the Boc group was removed according to procedure described in Example IG to give the title compound along with the other isomer with tert-butyl group attached to the tetrazole ring.
  • Example 77A 3-Hydroxy-pyridine-2-carboxylic acid tert-butyl ester 3-Hydroxypicolinic acid (500 mg, 3.6 mmol) was sti ⁇ ed in toluene (4mL) and heated to 80 °C. NN-dimethylformamide di-t-butyl acetal (1.9 ml, 7.97 mmol) was added in portions. The mixture was sti ⁇ ed for 2 hours and then concentrated. It was purified by column chromatography to give the product (300 mg, 46 %). MS (DCI) m/z 196 (M+H) + .
  • Example 77B The title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with the above ester followed by removal of the Boc group described in Example IG.
  • 1H ⁇ MR (500 MHz, MeOH-d ) ⁇ ppm 2.00 - 2.10 (m, 1 H), 2.11 - 2.45 (m, 6 H), 2.54 - 2.69 (m, 1 H), 3.67 (t, J 7.02
  • Example 78 (2S1-1 -RT2S,5R)-5- ⁇ A-(l -tert-butyl- lH-tet ⁇ aazol-5-yl -2- isopropylphenoxylmethyl ⁇ py ⁇ olidin-2-yl)carbonyllpy ⁇ olidine-2-carbonitrile
  • the title compound was obtained when the tert-butyl group was migrated onto the tetrazole ring in the removal of the Boc group in Example 76D.
  • the title compound was obtained when the tert-butyl group was migrated onto the tetrazole ring in the removal of the Boc group in Example 50B.
  • Example 80A 5-Chloro-2-hydroxy-benzoic acid tert-butyl ester 5-Chloro-2-hydroxy-benzoic acid (500 mg, 2.9 mmol), DCC (720 mg, 3.5 mmol) were mixed in t-butanol (5 mL). DMAP (50 mg) was added to the mixture. After 2 hours, the mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0% then 10% EtOAc/Hexane) to give the desired tert-butyl ester (600 mg, 90%). MS (DCI) m/z 229, 231 (M+H) + .
  • Example 80B 5-chloro-2-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yncarbonyl ⁇ y ⁇ olidin-2- yl)methoxylbenzoic acid
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F the above phenol followed by removal of the Boc group described in Example IG.
  • Example 81 A (2-Hydroxy-phenyl)-acetic acid tert-butyl ester Di-tert-butyl dicarbonate (218 mg, 0.1 mmol) was added to a solution of (2- hydroxybenzyl)triphenylphosphonium bromide (300 mg, 0.67 mmol) and triethylamine (0.32 mL, 0.3 mmol) in dry dichloromethane at room temperature under argon atmosphere. The mixture was sti ⁇ ed for 16 h and then poured into aqueous pH 7 buffer solution.
  • Example 8 IB ⁇ 2-
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with the above phenol followed by removal of the Boc group described in Example IG.
  • Example 82 3-IY(2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin- 1 -yl1carbonyl ⁇ py ⁇ olidin-2-yl)methoxyl-4- fluorobenzoic acid
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 4-fluoro-3-hydroxy-benzoic acid tert-butyl ester followed by removal of the Boc group described in Example IG.
  • Example 83 3-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-vncarbonyl ⁇ y ⁇ olidin-2-yl)methoxyl-4- isopropylbenzoic acid ( The title compound was synthesized by substituting 3-hydroxypicolinic acid in Example 77 with 3-hydroxy-4-isopropyl-benzoic acid (Journal; Croxall; Sowa; Nieuwland; JACSAT; J.Amer. Chem.Soc; 1935, 57, 1549.). 1H NMR (500 MHz,
  • Example 84 2-r5-(2-Cyano-py ⁇ olidine- 1 -carbonyl)-py ⁇ olidin-2-ylmethoxy1-naphthalene- 1 - carboxylic acid
  • the title compound was synthesized by substituting 3-hydroxypicolinic acid in Example 77 with 2-hydroxy-naphthalene-l -carboxylic acid.
  • Example 85 3-chloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl
  • Example 85A 3-Chloro-4-hydroxy-N,N-dimethyl-benzamide
  • 3-Chloro-4-hydroxy-benzoic acid 800 mg, 4.6 mmol
  • DCC (856 mg, 5.4mmol)
  • HOBt 540 mg, 5.4 mmol
  • Example 85B The title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with the above phenol followed by removal of the Boc group described in Example IG.
  • Example 86 (2S)-l-r((2S,5R)-5- ⁇ r(2-chloro-l-oxidopyridin-3-yl)oxylmethyl ⁇ py ⁇ olidin-2- yl)carbonyr
  • Example 86A 2S-(2-Chloro-pyridin-3-yloxymethyl)-5R-(2S-cyano-py ⁇ olidine-l-carbonyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the compound of example 14A (0.167 mmol), 2-chloro-pyridin-3-ol (0.3 mmol) and triethylamine (0.334 mmol) were mixed in 2 mL of benzene.
  • Example 86B (2S)-l-r((2S,5R)-5- ⁇ r(2-chloro-l-oxidopyridin-3-yl)oxylmethyl)py ⁇ olidin-2- yl)carbonyllpy ⁇ olidine-2-carbonitrile
  • the above compound (77 mg, 0.14 mmol) and mCPBA (96 mg, 77%, 0.35 mmol) were mixed in CH C1 2 .
  • the reaction was sti ⁇ ed over night and purified by reverse phase HPLC to provide the co ⁇ esponding N-oxide. (51 mg, 64 %).
  • the Boc group was removed according to Example IG to give the title compound.
  • Example 87 (2S)-l-( ⁇ (2S,5R)-5-r(2-chloro-4-mo ⁇ holin-4-yl ⁇ henoxy)methyll ⁇ y ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonitrile
  • Pd 2 (dba) 3 5 mg, 0.005 mmol
  • (o- bi ⁇ henyl)P(t-Bu) 2 3 mg, 0.01 mmol
  • ⁇ aH 11 mg, 0.27 mmol
  • compound of Example 63A 45 mg, 0.088 mmol
  • mophline 40 ⁇ L
  • Example 88 A 2S-(2S-Cyano-py ⁇ olidine-l-carbonyl)-5R-(2-chloro-4-nitro-phenoxymethyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 2-chloro-4-nitro-phenol.
  • MS (ESI) m/z 479, 481 (M+H) + .
  • Example 88B 2R-(4-Amino-2-chloro-pheno ⁇ ymethyl)-5S-(2S-cyano- ⁇ y ⁇ olidine-l-carbonyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the above compound (50 mg, 0.14 mmol) and NH C1 (8 mg, 0.14 mmol) were mixed in EtOH/H 2 O (ImL : 0.2 mL).
  • Iron powder 25 mg, 0.98 mmol
  • Example 88C (2S)-l-( ⁇ (2S,5R)-5-r(4-amino-2-chloro ⁇ henoxy)methyllpy ⁇ olidin-2- yl) carbonyl)py ⁇ olidine-2-carbonitrile
  • the Boc group was removed according to Example IG to give the title compound.
  • Example 89A 4-Hydroxy-naphthalene-l -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-hydroxypicolinic acid in Example 77 A with 4-hydroxy-naphthalene-l -carboxylic acid.
  • Example 89B 3 Chloro-4-hydroxy-naphthalene-l -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 5-hydroxy-nicotinic acid tert-butyl ester in Example 52B with the above ester.
  • MS (ESI) m/z 279, 281 (M+H) + .
  • Example 89C The title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with the above ester followed by removal of the Boc group described in Example IG.
  • Example 90 3-bromo-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl>py ⁇ olidin-2- yl)methoxy "
  • benzoic acid The title compound was synthesized using the same reaction sequence of Example 80 by substituting 5-chloro-2-hydroxy-benzoic acid in Example 80A with 5- bromo-2-hydroxy-benzoic acid.
  • Example 91 6-chloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yncarbonyl ⁇ py ⁇ olidin-2- yl)methoxy1nicotinic acid 1 -oxide
  • the title compound was synthesized by substituting 2S-(2-chloro-pyridin-3- yloxymethyl)-5R-(2S-cyano-py ⁇ olidine- 1 -carbonyl)-py ⁇ olidine- 1 -carboxylic acid tert-butyl ester (Example 86A) in Example 86B with (2S)-l- ⁇ (5i?)-5-((5-carboxy-2- chloropyridyl-3-oxy)-methyl)-L-prolyl ⁇ -py ⁇ olidine-2-carbonixrile (Example 52C).
  • Example 92 6-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl>py ⁇ olidin-2-yl)methoxy1-2- naphthoic acid
  • the title compound was synthesized by substituting 5-chloro-2-hydroxy- benzoic acid in Example 80 with 6-hydroxy-naphthalene-l -carboxylic acid.
  • Example 93 (2S)-l-r((2S,5R)-5- ⁇ r2-chloro-4-(methylsulfonyl)phenoxylmethyl ⁇ y ⁇ olidin-2- yl)carbonyllpy ⁇ olidine-2-carbonitrile
  • Example 93A 2-chloro-4-methanesulfonyl-phenol 4-Methanesulfonylphenol (2.0 g, 11.6 mmol) mixed with 21 :14 mL of EtOH onc HCl was cooled to 0 °C, then KClO 3 (0.708 g, 5.81 mmol) dissolved in 17 mL of water was added slowly. After reaction overnight, the mixture was extracted with EtOAc and the extracts were concentrated in vacuum.
  • Example 93B (2S)-l-r((2S,5R)-5- ⁇ r2-chloro-4-(methylsulfonyl)phenoxy1methyl>py ⁇ olidin-2- yl)carbonyllpy ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 2-chloro-4-methanesulfonyl-phenol followed by removal of the Boc group described in Example IG.
  • Example 94B 2R-r2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-chloro-phenoxymethyl1-5S-(2S- cyano-pyrrolidine-l-carbonyl)-pyrrolidine-l -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with the above phenol.
  • MS (ESI) m/z 578, 580 (M+H) + .
  • Example 94C (2S)- 1 -f((2S,5R)-5- ⁇ r4-chloro-2-(hydrox ⁇ methyl) ⁇ henoxy1meth ⁇ py ⁇ olidin-2- yl)carbonyllpy ⁇ olidine-2 -carbonitrile
  • the above compound (100 mg, 0.17 mmol) in THF (ImL) was treated with TBAF (IM in THF, 0.1 mL). After the reaction was over, the product was purified by reverse phase HPLC to give the desired product.
  • the Boc group was removed according to Example IG to give the title compound.
  • Example 89 by substituting 4-hydroxy-naphthalene-l -carboxylic acid in Example 89A with 6-hydroxy-naphthalene-2-carboxylic acid.
  • Example 96A 6-Chloro-benzo
  • the title compound was synthesized by substituting 5-hydroxy-nicotinic acid tert-butyl ester in Example 52B with sesamol.
  • Example 96B (2S)-l-r((2S,5R)-5- ⁇ r(6-chloro-l,3-benzodioxol-5-yl)oxylmethyl ⁇ y ⁇ olidin-2- yl)carbonyl1py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with the above phenol followed by removal of the Boc group described in Example IG.
  • Example 97A 2-(4-Amino-naphthalen-l-yloxymethyl)-5-(2-cyano-py ⁇ olidine-l-carbonyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with 4-amino-naphthalen-l-ol HCl salt.
  • MS (ESI) m/z 465 (M+H) + .
  • Example 97B N- (4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin- 1 -yl1carbonyl ⁇ py ⁇ olidin-2-yl)methoxyl- l-naphthyl ⁇ methanesulfonamide
  • the compound of Example 97A (32 mg, 0.07 mmol) was dissolved in CH 2 C1 2 (ImL) and pyridine (0.5 mL) in a microwave reaction tube.
  • Example 98 (2S)-l-r((2S,5R)-5- ⁇ r2-bromo-4-(methylsulfonyl)phenoxylmethyl>py ⁇ olidin-2- yl)carbonyl1py ⁇ o ⁇ idine-2-carboni ⁇ rile
  • Example 98A 2-bromo-4-methanesulfonyl-phenol 4-Methanesulfonylphenol was brominated using the procedure described in Example 47A. MS (DCI) m/z 252, 254 (M+H) + .
  • Example 98 B (2S)-l-r((2S,5R)-5- ⁇ r2-bromo-4-(methylsulfonyl)phenoxy1methyl ⁇ py ⁇ olidin-2- yl)carbonyl1py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 2-chloro-4-methanesulfonyl-phenol followed by removal of the Boc group described in Example IG.
  • IH NMR 400 MHz,
  • Example 99 (2S)-l-r((2S,5R)-5- ⁇ r(6-bromo-l,3-benzodioxol-5-yl)oxy1methyl ⁇ py ⁇ olidin-2- yl)carbonyl1py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with the above phenol followed by removal of the Boc group described in Example IG.
  • Example 100A 2R-r2-Chloro-4-(2-chloro-benzenesulfonylamino)-phenoxymeth ⁇ ll-5S-(2S-cyano- py ⁇ olidine-l-carbonyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester
  • the compound of Example 88B (32 mg, 0.07 mmol) was dissolved in CH 2 C1 2 (ImL) and pyridine (0.5 mL) in a microwave reaction tube.
  • 2-Chloro-benzenesulfonyl chloride (6.0 ⁇ L, 0.21 mmol) was added. It was reacted under microwave condition at 130 °C for 20 minutes. The mixture was filtered and purified by reverse phase HPLC to provide the title compound (30 mg, 70 %).
  • MS (ESI) m/z 623, 625 (M+H) + .
  • Example 100B (2S)- 1 -f((2S,5R)-5- ⁇ f(6-bromo- 1 ,3-benzodioxol-5-yl)oxy1methyl ⁇ y ⁇ olidin-2- yl)carbonyl1py ⁇ olidine-2-carbonitrile
  • the Boc group was removed according to Example IG to give the title compound.
  • Example 101 N- ⁇ 3-chloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yncarbonyl ⁇ py ⁇ olidin-2- yl)methoxylphenyl ⁇ methanesulfonamide
  • the title compound was synthesized by substituting 2-chloro-benzenesulfonyl chloride in Example 100A with methanesulfonyl chloride.
  • Example 102 N- ⁇ 3-chloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxylphenyl ⁇ acetamide 2R-(4-An ⁇ ino-2-chloro-phenoxymethyl)-5S-(2S-cyano-py ⁇ olidine-l- carbonyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (Example 88B) (32 mg, 0.07 mmol) was dissolved in CH 2 C1 2 (ImL).
  • Example 103 (2S)-l-( ⁇ (2S,5R)-5-r(l-benzothien-4-yloxy)methyll ⁇ y ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonitrile
  • Example 103 A 2R-(Benzo
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with benzo[b]thiophen-4-ol (JAm Chem Soc 1935, 57, 1611).
  • Example 103B (2S)-l-( ⁇ (2S,5R)-5-r(l-benzothien-4-yloxy)methynpyrrolidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carbonitrile
  • the above ether 50 mg was treated with 2 mL of 4N HCl in isopropanol (prepared by diluting 2 mL of cone HCl to 6 mL with isopropanol) at room temperature for 4 hours.
  • Purification by reverse HPLC [0-70% CH 3 CN/H 2 O with 0.1% trifluoroacetic acid (TFA) in aq. eluent] gave the title compound.
  • 1H NMR 400 MHz, MeOH-d4) ⁇ ppm 2.06 - 2.46 (m, 8 H), 2.56 - 2.69 (m, 1 H), 3.63 - 3.75 (m, 2
  • Example 104A 2-Methanesulfonyl-phenol 2-Methylsulfanyl- ⁇ henol (lg, 7.1 mmol) and mCPBA (8 g, 77%, 35.5 mmol) were mixed in CH 2 C1 2 . The reaction was sti ⁇ ed over night and purified by silica gel chromatography to provide the title compound (900 mg, 75 %). MS (DCI) m/z 173 (M+H) + .
  • Example 104 (2S)-l-r((2S,5R)-5- ⁇ r4-bromo-2-(methylsulfonyl)phenoxylmethyl) ⁇ y ⁇ olidin-2- yl)carbonyllpy ⁇ olidine-2-carbonitrile
  • the title compound was synthesized using the same reaction sequence of Example 56 by substituting 3-hydroxy benzoic acid in Example 56A with 2- methanesulfonyl-phenol and the rest of the reaction sequence.
  • Example 105 6-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2-yl)methoxyl-l- naphthoic acid
  • the title compound was synthesized by substituting 3-hydroxypicolinic acid in Example 77 A with 6-hydroxy-naphthalene-l -carboxylic acid and the rest of the reaction sequence.
  • Example 106A 2R-(4-Amino-2-bromo-phenoxymethyl)-5S-(2S-cyano-py ⁇ olidine-l-carbonyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 2-chloro-4-nitro-phenol in Example 88 A with 2-bromo-4-nitro-phenol and subsequent reduction of the nitro group as described in Example 88B.
  • MS (ESI) m/z 493, 495 (M+H) + .
  • Example 106B The title compound was synthesized by substituting 2R-(4-amino-2-chloro- phenoxymethyl)-5S-(2S-cyano-py ⁇ olidine-l-carbonyl)-py ⁇ olidine-l-carboxylic acid tert-butyl ester in Example 102 with the above amine followed by the removal of the Boc group according to Example IG.
  • Example 107A The compound of Example 106A (34 mg, 0.07 mmol) was dissolved in CH 2 C1 2 (ImL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride (6.0 ⁇ L, 0.21 mmol) was added. The mixture was heated to 130 °C in a microwave reactor and kept for 20 minutes. The mixture was filtered and purified by reverse phase HPLC to provide the title compound (30 mg, 70 %). MS (ESI) m/z 571, 573 (M+H) + .
  • Example 107B N- ⁇ 3-bromo-4-r((2R,5S)-5- ⁇ r(2S)-2-c ⁇ ano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxylphenyl ⁇ methanesulfonamide
  • the Boc group was removed according to Example IG to give the title compound.
  • Example 108 N- ⁇ 3-bromo-4-r((2R,5S)-5-(r(2S)-2-cyanopy ⁇ olidin-l-yncarbonyl ⁇ y ⁇ olidin-2- yl)methoxylphenyl ⁇ benzenesulfonamide
  • the title compound was synthesized by substituting methanesulfonyl chloride in Example 107 A with phenyl sulfonyl chloride followed by the removal of the Boc group as described in Example 1 G.
  • Example 109 N- ⁇ 3-bromo-4-r((2R,5S)-5- ⁇ r(2S)-2-cvano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ y ⁇ olidin-2- yl)methoxy1phenyl ⁇ -2-chlorobenzenesulfonamide
  • the title compound was synthesized by substituting methanesulfonyl chloride in Example 107A with 2-chloro-benzenesulfonyl chloride followed by the removal of the Boc group as described in Example IG.
  • Example 110 methyl 2,3-dichloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l- yllcarbonyl ⁇ py ⁇ olidin-2-yl)methoxylbenzoate
  • Example 110A 2,3-dichloro-4-hydroxy-benzoic acid methyl ester
  • the title compound was synthesized by substituting l-benzyloxy-4-bromo-2- tert-butyl-benzene in Example 47C with 2,3-dichloro-4-bromobenzene.
  • MS (ESI) m/z
  • Example HOB methyl 2,3-dichloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopyrrolidin-l- yncarbonyl ⁇ py ⁇ olidin-2-yl)methoxy1benzoate
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 2,3-dichloro-4-hydroxy-benzoic acid methyl ester followed by removal of the Boc group described in Example 103B.
  • Example 111A 3-hydroxy-4-methoxy-benzoic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-hydroxypicolinic acid in
  • Example 11 IB 3-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl ⁇ y ⁇ olidin-2-yl)methoxy1-4- methoxybenzoic acid
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 3-hydroxy-4-methoxy-benzoic acid tert-butyl ester followed by removal of the Boc group described in Example 103B.
  • Example 112 2,3-dichloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yncarbonyl ⁇ py ⁇ olidin-2- yl)methoxylbenzoic acid
  • Example 112A 2,3-dichloro-4-hydroxy-benzoic acid tert-butyl ester
  • the title compound was synthesized by substituting 4-benzyloxy-3-tert-butyl- benzoic acid methyl ester in Example 47D with 2,3-dichloro-4-hydroxy-benzoic acid methyl ester (made in Example 110A).
  • Example 112B 2,3-dichloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yncarbonyl ⁇ py ⁇ olidin-2- yl)methoxylbenzoic acid
  • Example 112A 2,3-dichloro-4-hydroxy-benzoic acid tert
  • Example 112C 2,3-dichloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ y ⁇ olidin-2- yl)methoxylbenzoic acid
  • the Boc and tert-butyl groups were removed by procedure described in Example 103B.
  • Example 113 (2S)-l-( ⁇ (2S,5R)-5-r(2,4-dichloro-5-nifro ⁇ henoxy)methynpy ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carboni ⁇ rile
  • Example 113 A 2S-(2S-Cyano-py ⁇ olidine-l-carbonyl)-5R-(2,4-dichloro-5-nitro-phenoxymethyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 2,4-dichloro-5-nitrophenol.
  • Example 113B (2S)-l-( ⁇ (2S,5R -5-[(2,4-dichloro-5-nifrophenoxy)methynp ⁇ olidin-2- yl ⁇ carbonyl)py ⁇ olidine-2-carboni ⁇ rile
  • the Boc group of the above ether was removed according to Example 103B.
  • Example 114 tert-butyl 2,3-dichloro-4-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l- yl1carbonyl>py ⁇ olidin-2-yl)methoxylbenzoate
  • the title compound was synthesized when only the Boc group in Example
  • Example 115 ethyl 4-chloro-3-r((2R,5S)-5- ⁇ r(2S -2-cyanopy ⁇ olidin-l-yncarbonyl ⁇ py ⁇ olidin-2- ypmethoxylbenzoate
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 4-chloro-3-hydroxy-benzoic acid ethyl ester followed by removal of the Boc group described in Example 103B.
  • Example 116 isopropyl 4-chloro-3-[((2R,5S)-5- ⁇ [(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin- 2-yl)methoxy ⁇ benzoate
  • Example 116A 4-chloro-3-hydroxy-benzoic acid isopropyl ester 4-Chloro-3-hydroxy-benzoic acid (lOOmg, 0.58 mmol) and 1 mL of isopropanol were mixed and then heated to 85 °C for overnight. The mixture was then concenfrated in vacuum and the resulting residue was purified by flash chromatography (8-20% EtOAc/Hex) to give the desired ester (94 mg, 75%). MS (DCI) m/z 215 (M+H) + , 232 (M+NE ) "1" .
  • Example 116B isopropyl 4-chloro-3-[((2R,5S)-5- ⁇ F(2S)-2-cyanopy ⁇ olidin-l-yl1carbonyl)py ⁇ olidin- 2-yl)methoxylbenzoate
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 4-chloro-3-hydroxy-benzoic acid iso-propyl ester followed by removal of the Boc group described in Example 103B.
  • Example 117 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin- 1 -yllcarbonyl ⁇ y ⁇ olidin-2- yl)methoxylphenyl
  • Example 117A 2-(5-Amino-2,4-dichloro-phenoxymethyl)-5-(2-cyano-py ⁇ olidine-l-carbonyl)- pyrrolidine-1 -carboxylic acid tert-butyl ester 2S-(2S-Cyano-py ⁇ olidine- 1 -carbonyl)-5R-(2,4-dichloro-5-nitro- phenoxymethyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester (from Example 113A) (934 mg, 1.82 mmol), iron powder (708 mg, 12.7 mmol), NH CI (68 mg, 1.27
  • Example 117B 2-(5-Acetylamino-2,4-dichloro-phenoxymethyl)-5-(2-cyano-py ⁇ olidine-l-carbonyl)- py ⁇ olidine-1 -carboxylic acid tert-butyl ester
  • acetyl chloride 0.25 mmol
  • water 50 ⁇ L
  • acetonitrile c.a. 1 mL
  • Example 118 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-vncarbonyl)py ⁇ olidin-2- ypmethoxylphenyl ⁇ acrylamide
  • the title compound was synthesized by substituting acetyl chloride in 117B with acryloyl chloride.
  • 1H NMR 500 MHz, MeOH- ⁇ ppm 2.02 - 2.44 (m, 7 H)
  • Example 119 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yncarbonyl ⁇ py ⁇ olidin-2- yl)methoxylphenyl ⁇ benzamide
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with benzoyl chloride followed by removal of the Boc group described in Example 103B.
  • Example 120 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxy1phenyl ⁇ -2-methoxyacetamide
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with methoxyacetyl chloride followed by removal of the Boc group described in Example 103B.
  • Example 121 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cvanopy ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxylphenyl ⁇ -2-(2-methoxyethoxy)acetamide
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with (2-methoxy-ethoxy)-acetyl chloride followed by removal of the Boc group described in Example 103B.
  • Example 122 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxy1phenyl ⁇ cyclopropanecarboxamide
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with cyclopropanecarbonyl chloride followed by removal of the Boc group described in Example 103B.
  • Example 123 ethyl 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbony py ⁇ olidin- 2-yl)methoxylphenylcarbamate
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with ethyl chloroformate followed by removal of the Boc group described in Example 103B.
  • Example 124 (2S)-l-( ⁇ (2S,5R)-5-r(5-(bis(methanesulfonyl))amino-2,4- dichlorophenoxy)methyllpy ⁇ olidin-2-yl)carbonyl)py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with methanesulfonyl chloride followed by removal of the Boc group described in Example 103B.
  • Example 125 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-vncarbonyl> ⁇ y ⁇ olidin-2- yl)methoxy]phenyl ⁇ - 1 -phenylmethanesulfonamide
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with benzylsulfonyl chloride followed by removal of the Boc group described in Example 103B.
  • Example 126 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ py ⁇ olidin-2- yl)methoxy Ipheny 1 ⁇ -N'-phenylurea
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with phenylisocyanate followed by removal of the Boc group described in Example 103B.
  • Example 128 N- ⁇ 2,4-dichloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl>py ⁇ olidin-2- yl)methoxylphenyl ⁇ -N'-(4-nitrophenyl)urea
  • the title compound was synthesized by substituting acetyl chloride in Example 107B with 5-nitrophenylisocyanate followed by removal of the Boc group described in Example 103B.
  • 1H NMR 500 MHz, MeOH-d ⁇ ⁇ ppm 2.06 - 2.46 (m, 8
  • Example 129 (2S)-l-( ⁇ (2S,5R)-5-r(5-amino-2,4-dichlorophenoxy)methynpy ⁇ olidin-2- yl> carbonyl)py ⁇ olidine-2-carbonitrile
  • the Boc group in 2R-(5-amino-2,4-dichloro-phenoxymethyl)-5S-(2S-cyano- py ⁇ olidine-l-carbonyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester (made in Example 107 A) was removed according to the procedure described in Example 103B to give the title compound.
  • Example 130 isopropyl 6-chloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yl1carbonyl>py ⁇ olidin- 2-yl)methoxylmcotinate
  • Example 130A 5-hydroxy-nicotinic acid isopropyl ester The title compound was synthesized by substituting 4-chloro-3- hydroxybenzoic acid in Example 116A with 5-hydroxy-nicotinic acid. MS (DCI) m/z 182(M+H) + .
  • Example 13 OB 6-chloro-5-hydroxy-nicotinic acid isopropyl ester
  • the title compound was synthesized by substituting 5-hydroxy-nicotinic acid tert-butyl ester in Example 52B with 5-hydroxy-nicotinic acid isopropyl ester
  • Example 130C isopropyl 6-chloro-5-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yl1carbonyl ⁇ py ⁇ olidin- 2-yl)methoxylnicotinate
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 6-chloro-5-hydroxy-nicotinic acid isopropyl ester followed by removal of the Boc group described in Example 103B.
  • Example 131 A l-Chloro-2-methanesulfonyl-4-methoxy-benzene
  • the title compound was synthesized by substituting 4-methanesulfonylphenol in Example 93 A with 2-methanesulfonyl-4-methoxybenzene.
  • MS (DCI) m/z 238 (M+NH ) + .
  • the other chlorinated product, 2-chloro-3-methanesulfonylbenzene was separated from the title product by reverse-phase HPLC.
  • Example 13 IB 4-Chloro-3-methanesulfonyl-phenol l-chloro-2-methanesulfonyl-4-methoxy-benzene obtained above (282 mg, 1.28 mmol) dissolved in 3 mL of dichloromethane was cooled to -78 °C, and then BBr 3 solution (IM in CH 2 C1 2 , 1.9 mL) was added slowly. The reaction was sti ⁇ ed overnight during which the reaction was gradually warmed to room temperature. The reaction was quenched by careful addition of water, extracted with EtOAc. The combined extracts were dried over Na 2 SO 4 and concentrated in vacuum. The resulting residue was purified by flash chromatography (30-45% EtO Ac/Hex) to give the desired phenol. MS (DCI) m/z 224 (M+NH 4 ) + .
  • Example 131 C (2S)-l-r((2S,5R)-5- ⁇ r4-chloro-3-(methylsulfonyl)phenoxylmethyl ⁇ py ⁇ olidin-2- yl)carbonyllpy ⁇ olidine-2-carbonixrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 4-chloro-3-methanesulfonyl-phenol followed by removal of the Boc group described in Example 103B.
  • Example 132 (2S)-l-r((2S,5R)-5- ⁇ r2-chloro-3-(methylsulfonyl) ⁇ henoxylmethyl ⁇ py ⁇ olidin-2- yl)carbonyl1py ⁇ olidine-2-carbonitrile
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 2-chloro-3-methanesulfonyl-phenol (from Example 131 A) followed by removal of the Boc group described in Example 103B.
  • Example 133 ethyl 3-r((2R,5S)-5- ⁇ r(2S)-2-cyanopy ⁇ olidin-l-yllcarbonyl ⁇ y ⁇ olidin-2- yl)methoxy1-4,5-difluorobenzoate
  • Example 133 A 3,4-difluoro-5-hydroxy-benzoic acid ethyl ester
  • the title compound was synthesized by substituting l-benzyloxy-4-bromo-2- tert-butyl-benzene in Example 47C with 2,3-difluoro-5-bromophenol in EtOH.
  • Example 133B ethyl 3-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ y ⁇ olidin-2- yl)methoxy1-4,5-difluorobenzoate
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 3,4-difluoro-5-hydroxylbenzoic acid ethyl ester followed by removal of the Boc group described in Example 103B.
  • Example 134 3-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ v ⁇ olidin-l-yncarbonyl ⁇ y ⁇ olidin-2-yl)methoxy1-4,5- difluorobenzoic acid
  • Example 134A 3,4-Difluoro-5-hydroxy-benzoic acid tert-butyl ester
  • the title compound was synthesized by substituting 4-benzyloxy-3-tert-butyl- benzoic acid methyl ester in Example 47D with 3,4-difluoro-5-hydroxy-benzoic acid ethyl ester (form Example 133 A).
  • MS (DCI) m/z 231(M+H) + , 248 (M+NH 4 ) + .
  • Example 134B 2R-(5-tert-butoxycarbonyl-2,3-difluoro-phenoxymethyl)-5S-(2S-cyano-py ⁇ olidine-l- carbonyl)-py ⁇ olidine-l -carboxylic acid tert-butyl ester
  • the title compound was synthesized by substituting 3-tert-butyl-4-hydroxy- benzoic acid tert-butyl ester in Example 47F with 4,5-difluoro-3-hydroxylbenzoic acid tert-butyl ester.
  • Example 134C 3-r((2R,5S)-5- ⁇ r(2S)-2-cvano ⁇ v ⁇ olidin-l-yncarbonyl ⁇ y ⁇ olidin-2-yl)methoxy1-4,5- difluorobenzoic acid Both Boc and tert-butyl groups were removed using procedure described in Example 103B.
  • Example 135 tert-butyl 3-r((2R,5S)-5- ⁇ r(2S)-2-cyano ⁇ y ⁇ olidin-l-yllcarbonyl ⁇ y ⁇ olidin-2- yl)methoxy1-4,5-difluorobenzoate
  • the title compound was obtained when only the Boc group in Example 134B was removed using the procedure described in Example 103B.
  • 1H NMR (400 MHz, MeOH-d ⁇ ) ⁇ ppm 1.59 (s, 9 H), 2.03 (ddd, J 17.18, 13.04, 8.44 Hz, 1 H), 2.11 - 2.44

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Abstract

La présente invention porte sur des composés de formule (I), inhibant la dipeptidyle peptidase IV (DPP-IV) et utilisés pour la prévention et le traitement du diabète, notamment du diabète de type II, ainsi que l'hyperglycémie, le syndrome X, l'hyperinsulinémie, l'insuffisance de cellules bêta, l'obésité, les troubles de la satiété, l'athérosclérose et diverses maladies immunomodulatrices.
PCT/US2004/028886 2003-09-04 2004-09-07 Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv) WO2005023762A1 (fr)

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