WO2005023762A1 - Pyrrolidine-2-carbonitrile derivatives and their use as inhibitors of dipeptidyl peptidase-iv (dpp-iv) - Google Patents

Pyrrolidine-2-carbonitrile derivatives and their use as inhibitors of dipeptidyl peptidase-iv (dpp-iv) Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
group
heteroaryl
alkylsulfonyl
aryl
carboxy
Prior art date
Application number
PCT/US2004/028886
Other languages
French (fr)
Inventor
Zhonghua Pei
Xiaofeng Li
Kenton L. Longenecker
Hing L. Sham
Paul E. Wiedeman
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO2005023762A1 publication Critical patent/WO2005023762A1/en

Links

Classifications

    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to compounds of formula (I), (I), 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, b-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.

Description

Pharmaceutical Compositions As Inhibitors of Dipeptidyl Peptidase-IV (DPP-IV)
Field of the Invention 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, β-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.
Background of the Invention 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-
1) and GIP (gastric inhibitory peptide/ glucose-dependent insulinotropic polypeptide). 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. However, active 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. To circumvent the drawback of the short half-life of GLP-1, 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. To accomplish this goal, the compound in question must exhibit both potent inhibition of the enzyme and a desirable pharmacokinetic profile. Because 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. Several issues complicate the task of preparing a 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.
Figure imgf000004_0001
But the 2-cyanopyrrolidide moiety has liabilities as well. In particular, 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. Thus, cyanopyrrolidide-containing DPP-IV inhibitors tend to have limited chemical stability, which is reflected in poor pharmacokinetic profiles. Intramolecular cyclization
Figure imgf000005_0001
Figure imgf000005_0002
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.
Summary of the Invention The present invention is directed to compounds of formula (I),
Figure imgf000005_0003
(I), or a therapeutically acceptable salt or prodrug thereof, wherein A is selected from the group consisting of
Figure imgf000005_0004
or therapeutically suitable salt, ester or prodrug, thereof, wherein R] is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RgRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R\ and R2, 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; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; ^ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RJRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; with the proviso that if R] and R2 and the carbon atoms to which they are attached form a benzene ring, then R4 is not carboxylic acid; Ra and Rb 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; Rπ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R12 and R13 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R14 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 3 and R24 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, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R3ι is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaR N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaR N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R^ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; « is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R43 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R44 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; 51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R5 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R51 and R5 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; Rδ2, Rδ3, Rβ4 and R^ are each independently selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RJlbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein When A is selected from the group consisting of
Figure imgf000012_0001
the nitrogen of the pyridine group of A may be optionally substituted with an N- oxide; provided that exactly one of R^ or R44 is hydrogen. Accordingly, 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). According to another embodiment of the present invention, there is provided a method for treating type 2 diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance, β-cell failure, obesity, satiety disorders, hypercholesterolemia, and hypertriglyceridemia comprising administering a therapeutically effective amount of a compound of formula (I). According to still another embodiment, 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.
Detailed Description of the Invention Accordingly, the principle embodiment of the present invention is directed toward a compound of formula (I),
Figure imgf000013_0001
(I), or a therapeutically acceptable salt or prodrug thereof, wherein A is selected from the group consisting of
Figure imgf000013_0002
or therapeutically suitable salt, ester or prodrug, thereof, wherein Rt is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or Ri and R2, 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; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R.J is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; with the proviso that if R] and R2 and the carbon atoms to which they are attached form a benzene ring, then R is not carboxylic acid; Ra and Rb 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; Rπ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R12 and R13 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R14 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 1 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R23 and R 4 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, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R31 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R33 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; I π is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; I ι3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R( is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R5ι is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R52 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R51 and Rs2 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; Rβ , Rδ3, R$4 and R65 are each independently selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein A is selected from the group consisting of
Figure imgf000020_0001
the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of R-u or R44 is hydrogen. Another embodiment of the present invention discloses compounds of formula
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000020_0002
Ri is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfbnyl, 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, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycyano, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and Ra and R 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
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000021_0001
R! is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, 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, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaR N-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and
1,2,3-triazolyl; and Ra and Rb 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
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000022_0001
Ri is selected from the group consisting of halo, alkoxy, cyano, alkyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylsulfonyl, heteroaryl and hydroxyalkyl, wherein the heteroaryl is pyrazolyl; R2 is selected from the group consisting of hydrogen, halo and alkylsulfonyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, carboxy, carboxyalkoxy, alkylsulfonyl, heteroaryl and heterocycle, wherein the heteroaryl is tetrazolyl; R4 is selected from the group consisting of hydrogen, RaRbN-, alkoxycarbonyl, cyano, carboxy, alkylsulfonylNH and nitro; and Ra and Rb 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 (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000023_0001
R\ and R2, 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; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; φ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; with the proviso that if Ri and R2 and the carbon atoms to which they are attached form a benzene ring, then is not carboxylic acid; and Ra and Rb 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
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000024_0001
RΪ and R2 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; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, alkoxy 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; with the proviso that if R} and R2 and the carbon atoms to which they are attached form a benzene ring, then R is not carboxylic acid; and Ra and Rb 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 (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000025_0001
RΪ and R2, 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; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, carboxy, carboxyalkoxy, alkylsulfonyl, heteroaryl, heterocycle, wherein the heteroaryl is tetrazolyl; R4 is selected from the group consisting of hydrogen, RaRbN-, alkoxycarbonyl, alkoxy cyano, alkylsulfonylNH and nitro; and Ra and Rb 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 (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000025_0002
Rπ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R12 and R13 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; and R14 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000026_0001
Rπ is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, 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, thiophenyl, triazinyl and 1,2,3-triazolyl; R1 and R13 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; and R14 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000027_0001
Rπ is selected from the group consisting of halo, alkoxy, cyano and carboxy; R12 and R13 together with the carbon atoms to which they are attached, form a substituted or unsubstituted benzene; and R1 is hydrogen. Another embodiment of the present invention discloses compounds of formula
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000027_0002
R21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R23 and R24 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, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazolyl. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000028_0001
R21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, 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, thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 and R2 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, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazolyl. Another embodiment of the present invention discloses compounds of formula
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000029_0001
R21 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 R24 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
Figure imgf000029_0002
R3ι is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-,
RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R33 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R34 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl,
RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; 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
Figure imgf000031_0001
R31 is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-,
RaRbNcarbonyl, 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,
1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R32 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R33 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R34 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; 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
Figure imgf000032_0001
R31 is halo; R32 is hydrogen; R3 is hydrogen; R3 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
Figure imgf000032_0002
R ι is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; ILa is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio,
RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; I β is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R44 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of ^ or R44 is hydrogen. Another embodiment of the present invention discloses compounds of formula
(I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000033_0001
R41 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, 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, thiophenyl, triazinyl and 1,2,3-triazolyl; I ι is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R« is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R44 is selected from the group consisting of hydrogen^ halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of R^ or 4 is hydrogen. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000034_0001
Rzu is selected from the group consisting of hydrogen, halo and carboxy; R42 is hydrogen; R43 is selected from the group consisting of hydrogen, halo, alkoxycarbonyl and carboxy; R44 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 R44 is hydrogen. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000035_0001
R51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaR 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R52 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R 1 and R52 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and
1,2,3-triazolyl; 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
Figure imgf000036_0001
R51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, 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, thiophenyl, triazinyl and 1,2,3-triazolyl; R52 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R51 and R52 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, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; 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
Figure imgf000037_0001
R51 and R52 together with the carbon atoms to which they are attached, form a benzene; and R53 is hydrogen. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000037_0002
Rg2, Re, Rδ4 and Res are each independently selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl. Another embodiment of the present invention discloses compounds of formula (I), or therapeutically suitable salt, ester or prodrug, thereof, wherein A is
Figure imgf000038_0001
R62, R63, Re4 and Rβ5 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 β-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 maπow 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). Definitions As used throughout this specification and the appended claims, the following terms have the following meanings:
Definitions As used throughout this specification and the appended claims, the following terms have the following meanings: The term "alkenyl, " as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon- carbon double bond formed by the removal of two hydrogens. The term "alkenyl," as related to the compounds of the present invention, refer to C2-alkenyl, C3-alkenyl, C4- alkenyl, Cs-alkenyl, C6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl or Cio-alkenyl. Representative examples of alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2- methyl-1-heptenyl, and 3-decenyl. The term "alkenylcarbonyl," as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert- butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. The term " alkoxyalkylcarbonyl," as used herein, refers to an alkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term "alkoxyalkoxy," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy. The term "alkoxyalkoxycarbonyl," as used herein, refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term " alkoxyalkoxyalkyl" as used herein, refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term " alkoxyalkoxyalkylcarbonyl" as used herein, refers to an alkoxyalkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term "alkoxycarbonyl, " as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term "alkyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term "alkylsulfonyl," as used herein, refers to an alkyl group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein. The term "alkoxysulfonyl," as used herein, 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. The term "alkylthio," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl. The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term "aryl," as used herein, 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. The aryl groups of the present invention can be substituted with 0, 1, 2, or 3 substituents wherein each substitutent occuπence 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, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl and RaRbNsulfonyl, wherein Ra and Rb 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, and wherein the substitutuent aryl, heteroaryl, heterocycle, cycloalkyl, the aryl of arylalkyl, the heteroaryl of heteroarylalkyl, the heterocycle of heterocyclealkyl, and the cycloalkyl of cycloalkylalkyl may be substituted with 0, 1 or 2 substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, and alkylcarbonyl, wherein Ra and R are defined herein. The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2- phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl. The term "arylcarbonyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term "arylalkylsulfonyl," as used herein, refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. The term "arylsulfonyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. The term "carbonyl," as used herein, refers to a -C(O)- group. The term "carboxy," as used herein, refers to a HO2C- group. The term "carboxyalkyl," as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxy ethyl, and 3-carboxypropyl. The term " carboxyalkoxy," as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "cyano," as used herein, refers to a NC- group. The term "cyanoalkyl," as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl. The term "cycloalkyl," as used herein, 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. Examples of monocyclic ring systems 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. l)heptane, bicyclo(2.2.2)octane, bicyclo(3.2.2)nonane, bicyclo(3.3.1)nonane, and bicyclo(4.2.1)nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo(3.3.1.03'7)nonane and tricyclo(3.3.1.13,7)decane (adamantane). The 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, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl and RaRbNsulfonyl, wherein Ra and Rb are defined herein, and wherein the substituent aryl, heteroaryl and heterocycle groups may be optionally 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, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, halo, haloalkyl, haloalkoxy, haloalkylthio and hydroxy. The term "cycloalkylalkyl," as used herein, 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. The term "cycloalkylcarbonyl," as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term "dialkylsulfonyl," as used herein, refers to two independent alkyl groups, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. The term "formyl," as used herein, refers to a -C(O)H group. The term "formylalkyl," as used herein, 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. The term "halo" or "halogen," as used herein, refers to C1-, Br-, I- or F-. The term "haloalkyl," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3- fluoropentyl. The term "haloalkoxy," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "haloalkylthio," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkylthio group, as defined herein. The term "heteroaryl," as used herein, 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,
7,8-dihydroisoquinolinyl, 5,6-dihydroquinolinyl, 7,8-dihydroquinolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyπolyl, pyridinium N-oxide, quinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl. According to the present invention, 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, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl and RaRbNsulfonyl, wherein Ra and Rb 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, and wherein the substituent aryl, heteroaryl, heterocycle, cycloalkyl, the aryl of arylalkyl, the heteroaryl of heteroarylalkyl, the heterocycle of heterocyclealkyl, and the cycloalkyl of cycloalkylalkyl may be substituted with 0, 1 or 2 substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-,
RaRbNcarbonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, and alkylcarbonyl. The term, "heteroarylalkyl," as used herein, refers to a heteroaryl group as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "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. Representative examples of the monocyclic heterocyclic ring 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, moφholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyπolinyl, pyπolidinyl, tefrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholmyl, 1,1-dioxidothiomorpholinyl (thiomorpholme sulfone), thiopyranyl, and trithianyl. 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. Representative examples of the bicyclic heterocyclic ring 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. Representative examples of 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. According to the present invention, 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, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl and RaRbNsulfonyl, wherein Ra and R 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, and wherein phenyl, heteroaryl, heterocycle, cycloalkyl, the aryl of arylalkyl, the heteroaryl of heteroarylalkyl, the heterocycle of heterocyclealkyl, and the cycloalkyl of cycloalkylalkyl can be substituted with 0, 1 or 2 substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, and alkylcarbonyl. The term "heterocyclealkyl," as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyl and the like. The term "heterocyclecarbonyl," as used herein, 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. The term "hydroxy," as used herein, refers to an -OH group. The term "hydroxyalkyl," as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, 2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl and the like. The term "mercapto," as used herein, refers to a -SH group. The term "mercaptoalkyl," as used herein, refers to a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl. The term "nitro," as used herein, refers to a -NO2 group. The term "sulfonyl," as used herein, refers to a -SO2- group. The term " aRbN-," as used herein, refers to both Ra 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. The term " RaRbNcarbonyl," as used herein, refers to RaRbN, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term " RaRbNcarbonylalkyl," as used herein, refers to RaRbNcarbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term " RaRbNsulfonyl," as used herein, refers to RaRbN, 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, β-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, β-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases. The present compounds can exist as therapeutically suitable salts. The term "therapeutically 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. Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmoφholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'- dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like, are contemplated as being within the scope of the present invention. The present compounds can also exist as therapeutically suitable prodrugs. The term "therapeutically suitable 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. The term "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. Individual 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. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Therapeutic compositions of the present compounds comprise an effective amount of the same formulated with one or more therapeutically suitable excipients. The term "therapeutically suitable excipient," as used herein, represents a non-toxic, solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Examples of therapeutically suitable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like. These therapeutic compositions can be administered parenterally, intracisternally, orally, rectally, or intraperitoneally. Liquid dosage forms for oral administration of the present compounds comprise formulations of the same as emulsions, microemulsions, solutions, ' suspensions, syrups, and elixirs. In addition to the compounds, the liquid dosage forms can contain diluents and/or solubilizing or emulsifying agents. Besides inert diluents, 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 amoφhous material with poor water solubility. The rate of absoφtion of the compounds depends upon their rate of dissolution which, in turn, depends on their crystallinity. Delayed absoφtion 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. In such forms, 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. With capsules, tablets, and pills, the 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. In these forms, 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. Absoφtion enhancers can also be used to increase the flux of the compounds across the skin, and the rate of absoφtion can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel. Disorders that can be treated or prevented in a patient by administering to the patient, a therapeutically effective amount of compound of the present invention in such an amount and for such time as is necessary to achieve the desired result. The term "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 prefeπed 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. In general, 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.
Biological Data
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 (NH4)2SO at 90% saturation (662 g solid ammonium sulfate per liter of solution). The solubilized precipitate was chromatographed on Sephadex G-
200 (1 m x 5 cm) equilibrated with a 10 mM Tris-HCl buffer pH 7.5 containing NaCl at a final concentration of 0.1 and developed from the bottom. Fractions containing enzymatic activity were pooled, chromatographed on DE-52 (16 x 2.5 cm) equilibrated with 10 mM Tris-HCl, pH 7.5, and eluted with a 250-mL linear 0-0.4 M NaCl gradient prepared in 10 mM Tris-HCl. 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 )2SO4 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% (NH4)2SO4, 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. Box 3605, Manassas, VA), cultured and maintained at 37 °C with 5% CO2 in low, glucose DMEM media supplemented with 10% Fetal Bovine Serum and antibiotic/antimycotic. In preparation for making an extract, cells were seeded at a density to achieve confluence within 7 days. The cells were cultured for an additional
14 days to allow for maximal DPPIV expression. On the day of harvest, cells were washed once with Dulbecco's PBS and solubilized in a 10 mM NaCl containing 50 mM Tris HC1, 0.5% Nonidet P40 and 0.3 ug/mL aprotinin at pH 8.0. The extract was clarified by centrifugation at 35,000 g for 30 minutes at 4 °C. Inhibition constant determination for DPP-IV DPP-IV activity was determined by measuring the rate of hydrolysis of a surrogate substrate Gly-Pro-7-amido-methylcoumarin (Gly-Pro-AMC, Catalogue #G- 2761, Sigma, St. Louis, MO). The assay is carried out at room temperature in black 96 well polypropylene or polyethylene plates in a total volume of 100 μL per well. Appropriate dilutions of the compounds are made in DMSO and then diluted ten fold into water. 10 μL of 5 concentrations of the compound of formula (I) (inhibitor) or 10% DMSO in water are added to individual wells containing 80 μL 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 μL of either 280, 700, 1750, or 3500 μM 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. For each concentration of compound of formula (I) (inhibitor) or DMSO control, 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 μM to about 0.03 μM. For the determination of chemical stability, compounds of the present invention are assayed using the following protocol:
Chemical Stability Assay A solution of each DPP-IV compound was prepared in an appropriate mobile phase. This was injected and analyzed by HPLC to identify the parent drug peak in the chromatograms. Stability solutions were prepared in 50 mM phosphate buffer pH 7.4 adjusted to μ=0.155. Samples were weighed using a Mettler-Toledo microbalance and transfeπed into a 20 ml glass scintillation vial or a volumetric flask. The phosphate buffer pH 7.4 was added with an EDP Plus 10 ml electronic pipette. The samples were sonicated for approximately 2 minutes and filtered using a PTFE membrane syringe filter. The filtrate was transfeπed 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. After data acquisition was completed, the chromatograms were processed for each compound. The rate and half-life were determined from a plot of log10 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. Prefeπed compounds of the present invention are potent inhibitors of DPP-IV (with KΪ values <10 nM) and are resistant to the internal cyclization reaction described above (T 2 >10 hours, suitable for once-daily dosing). These compounds are uniquely suited for the blockade of DPP-IV activity, and the treatment of diseases related to excessive DPP-IV activity, in a human therapeutic setting. As disclosed in WO04/016587, compounds , β and γ typify DPP-IV inhibitors where activity and stability are not simultaneously achieved. Thus, Comparative compound α is a relatively potent inhibitor of DPP-IV (KT = 8.3 nM), but suffers from poor intrinsic chemical stability (T 2 = 5.3 hrs). On the other hand, Comparative compound β and Comparative compound γ are sufficiently stable to cyclization (chemical stability half-lives of 16.4 and 12.2 hours, respectively), but neither is potent as a DPP-IV inhibitor (KΪ = 33 and 720 nM).
Figure imgf000054_0001
Comparative compound α Comparative compound β Comparative compound γ 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.
Table I. DPP-IV inhibitory potency and chemical stability data for representative compounds
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
As inhibitors of DPP-IV action, 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, β-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, β-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. 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.
Figure imgf000058_0001
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. Important 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). 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. The active GLP-1 (7-36) amide is an incretin that increases glucose stimulated insulin secretion (Drucker, D. J. Diabetes, 1998, 47, 159-169). 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. In this regard, 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,
205-11; Ahren, B., BioEssays 1998, 20, 642-51). GLP-1 based therapy has therapeutic potential for the treatment of type 2 diabetes. However, 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). The short half-life of 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. Abdominal/visceral obesity and insulin resistance characterize both syndromes (Reaven, GM, Physiol. Rev. 1995, 75, 473-86; Johansson, et al., Metabolism 1995, 44, 1126-29). Growth hormone favorably effects some of the perturbations associated with abdominal/visceral obesity, including reduction in abdominal/visceral obesity, improved insulin sensitivity and lipoprotein metabolism and reduction in diastolic blood pressure (Baπeto-Filho, et al., J. Clin. Endocrinol. Metab. 2002, 87(5), 2018-23; Colao et al., J. Clin. Endocrinol. Metab. 2002, S7(3), 1088-93; Gotherstrom, et al., J. Clin. Endocrinol. Metab. 2001, 86(10), 4657-65; Johannsson, et al., J. Endocrinol. Invest. 1999, 22(5 Suppl), 41-6; Johannsson, et al., J. Clin. Endocrinol. Metab. 1997, 52(3), 727-34). For the treatment of diabetes or Syndrome X, 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 chloφropamide, glipizide, glyburide, and the like, an insulin sensitizing agent such as a PPARγ agonist such as froglitazone, pioglitazone, rosiglitazone, and the like, an α-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-4, or other such anti-diabetic agents that are known to one skilled in the art. The ability of the compounds of the present invention to treat diabetes, alone or in combination with another agent, can be demonstrated according to the methods described by Zander, M.; Mustafa, T.; Toft-Nielsen, M.-B.; Madsbad, S.; Hoist, J. J. in Diabetes Care 2001, 24, 720-725; or, according to the methods described herein. 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. due to longer stability in vivo. DPP-IV inhibition would be predicted to increase GHRH levels and thus serum growth hormone levels. 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 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. 1998, 68, 525-530; Gutzwiller, et al., Am. J. Physiol. 1999, 276, R1541-R1544.) DPP-IV inhibition is predicted to increase the level of circulating GLP-1 (7-36) amide and thereby increases satiety in obesity and non-insulin-dependent diabetes mellitus. Therefore, the compounds of the present invention, including but not limited to those specified in the examples can be used in the treatment of obesity. For 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-
Nielsen, M.-B.; Madsbad, S.; Hoist, J. J. in Diabetes Care 1999, 22, 1137-1143. 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. 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.
Natl. Acad. Sci. 1994, 91, 3082-86; Tanaka, et al., Proc. Natl. Acad. Sci. 1993, 90, 4583). Soluble DPP-IV up-regulates the expression of the costimulatory molecule CD86 on monocytes through its dipeptidyl peptidase IV activity suggesting that ι 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).
Consequently, DPP-IV inhibition would be predicted to suppress certain immune responses and thus have therapeutic benefit in the treatment of immunomodulatory diseases. Therefore, 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. In addition to GLP-1, 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 absoφtion 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 malabsoφtion disorders. Chemokine receptors, especially CCR5 and CXCR4, act as cofactors for HIV-
1 entry into CD4+ cells and their coπesponding ligands can suppress HJV entry and thus replication. 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. 1998, 431, 236-40; Shioda, et al., Proc. Natl. Acad. Sci. 1998, 95(11), 6331-6; Proost, et al., FEBSLett. 1998, 432, 73-6). 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). Expression of DPP-IV on the surface of HSC decreases homing and engraftment to bone maπow 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 maπow 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). In contrast, 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.
Synthetic Methods The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that together illustrate the methods by which the compounds of the invention may be prepared. The synthesis of compounds of formula (I) wherein the groups
Figure imgf000063_0001
and R2 are as defined above unless otherwise noted below, are exemplified below.
Scheme 1
Figure imgf000063_0002
As shown in Scheme 1, 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-pyπolidino-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-methylmoφholine or diisopropylethylamine in solvents such as but not limited to dichloromethane to provide compounds of general formula 3. 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).
Scheme 2
Figure imgf000064_0001
Scheme 1 >-
Figure imgf000064_0002
As shown in Scheme 2, ethyl (S)-(+)-2-pyπolidone-5-carboxylate 5 can be treated with di-tert-butyl dicarbonate ((Boc)2O) in solvents such as but not limited to THF, dioxane or acetonitrile followed by treatment with Grignard reagents of general formula RϊBAMgBr, wherein Rl5 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. The treatment of compounds of general formula 7 under conditions of 50 psi of hydrogen in the presence of a palladium catalyst such as 10% palladium on carbon with provide compounds of general formula 8. The protection of the nitrogen of compounds of general formula 8 using di-tert-butyl dicarbonate ((Boc)2O) and a catalytic amount of DMAP in solvents such as but not limited to THF, dioxane or acetonitrile followed by the hydrolysis of the ester group using reagents such as but not limited to lithium hydroxide or sodium hydroxide in solvents such as aqueous ethanol or aqueous dioxane will provide compounds of general formula 9. The treatment of compounds of general formula 9 according to the conditions described in Scheme 1 outlining the coupling and deprotection will provide compounds of general formula 4, which are representative of compounds of the present invention.
Scheme 3
Figure imgf000065_0001
RjReNH NaCNBH3
Figure imgf000065_0002
As shown in Scheme 3, compounds of general formula 10 when treated first with sodium bis(trimethylsilyl)amide followed by treatment with chloroformate such as but not limited to methyl chloroformate in solvents such as but not limited to THF will provide compounds of general formula j ,. Compounds of general formula 11 when first treated with a reducing agent such as but not limited to lithium borohydride in THF followed by the treatment with methanol and p-toluene sulfonic acid under heated conditions will provide compounds of general formula 12. Compounds of general formula 12 when treated with bis(trimethylsilyl)acetylene, tin (IV) chloride and aluminum chloride in solvents such as toluene and the like to provide compounds of general formula 13. Compounds of general formula 13 when treated with iodotrimethylsilane to remove the methoxycarbonyl protecting group followed by treatment with tetrabutylammonium fluoride to remove the silyl group will provide compounds of general formula 14. The nitrogen of compounds of general formula 14 can be protected by treatment with di-tert-butyl dicarbonate and a catalytic amount of DMAP in solvents such as but not limited to THF and the acetylene group can be converted to an alkene by treatment under an atmosphere of hydrogen in the presence of 5% palladium on barium sulfate in solvent such as but not limited to THF to provide compounds of general formula 15. The hydrolysis of the ester of compounds of general formula 15 by treatment with lithium hydroxide in solvents such as aqueous methanol followed by treatment with compound of general formula 2 according to the conditions outlined in Scheme 1 to provide compounds of general formula 16. Compounds of general formula 16 can be treated first with ozone followed by treatment with methyl sulfide to provide compounds of general formula 17. The aldehyde functionality of compound of formula 17 can be treated with a primary or secondary amine such as RΪRJNH and sodium cyanoborohydride in solvents such as but not limited to THF to provide compound of general formula 18 wherein Rι and Re are as defined in formula (I). Compounds of formula J 5 can then be treated with trifluoroacetic acid to remove the Boc group to provide compound of general formula 19 which are representative of compounds of the present invention.
Scheme 4
Figure imgf000066_0001
As shown in Scheme 4, 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 R2-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.
Scheme 4a
Figure imgf000067_0001
Figure imgf000067_0002
22
Alternatively, Compounds of general formula 20 can be treated with compounds of formula Rt 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.
Scheme 5
Figure imgf000067_0003
Alternatively, 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. Alternatively, 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 6
Figure imgf000068_0001
Compounds of general formula 16 which can be obtained as described in Scheme 3 can be treated with arylhalides, palladium acetate and tri-ortho- tolylphosphine in solvents such as but not limited to THF to provide compounds of general formula 26. Compounds of general formula 26 can be converted to compounds of general formula 27 through methods described above or through methods known to those skilled in the art for removing a Boc protecting group from a nitrogen.
Scheme 7
Figure imgf000069_0001
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. 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.
Scheme 8
Figure imgf000070_0001
Additionally, 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 R1NH2 to provide compounds of general formula 35. Compounds of general formula 35 can be treated with TFA to provide compounds of general formula 36.
Scheme 9
Figure imgf000070_0002
As shown in Scheme 9, 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 coπesponding 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.
Scheme 10
Figure imgf000071_0001
As shown in Scheme 10, 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. The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incoφorated by reference. Compounds of the invention were named by ACD/ChemSketch version 5.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature.
Experimentals
Example 1 (2S)- 1 -((5S)-5 -ethyl-L-prolyl)pyπolidine-2-carbonitrile
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:
(a) St-Denis, Y,; Augelli-Szafran, C.E.; Bachand, B.; Berryman, K.A.; DiMaio, J.; Doherty, A. M.;Edmunds, J.J.;Leblond, L.; Levesque, S.; Narasimhan, L.S.; Penvose- Yi, J.R.; Rubin, J.R.; Tarazi, M.; Winocour, P.D.; Siddiqui, M.A. Biorg. Med. Chem. Lett. 1998, 8, 3193-3198. (b) Jain, R. Org. Prep. Procd. Intl. 2001, 33, 405-409; was dissolved in 6 mL of THF, and the mixture was cooled to -4-0 °C. Ethyl magnesium bromide solution (1.0 M in THF, 10.84 mL, 10.84 mmol) was added slowly via syringe. After 2 hours, the reaction flask was placed in a freezer (approx -20 °C) overnight. Saturated aqueous NH4C1 and 1 N HC1 were added, and the mixture was extracted with ethyl acetate (3X). The combined organic extracts were dried over Na2SO , concentrated and purified by flash chromatography (30% ethyl acetate hexane) to provide the titled compound (2.018 g, 78%). MS (ESI) m/z 288 (M+H)+, 310 (M+Na)+.
Example IB 5-ethyl-3,4-dihydro-2H-pyπole- (2S)-carboxylic acid ethyl ester The ester from Example 1A was dissolved in 3 mL of CH C12 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 IC 5S-ethyl-pyπolidine-2S-carboxylic acid ethyl ester The material from Example IB was dissolved in 32 mL of EtOH and mixed with 0.30 g of 10% Pd/C under 60 psi of H2 overnight. The catalyst was removed by filtration, and the filtrate was concentrated to provide the titled compound. MS (Cl) m/z = 172 (M+H)+. Example ID 5S-Ethyl-pyrrolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester The material from Example IC (18.08 mmol), 4-(dimethylamino)pyridine (0.904 mmol) and triethylamine (36.16 mmol) were mixed in 40 mL of CH2C12, and then di-tert-butyl dicarbonate (19.89 mmol) was added. After stirring overnight, the mixture was washed with 1 N HC1 and brine, and then purified by flash column chromatography (15-20% ethyl acetate/hexane) to provide the titled compound (3.73 g, overall 80%). MS (ESI) m/z 258(M+H)+. (α)20 D= - 35.86° (c 1.45, MeOH).
Example IE 5S-Ethyl-pyπolidine-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 Na2SO and concentrated to provide the title compound which was used without further purification in the next step.
Example IF 2S-(2S-Cyano-p yπolidine- 1 -carbonyl)-5S- ethyl-pyrrolidine-1 -carboxylic acid tert-butyl ester The material prepared in Example IE (201 mg, 0.88 mmol), 2S- cyanopyπolidine hydrochloride (1.1 mol) and PyBOP (641 mg, 1.23 mmol) were mixed in 3.5 mL of CH2C12 followed by addition of 422 μL of dusopropylethylamine
(2.42 mmol). After 5 hours, acetonitrile (MeCN) (3 mL) was added and the mixture was purified by reverse-phase HPLC (50 mg of crude material dissolved in MeCN/MeOH was injected into a Waters C18 column (7 micron, 25x100 mm) and eluted using a linear gradient of 5% to 100% CH3CN/H2O). The aqueous phase contained 10 mM NH4OAc. Fraction collection was trigered by UV absoφtion at 210 nm.) to provide 187 mg of title compound (69%).
Example 1G (2S)- 1 -((5S)-5 -ethyl-L-prolyl)pyπolidine-2-carbonitrile The sample of Example IF (180 mg) dissolved in 1 mL of CH2C12 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% CH3CN H2O contained 0.1% TFA.) to provide the title compound as the coπesponding trifluoroacetic acid salt (147 mg). 1H NMR (400 MHz, MeOH-d4,) δ 1.07 (t, J = 7.5 Hz, 3H), 1.70-1.82 (m, 2H), 1.95 (m, IH), 2.10-2.38 (m, 6H), 2.52 (m,
IH), 3.60 (m, IH), 3.64 (dd, J!=J2=6.8 Hz, 2H), 4.62(dd, J = 5.4, 9.4 Hz, IH), 4.82 (dd, J = 4.3, 8.0 Hz, IH) ppm. 13C NMR (MeOH- t, 100 MHz) δ 11.2, 25.8, 26.1, 28.9, 30.0, 30.8, 47.6, 48.2, 60.3, 64.3, 119.2, 168.9 ppm. MS (ESI) m/z 222 (M+H)+. Example 2 (2S)- 1 -((5ig)-5-phenyl-L-prolyl)pyπolidine-2-carboniτrile The title compound was synthesized by substituting 5S-ethyl-N-Boc-2S- proline in Example 1 with 5R-ρhenyl-N-Boc-2S-ρroline. H NMR (MeOH-d4, 500 MHz) δ 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 3 (2S)-4,4-difluoro- 1 -((5S)-5-methyl-L-prolyl)pyπolidine-2-carbonitrile
Example 3A 4-Oxo-pyπolidine-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 CH2C12 and cooled to -78 °C. DMSO (1.33 mL, 18.70 mmol) was added via syringe. After 5 minutes, 4R-hydroxy-pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.83 g, 7.48 mmol) in 12 mL of CH2C12 was added. After 30 minutes, Et3N (3.64 mL) was added. The mixture was stiπed at -78 °C for 40 minutes, then at 0 °C for 30 minutes. The mixture was diluted with CH C12 (ca. 30 mL) and IN HC1 was added. The organic layer was washed with brine, dried with Na2SO4 and concentrated to provide the titled compound (2.20 g). MS (Cl) m/z 244 (M+H)+. . Example 3B 4,4-Difluoro-pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The compound from Example 3 A (2.20 g) in 15 mL of CH2C12 was cooled to - 50 °C, then Et2NSF3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stiπed overnight. NaHCO3 solution was added slowly to the mixture and the mixture was extracted with dichloromethane
(3X). The combined organics were dried with Na SO4 and purified with flash chromatography (10% ethyl acetate/hexane) to provide the difluoroester (1.81 g, 91%). MS (Cl) m/z 266 (M+H)+. Example 3C 4,4-Difluoro-pyπolidine-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.
The organic extracts were dried with Na2SO4 and concentrated to provide the crude acid (1.82 g).
Example 3D 2S-Carbamoyl-4,4-difluoro-pyπolidine-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 NH3 in dioxane were added. After stirring overnight, the mixture was concentrated in vacuo and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4, concentrated and purified by flash chromatography (70% ethyl acetate/hexane) to provide the title amide (0.82 g, 48%). MS (ESI) m/z 251 (M+H)+. 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 CH2C12 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-pyπolidine- 1 -carbonyl)-5S-methyl-pyπolidine- 1 - carboxylic acid tert-butyl ester The compound from Example 3E (303 mg, 0.93 mmol), 5S-methyl- pyπolidine-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 Et3N was added until the pH of the mixture reached 6-7 (wet pH paper). The mixture was stiπed overnight and purified by reverse-phase HPLC to provide the titled compound. (170 mg, 56%).
Example 3G 2S-(2S-Cyano-4,4-difluoro-pyπolidine- 1 -carbonyl)- 5S-methyl-pyπolidine-l -carboxylic acid tert-butyl ester The compound of Example 3F (160 mg, 0.44 mmol) and imidazole (1.25 eq.) were mixed in 3 mL of pyridine and cooled to -30 °C, then POCl3 (2.5 eq.) was added via syringe. The mixture was then placed in a freezer (-20 °C) overnight. Saturated NH4C1 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 Na2SO4 and concentrated to provide the title compound (147 mg).
Example 3H (2S)-4,4-difluoro- 1 -((5S)-5-methyl-L-prolγl)pyπolidine-2-carbonitrile The Boc group of Example 3G was removed as described in Example 1G to provide the title compound. 1H NMR (500 MHz, MeOH-d4) δ 1.48 (d, J=6.5 Hz, 3H), 1.78 (dq, J = 8.7, 13.8 Hz, IH), 2.10 (m, IH), 2.25 (m, IH), 2.65 (m, IH), 2.80-2.95
(m, 2H), 3.78 (m, IH), 4.10 (m, IH), 4.58 (dd, J = 6.2, 12.0 Hz), 5.14 (dd, J = 4.5, 9.2 Hz) ppm. 13C NMR (MeOH-c , 100 MHz) δ 17.0, 28.8, 32.0, 37.8 (t, J = 25.4 Hz), 46.1, 53.2 (t, J = 32.6 Hz), 58.6, 60.3, 117.7, 127.0 (t, J = 249 Hz), 169.3 ppm. MS (ESI) m z 244 (M+H)+. Example 4 3-{((2S,5S)-5-methylpyπolidin-2-yl)carbonyl}-l,3-thiazolidine The title compound was synthesized by substituting 2S-cyanopyπolidine in
Example 1 with thiazolidine and using the methyl pyπolidine prepared as described in Example 5. 1H NMR (500 MHz, MeOH-d4) δ 1.48 (d, J=6.55 Hz, 3 H) 1.73 (m, 1 H) 2.13 (m, 1 H) 2.24 (m, 1 H) 2.51 (m, 1 H) 3.09 (m, 1 H) 3.16 (m, 1 H) 3.75 (m, 2 H) 3.88 (m, 1 H) 4.52 (m, 1 H) 4.61 (dd, J=9.51, 5.77 Hz) and 4.67 (m, 2 H) ppm. 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. 1H NMR (MeOH-d4, 400 MHz) δ 1.49 (d, J=6.75 Hz, 3 H), 1.75 (dq, J=13.08, 8.84 Hz, 1 H), 2.16 (m, 3 H), 2.28 (m, 3 H), 2.54 (m, 1 H), 3.64 (t, J=6.60 Hz, 2 H), 3.80 (m, 1 H), 4.61 (dd, J=9.51, 5.83 Hz, 1 H), 4.83 (dd, J=7.98, 4.30 Hz, 1 H) ppm. 13C NMR (MeOH-d4, 100 MHz) δ 17.0, 26.1, 29.1, 30.8, 32.1, 47.6, 48.2, 58.6, 60.6, 119.2, 168.9 ppm. MS (ESI), m/z 208(M+H)+.
Example 6 (2S)- 1 -((5S)-5-ethyl-L-prolyl)-4,4-difluoropyπolidine-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. 1H NMR (400 MHz, MeOH-dj) δ 0.79 (t, J=7.52 Hz, 3 H), 1.49 (m, 2 H), 1.66 (m, 1 H), 1.81 (m, 1 H), 2.01 (m, 1 H), 2.23 (m, 1 H), 2.60 (m, 2 H), 3.30 (dt, J=16.88, 6.90 Hz, 1 H), 3.83 (m, 2 H), 4.34 (dd, J=9.36, 5.68 Hz, 1 H), 4.86 (dd, J=9.21, 4.30 Hz, 1 H) ppm. MS (ESI) m/z 258 (M+H)+. Example 7 (2S)- 1 -((5i?)-5-ethyl-L-prolyl)pyπolidine-2-carbonitrile
Example 7A 5R-ethyl-pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 5S-Vinyl-pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
(Example 22B, lg) and 10% Pd/C (200 mg) were stiπed 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}pyπolidine-2-carbonitrile The title compound was synthesized by substituting 5S-ethyl-pyπolidine-l,2S- dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in Example 1 with 5R-ethyl- pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester prepared in Example 7A. 1H NMR (300 MHz, MeOH-d^) δ 2.03 (m, 10 H) 2.64 (m, 1 H) 3.64 (t, J=6.61 Hz, 2 H) 4.55 (t, J=8.31 Hz, 1 H) 4.83 (m, 1 H), 0.92 (t, J=7.46, 3H) ppm. MS
(ESI) m/z 222 (M+H)+.
Example 8 (2S)- 1 -((5R)-5-isopropyl-L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting EtMgBr in Example 1 with i-PrMgBr. 1H NMR (400 MHz, MeOH-d4) δ 1.05 (d, J=6.75 Hz, 3 H) 1.14 (d, J=6.75 Hz, 3 H) 1.77 (m, 1 H) 2.19 (m, 7 H) 2.50 (m, 1 H) 3.33 (m, 1 H) 3.64 (t, J=6.75 Hz, 2 H) 4.62 (dd, J=9.51, 5.22 Hz, 1 H) 4.82 (dd, partially overlapped with solvent peak, J-4.60 Hz, 1 H) ppm. MS (ESI) m/z 236 (M+H)+.
Example 9 (2S)- 1 -((5R)-5- {((4-methoxyphenyl)amino)methyl) -L-prolyl)pyπolidine-2- carbonitrile Example 9A dimethyl (2S)-5-oxopyπolidine- 1 ,2-dicarboxylate In a procedure adapted from Li, H.; Sakamoto, T.; Kato, M.; Kikugawa, Y. Synth. Commun. 1995, 25(24), 4045-4052, to a cold (-78 °C) solution of methyl (S)- (+)-2-pyπolidone-5-carboxylate (4.80 grams, 33.5 mmol) in tetrahydrofuran (90 mL) was added a solution of lithium bis(trimethylsilyl) amide (1 M solution in hexanes, 40.0 mL, 40.0 mmol) dropwise via syringe over 15 minutes; then methyl chloroformate (2.90 mL, 36.9 mmol) was added dropwise via syringe over 5 minutes. The resulting slurry was stiπed 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). MS (DCI/NH3) m/e 202 (M+H)+; 1H NMR (300 MHz, CDC13): δ ppm 4.70 (dd, IH), 3.88 (s, 3H), 3.80 (s, 3H), 2.74-2.30 (m, 3H), 2.15-2.05 (m, IH). Example 9B dimethyl (2S)-5-methoxypyπolidine- 1 ,2-dicarboxylate To a cold solution (-78 °C) of dimethyl (2S)-5-oxoρyπolidine-l,2- dicarboxylate (5.80 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 stiπed at -78 °C for 30 minutes and then quenched by the careful addition of saturated sodium bicarbonate solution (50 mL). After warming to 0 °C, 30% hydrogen peroxide (6 mL) was carefully added dropwise. The mixture was stirred for 30 minutes at room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (300 mL) and brine (200 mL). The milky aqueous layer was separated and further extracted with ethyl acetate (2 X 300 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to a light yellow oil. The yellow oil was taken up in methanol (50 mL) containing jcαra-toluenesulfonic acid hydrate (487 mg, 2.6 mmol) and stiπed at room temperature for 16 hours. 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. (mixture of amide bond rotomers) 1H NMR (300 MHz, CDC13): δ ppm 5.37 (d, IH), 5.33 (dd, IH), 5.24 (d, IH), 5.18 (dd, IH), 4.44-4.31 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.42 (s, 3H), 3.34 (s, 3H). Example 9C dimethyl (2S,5i?)-5-((trimethylsilyl)ethynyl)pyπolidine- 1 ,2-dicarboxylate and dimethyl (2S,5S)-5-((trimethylsilyl)ethynyl)pyπolidine- 1 ,2-dicarboxylate Using a procedure adapted from Beal, L.M.; Liu,B.; Chu, W.; Moeller, K.D. Tetrahedron 2000, 56, 10113-10125, to a cold -45 °C solution of dimethyl (2S)-5- methoxypyπolidine-l,2-dicarboxylate (3.30 g, 15.20 mmol) and bistrimethylsilylacetylene (5.20 g, 30.4 mmol, 2.0 equiv) in methylene chloride (45 mL) was added a solution of tin (IV) chloride (1 Min methylene chloride, 20.0 mL, 20.0 mmol, 1.3 equiv) dropwise via syringe over 15 minutes. To the dark yellow solution was added solid aluminum chloride (2.77 g, 20.8 mmol, 1.4 equiv) in one portion. The resulting mixture was allowed to warm to room temperature and stiπed at room temperature for 48 hours. The reaction mixture was carefully poured into aqueous sodium bicarbonate solution (100 mL) with ice cooling. A white precipitate forms and 1 HC1 (ca. 50 mL) was added until the solids dissolved. This mixture was extracted with ethyl acetate (2 X 200 mL). The combined organic layers were filtered, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography eluting with 70% hexane/30% ethyl acetate to afford 1.9 grams of (2S,5S)-5-((trimethylsilyl)ethynyl)pyπolidine-l,2-dicarboxylate (trans compound
Rf of 0.3 in 70% hexane/30% ethyl acetate) and 1.7 grams of dimethyl (2S,5R)-5- ((trimethylsilyl)ethynyl)pyπolidine-l,2-dicarboxylate (cis compound Rf of 0.2 in 70% hexane/30% ethyl acetate). MS (DCI/NH3) m/e 284 (M+H)+; The compound exists as a mixture of rotomers. Data for trans isomer: 1H NMR (300 MHz, CDC13): δ ppm 4.60 (d, IH), 4.51 (d, IH), 4.30 (d, IH), 4.24 (d, IH), 3.62 (s, 3H), 3.59 (s, 3H),
3.57 (s, 3H), 3.54 (s, 3H), 2.40-2.28 (m, 2H), 2.11-2.04 (m, 2H), 1.90-1.81 (m, 4H), 0.0 (s, 18H). Data for cis isomer: 1H NMR (300 MHz, CDC13): δ ppm 4.55-4.40 (m, IH), 4.20-4.15 (m, IH), 3.59 (s, 6H), 2.15-1.89 (m, 4H), 0.00 (s, 9H). MS (DCI/NH3) m/e 284 (M+H)+.
Example 9D 5i?-Trimethylsilanylethynyl-pγrrolidine-2S-carboxylic acid methyl ester 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 stiπed 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-pyπolidine-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 pyπolidine (10.5 g), which was used in the next step without purification. MS (DCI) m/z 326 (M+H)+. This intermediate (32.9 mmol) was dissolved in THF (20 mL), and tefrabutylammonium fluoride (1 M solution in THF, 39.5 mL, 39.5 mmol ) was added to the mixture at 0 °C. After 30 minutes, the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel ( 30% EtOAc/Hexane) to provide the title product (6.9 g, 84%). MS (DCI) m/z 254 (M+H)+.
Example 9F 5R-Ethenyl-pyπolidine-l, 2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The above Boc-protected amine (6.9 g, 27.2 mmol) was dissolved in ethyl acetate (130 mL). 5% Pd/BaSO4 (260 mg) and quinoline (6.5 mL) were added. The mixture was stiπed under H (20 psi ) at room temperature for 4-5 minutes. The mixture was filtered, washed with 1 N HC1 and concentrated to provide 5i--vinyl- pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (6.2 g 100%). MS (DCI) m z 256 (M+H)+.
Example 9G 2S-(2S-Cyano-pyπolidine- 1 -carbonyl)-5i.- vinyl-pyπolidine- 1 -carboxylic acid tert- butyl ester The above vinyl starting material (6.9 g, 27.2 mmol) was was dissolved in 50 mL of ethanol and then 1.7 M LiOH (48 mmol) was added. The mixture was stiπed at room temperature for 2 hours until the starting material was consumed. The mixture was acidified with 1 N HC1 (pH= 2) and then extracted with ethyl acetate (3x). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude acid (6.9 g, 99%), which was used in the next step without purification. MS (DCI) m z 242 (M+H)+. 2S-cyanopyπolidine HC1 salt (22.6 mmol) and 2-(lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 6.35 g, 26.8 mmol) were combined with the above intermeidate in 10 mL of DMF, and then Et3N (4.4 mL, 30.6 mmol) was added. After stirring overnight, the mixture was concentrated and purified by flash chromatography (40%-50% EtOAc/Hexane) to provide the title compound (5.0 g, 74%). MS (ESI) m/z 320 (M+H)+.
Example 9H 2S-(2S-Cyano-pyπolidine- 1 -carbonyl)-5R- formyl-pyπolidine-1 -carboxylic acid tert-butyl ester The compound of Example 9G (0.34 g, 1.06mmol) in 2 mL each of CH2C12 and MeOH was cooled to -78 °C, and O3 was bubbled into the mixture for 30 minutes. Then O2 was bubbled for 5 minutes followed by the addition of Me2S (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%). MS (DCI) m/z 322 (M+H)+. Example 91 2S-(2S-Cyano-ρyπolidine- 1 -carbonyp-5 iϋ- {((4-methoxy-phenyl)-methyl-amino)- methyl}-pyπolidine-l -carboxylic acid tert-butyl ester The compound from Example 9H (50 mg, 0.155 mmol), and 4-methoxyaniline (2 eq.) were mixed in 1 mL each of MeOH and MeOH buffer (pH = 4, NaOAc: HOAc, 1:1). The mixture was stiπed for 0.5 hour and NaCNBH3 (25 mg, 0.19 mmol) was added. The mixture was filtered after 2 hours and purified by reverse phase HPLC (linear gradient of 0% to 70% acetonitrile/ 0.1% aqueous trifluoroacetic acid) to provide the desired product. Example 9J (2S)-l-((5R)-5-{((4-methoxyphenyl)amino)methyl}-L-prolyl)pyπolidine-2- carbonitrile The Boc group of Example 91 was removed as described in Example 1G to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ 1.76 (m, 1 H), 1.99 (m, 2 H), 2.25 (m, 5 H), 3.14 (m, 1 H), 3.50 (m, 3 H), 3.69 (s, 3 H), 4.36 (m, 2 H), 4.62 (m, IH), 6.56 (d, J=9.21 Hz, 2 H), 6.73 (d, J=8.90 Hz, 2 H) ppm. MS (DCI) m/z 329 (M+H)+.
Example 10 (2S)- 1 -((5R)-5- {((4-memylphenyl)amino)methyl} -L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-methoxyaniline in Example 9 with 4-methylaniline. 1H NMR (500 MHz, MeOH-d4) δ 1.66 (m, 1 H), 1.95 (m, 2 H), 2.18 (m, 4 H), 2.30 (m, 2 H), 2.42 (m, 2 H), 3.07 (m, 1 H), 3.35 (m, 1 H), 3.48 (m, 1 H), 3.58 (dd, J=14.97, 4.68 Hz, 1 H), 4.37 (m, 2 H), 4.59 (m, 1 H), 6.46 (d, J=8.42 Hz, 2 H), 6.90 (d, J=8.42 Hz, 2 H) ppm. MS (ESI) m/z 313 (M+H)+.
Example 11 6-((5-(2-cyano-pyπolidme-l-carbonyl)-pyπolidin-2-ylmethyl -amino)-nicotinonitrile The title compound was synthesized by substituting 4-methoxyaniline in Example 9 with 6-aminonicotinonitrile. 1H NMR (400 MHz, MeOH-d4) δ 1.92 (m, 1 H), 2.22 (m, 6 H), 2.60 (m, 1 H), 3.63 (m, 2 H), 4.02 (m, 2 H), 4.55 (m, 1 H), 4.67 (m, 1 H), 4.84 (m, IH), 6.70 (d, J=9.51 Hz, 1 H), 7.69 (d, J=l 1.05 Hz, 1 H), 8.43 (m, 1 H) ppm. MS (ESI) m/z 325 (M+H)+.
Example 12 (2S)- 1 -((5R)-5- {((4-bromophenyl)amino)methyl} -L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-methoxyaniline in
Example 9 with 4-bromolaniline. 1H NMR (500 MHz, MeOH-d4) δ 1.92 (m, 1 H), 2.23 (m, 6 H), 2.54 (m, 1 H), 3.52 (m, 2 H), 3.63 (m, 2 H), 3.95 (m, IH), 4.62 (m, J=9.04, 5.93 Hz, 1 H), 4.83 (dd, J=7.95, 4.52 Hz, 1 H), 6.65 (d, J=9.04 Hz, 2 H), 7.25 (d, J=9.04 Hz, 2 H) ppm. MS (DCI) m/z 377, 379 (M+H)+.
Example 13 (2S)-l-((5R)-5-{((phenyl)amino)methyl}-L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-methoxyaniline in Example 9 with aniline. 1H NMR (400 MHz, MeOH- j) δ 1.92 (m, 1 H), 2.20 (m, 6 H), 2.55 (m, 1 H), 3.59 (m, 4 H), 3.96 (m, 1 H), 4.61 (dd, J=9.21, 5.83 Hz, 1 H), 4.83
(m, J=3.38 Hz, 1 H), 6.71 (m, 3 H), 7.14 (m, 2 H) ppm. MS (ESI) m/z 299 (M+H)+.
Example 14 (2S)- 1 -((5i-)-5-(hydroxymethyl)-L-prolyl)pyπolidine-2-carboniτrile
Example 14A 2S-(2S-Cyano-pyπolidine- 1 -carbonyl)-5R- hydroxymethyl-pyπolidine-1 -carboxylic acid tert-butyl ester The compound of Example 9G (3.0 g, 9.3 mmol) in 6 mL each of CH2C12 and MeOH were cooled to -78 °C, and O3 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. The resulting oil was dissolved in 10 mL each of CH2C12 and EtOH followed by addition of NaBHj (0.534g, 14.1 mmol) and NaBH(OAc)3 (0.882 g, 4.2 mmol). After stirring for 1 hour, water was added, and the mixture was extracted with ethyl acetate (3X). The combined extracts were dried (Na2SO4), concentrated to provide the title alcohol (2.8 g, 93%). MS (DCI) m/z 324 (M+H4). Example 14B (2S)- 1 -((5-^)-5-(hydroxymethyl)-L-prolyl)pyπolidine-2-carbonitrile The compound of Example 14A was treated as described in Example 1G to provide the title compound. 1H NMR (300 MHz, MeOH-d4) δ 1.90-2.12 (m, 3H),
2.14-2.38 (m, 5H), 3.60-3.82 (m, 4H), 3.99 (m, IH), 4.50 (m, IH), 4.80 (m, IH) ppm. MS (ESI) m/z 224 (M+H)+, 242 (M+NH4)+.
Example 15 (2S)-l-{(5i?)-5-((4-bromophenoxy)methyl)-L-prolyl}pyπolidine-2-carbonitrile The compound of Example 14A (50 mg, 0.154 mmol), triphenylphosphine (53 mg, 0.200 mmol) and 4-bromophenol (0.17 mmol) were mixed in 1 mL of dry THF. Then diethyl azodicarboxylate (40% in toluene, 0.093 mL, 0.21 mmol) was added via a syringe. 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. 1H NMR (300 MHz, MeOH-d4) δ 1.99 (m, 1 H), 2.26 (m, 6 H), 2.59 (dq, J 3.22, 8.25 Hz, 1 H), 3.66 (m, 2 H), 4.12 (dt, J=15.68, 6.40 Hz, 1 H), 4.34 (d, J=5.76 Hz, 2 H), 4.68 (dd, J=8.99, 5.93 Hz, 1 H), 4.80 (m, J=7.46 Hz, 1 H), 6.96 (d, J=9.16 Hz, 2 H), 7.45 (d, .7=9.16 Hz, 2 H) ppm. MS (ESI) m/z 378/380 (M+H)+.
Example 16 (2S)- 1 - {(5S)-5-((4-bromophenoxy)meth.yl)-L-prolyl}pyrrolidine-2-carbonitrile The trans alcohol was synthesized by substituting the coπesponding cis olefin in Example 14 with the coπesponding trans olefin. MS (DCI) m/z 324 (M+H+). The title compound was synthesized by substituting the 5R alcohol in Example 15 with the coπesponding 5S isomer. 1H NMR (500 MHz, MeOH-d4) δ 2.14 (m, 4 H), 2.32 (m, 3 H), 2.69 (s, 1 H), 3.68 (m, 2 H), 4.17 (dd, J 0.29, 6.86 Hz, 1 H), 4.27 (m, 1 H,) 4.32 (m, 1 H), 4.65 (t, J=7.80 Hz, 1 H), 4.85 (dd, J=7.95, 4.52 Hz, 1 H), 6.96 (d, J=9.05 Hz, 2 H), 7.45 (d, J=9.05 Hz, 2 H) ppm. MS (ESI) m/z + 378/380 (M+H)+.
Example 17 (2S)-l-((5S)-5-(hydroxymemyl)-L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting the 5R alkene in Example
14 with the coπesponding 5S isomer described in Example 22. 1H NMR ( 300 MHz, MeOH-d δ 1.92-12.04 (m, 2H), 2.11-2.38 (m, 5H), 2.61 (m, IH), 3.60-3.70 (m, 3H), 3.85 (m, IH), 3.91 (m, IH), 4.53 (m, IH), 4.80 (m, IH) ppm. MS (ESI) m/z 224 (M+H)+.
Example 18 (2S)-l-{r5i-)-5-((4-fluorophenoxy)methyl -L-prolyl}pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-bromophenol in
Example 15 with 4-fluorophenol. 1H NMR (500 MHz, MeOH-d δ 2.01 (m, 2 H),
2.25 (m, 7 H), 2.60 (m, 1 H), 4.12 (m, 1 H), 4.32 (m, 2 H), 4.68 (dd, J=9.04, 5.93 Hz,
1 H), 4.84 (dd, J=7.95, 4.52 Hz, 1 H), 7.04 ( , 5 H) ppm. MS (DCI) m/z 318 (M+H+).
Example 19 3- {(5i?)-5-((4-bromophenoxy)methyl)-L-prolyl} - 1 ,3-thiazolidine The title compound was synthesized by substituting 2S-cyanopyπolidine in Example 15 with thiazolidine. 1H NMR (MeOH-d^, 500 MHz) δ 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),
3.89 (m, 1 H), 4.12 (m, 1 H), 4.32 (m, 2 H), 4.54 (m, 1 H), 4.68 (dd, J=9.98, 4.68 Hz, 1 H), 4.75 (m, 1 H), 6.96 (d, J=9.04 Hz, 2 H), 7.44 (d, J=9.04 Hz, 2 H) ppm. MS (ESI) m/z 371/373 (M+H)+. Example 20 (2S)-l-{(5i-)-5-((2,6-dichlorophenoxy)memyl)-L-prolyl}pyπolidine-2-carbonitrile The title compoxmd was synthesized by substituting 4-bromophenol in Example 15 with 2,6-dichlorophenol. 1H NMR (500 MHz, MeOH-d ) δ 2.23 (m, 7 H), 2.62 (m, 1 H), 3.66 (m, 2 H), 4.21 (m, 1 H), 4.37 (m, 1 H), 4.43 (m, 1 H), 4.72 (dd, J=9.36, 5.93 Hz, 1 H), 4.86 (dd, J=7.80, 4.37 Hz, 1 H), 7.19 (t, J=8.11 Hz, 1 H),
7.45 (d, J=8.42 Hz, 2 H) ppm. MS (DCI) m/z 368, 370 (M+H) +.
Example 21 (2S)- 1 - {(5ig)-5-((2-chlorophenoxy)methyl)-L-prolyl}pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-bromophenol in Example 15 with 2-chlorophenol. 1H NMR (500 MHz, MeOH-d4) δ 1.97 (m, IH), 2.27 (m, 6 H), 2.59 (m, 1 H), 3.67 (m, 2 H), 4.22 (m, 1 H), 4.42 (m, 2 H), 4.69 (dd, J=8.73, 6.24 Hz, 1 H), 4.84 (dd, J=7.80, 4.37 Hz, 1 H), 7.01 (td, J=7.64, 1.25 Hz, 1 H), 7.16 (dd, J=8.11, 1.25 Hz, 1 H), 7.30 (m, 1 H), 7.41 (dd, J=7.80, 1.56 Hz, 1 H) ppm. MS (DCI) m/z 334, 336 (M+H) +. Example 22 (2S)- 1 -((5S)-5-vinyl-L-prolyl)pyπolidine-2-carbonitrile
Example 22A 5S-Ethynyl-pyπolidine-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)pyπolidine-l,2-dicarboxylate (10.2 g, 36 mmol, Example 9C) in chloroform (20 mL). The mixture was stiπed for 2 hours at 65 °C. The mixture was concentrated under reduced pressure. The above oil was dissolved in THF (30 mL), and tefrabutylammonium fluoride (1 M solution in THF, 43 mL, 43.2 mmol ) was added to the mixture at 0 °C. After 30 minutes, the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel (hexane/ethyl acetate, 1 :4) to provide the amine product (4.5g, 82%). MS (DCI) m/z 154 (M+H)+. The above amine (4.5 g, 29.4 mmol) and di-tert-butyl dicarbonate (7.39 g,
33.3 mmol) were dissolved in THF (20 mL). A catalytic amount of DMAP was added. The mixture was refluxed overnight and then concentrated under reduced pressure. The resulting oil was chromatographed on silica gel (hexane/ethyl acetate, 3:1) to provide the Boc-protected product (6.7 g, 90%). MS (DCI) m/z 254 (M+H)+.
Example 22B 5S-Vinyl-pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The above Boc-protected amine (6.2 g, 24.5 mmol) was dissolved in ethyl acetate (124 mL). 5% Pd/BaSO4 (248 mg) and quinoline (6.2 mL) were added. The mixture was stiπed under 20 psi H2 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%). MS (DCI) m/z 256 (M+H)+.
Example 22C 5S-Vinyl-ρyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester Example 22B (5.8 g, 24.1 mmol) was dissolved in 1.7 M LiOH (48 mmol) and ethanol (20 mL). The mixture was stiπed at room temperature for 2 hours until the starting material was consumed. The mixture was acidified with 1 N HC1 (pH= 2) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound (5.7 g, 100%). MS (DCI) m/z 242 (M+H)+. Example 22D 2S-(2S-Cyano-pyπolidine- 1 -carbonyl -5S- vinyl-pyπolidine-1 -carboxylic acid tert-butyl ester Example 22C (1.01 g, 4.14 mmol), 2S-cyanoρyπolidine 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 CH2C12 and DMF, and then Et3N (approx. 1.2 mL) was added until the pH of the mixture reached 6~7 (by wet pH paper). After stirring overnight, the mixture was concentrated and purified by flash chromatography to provide the title compound (0.92 g, 70%). MS (ESI) m/z 320 (M+H)+.
Example 22E (2S)-l-((5S)-5-vinyl-L-prolyl)pyπolidine-2-carbonitrile The Boc group of Example 22D was removed as described in Example 1G to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ 2.01 (m, 3 H), 2.25 (m,
5 H), 2.70 (m, 1 H), 3.65 (m, 2 H), 4.64 (t, J=8.29 Hz, 1 H), 4.83 (dd, J=7.83, 4.45 Hz, 1 H), 5.47 (d, J 0.43 Hz, 1 H), 5.56 (d, J= 7.18 Hz, 1 H), 6.00 (ddd, J=17.18, 10.13, 7.67 Hz, 1 H) ppm. 13C NMR (MeOH-c , 100 MHz) δ 26.1, 29.4, 30.8, 31.8,
47.6, 48.2, 59.9, 64.4, 119.2, 122.5, 132.8, 168.8 ppm. MS (ESI) m/z 220 (M+H)+.
Example 23 (2S)-l-{(5iyS)-5-((E)-2-(3-methylphenyl)vinyl)-L-prolyl}pyπolidine-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. It was heated to 100 °C for 30 minutes, cooled, filtered and then purified by reverse-phase HPLC. The Boc group was removed as described in Example 1G to provide the title compound. 1H NMR (400 MHz, MeOH- j) δ 2.22 (m, 10 H), 2.66 (m, 1 H), 3.66 (m, 2 H), 4.38 (m, 1 H ), 4.66 (dd, J=9.36, 5.37 Hz, 1 H), 4.85 (m, 1 H), 6.39 and 6.30 (dd, J=15.96, 8.59 Hz, 1 H), 6.83 and 6.86 (d, J=15.96 Hz, 1 H), 7.14 (d, J=7.36 Hz, 1 H), 7.28 (m, 3 H). MS (DCI) m/z 310 (M+H)+.
Example 24 (2S)-l-{(5R/S)-5-((E)-2-ρhenylvinyl)-L-prolyl>pyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with iodobenzene. 1H NMR (500 MHz, MeOH-c ,) 2.12 (m, 8H), 2.66 (m, IH); 3.57 (m, 2 H), 4.37 (m, 1 H), 4.57 (m, 2H), 6.24 and 6.35 (dd, J=15.75, 8.27 Hz, 1 H), 6.77 and 6.80 (d, J=15.75 Hz, 1 H), 7.21 (m, 1 H), 7.25 (m, IH), 7.40 (m, 2 H) ppm. MS (DCI) m/z 296 (M+H)+.
Example 25 (2S)-l-((5S/R)-5-((E)-2-(4-methylphenyl)vinyl)-L-ρrolyl}pyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-methyliodobenzene. 1H NMR (500 MHz, MeOH-cL δ 2.22 (m, 11 H), 2.59 and 2.76(m, 1 H), 3.66 (m, 2 H) 4.42 (m, 1 H), 4.65 (m, 1 H), 4.85 (dd, J=8.11, 4.37 Hz, 1 H), 6.30 and 6.39 (dd, J=15.75, 8.58 Hz, 1 H), 6.84 and 7.87 (d, J=15.75 Hz, 1 H), 7.14 and 7.26 (d, J=7.17 Hz, 2H), 7.26 (m, 2H) ppm. MS (DCI) m/z 310 (M+H)+.
Example 26 (2S)-l-{(5S/R)-5-((E)-2-(2-bromoρhenyl)vinyl)-L-prolyl}ρyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 2-bromoiodobenzene. 1H NMR (400 MHz, MeOH-d4) δ 0.91 (m, 8 H), 1.43 (m, 1 H), 2.33 (t, J=6.60 Hz, 2 H), 3.19 (m, 1 H), 3.33 (t, J=8.29 Hz, 1 H), 3.51 (dd, J=7.52, 4.45 Hz, 1 H), 4.98 (dd, J=15.65, 8.29 Hz, 1 H), 5.90 (m, 2 H), 6.03 (t, J=7.36 Hz, 1 H), 6.28 (d, J=7.98 Hz, 1 H), 6.33 (d, J=7.98 Hz, 1 H) ppm. MS (DCI) m/z 374, 376 (M+H)+. Example 27 (2S)-l-{(5S/i-)-5-((E)-2-(2-methylphenyl)vinyl)-L-prolyl}ρyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 2-methyliodobenzene. 1H NMR (500 MHz, MeOH-d4) δ 2.24 (m, 10 H), 2.75 (m, 1 H), 3.66 (m, 2 H), 4.48 (m, 1 H), 4.66 (m, 1 H), 4.85 (m, IH), 6.29 and 6.19 (dd, J=15.59, 8.42 Hz, 1 H), 7.22 (m, 4 H) 7.52 (m, 1 H) ppm. MS (DCI) m/z 310 (M+H)+.
Example 28 (2S)-l-{(5R/S)-5-((E)-2-(4-bromoρhenyl)vinyl)-L-ρrolyl>ρyπolidine-2-carbonitrile The compound was synthesized by substituting 3-methyliodobenzene in
Example 23 with 4-bromoiodobenzene. 1H NMR (400 MHz, MeOH-c ) δ 2.25 (m, 8 H), 2.77 (m, 1 H), 3.67 (m, 2 H), 4.47 (m, 1 H), 4.66 (m, 1 H), 4.85 (dd, J=7.67, 4.30 Hz, 1 H), 6.35 (dd, J=15.96, 8.29 Hz, 1 H), 6.88 (d, J=15.96 Hz, 1 H), 7.41 (d, J=8.59 Hz, 2 H), 7.53 (d, J=8.59 Hz, 2 H) ppm. MS (DCI) m/z 374, 376 (M+H)+.
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. 1H NMR (400 MHz, MeOH-d4) δ 2.19 (m, 8 H), 2.58 and 2.74 (m, 1 H), 3.65 (m, 2 H), 4.33 and 4.44 (m, 1 H), 4.64 (m, 1 H), 4.84 (m, 1 H), 6.10 and 6.19 (dd, J=15.65, 8.90 Hz, 1 H), 6.77 (m, 3 H), 7.33
(dd, J=8.59, 3.68 Hz, 2 H) ppm. MS (DCI) m/z 364 (M+H)+.
Example 30 (2S)-l-{(5S/i?)-5-((E)-2-(3,4-dimethoxyphenyl)vinyl)-L-prolyl}pyπolidine-2- i carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in
Example 23 with 2,4-dimethoxyiodobenzene. 1H NMR (400 MHz, MeOH-d δ 2.25
(m, 7 H), 2.58 and 2.74 (m, 1 H), 3.65 (m, 2 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 4.40 (m, 1
H), 4.65 (m, 1 H), 4.84 (dd, J=7.83, 4.45 Hz, 1 H), 6.18 and 6.26 (dd, J 5.65, 8.90 Hz, 1 H), 6.79 and 6.83 (d, J=15.65 Hz, 1 H), 6.93 (d, J=8.29 Hz, 1 H), 7.03 (m, 1 H),
7.11 (m, 1 H) ppm. MS (DCI) m z 356 (M+H)+.
Example 31 (2S)- 1 - {(5R/S)-5-((E)-2-(4-chloroρhenyl)vinyl)-L-prolyl}pyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-chloroiodobenzene. 1H NMR (500 MHz, MeOH-d4) δ 2.22 (m, 8 H), 2.76 (m, 1 H), 3.66 (t, J=5.6 Hz, 2H), 4.47 (m, IH), 4.65 (t, J=7.95 Hz, 1 H), 4.85 (dd, J=7.95, 4.52 Hz, 1 H) 6.33 (dd, J 5.91, 8.42 Hz, 1 H), 6.89 (d, J=15.91 Hz, 1 H), 7.37 (d, J=8.42 Hz, 2 H), 7.48 (d, J=8.42 Hz, 2 H) ppm. MS (DCI) m z 330, 332 (M+H)+.
Example 32 (2S)-l-{(5ig/S)-5-((E)-2-(l,3-benzodioxol-5-yl)vinyl)-L-ρrolyl>ρvπolidine-2- carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 5-iodo-benzo(l,3)dioxole. !H NMR (400 MHz, MeOH-d4) δ 2.03 (m, 2H), 2.26 (m, 8 H), 2.60 (m, 1 H), 3.65 ( , 2 H), 4.34 (m, 1 H), 4.64 (dd, J=9.51, 5.22 Hz, 1 H), 4.84 (dd, J=7.83, 4.45 Hz, 1 H), 5.96 (s, 2 H), 6.23 (dd, J=15.65, 8.59 Hz, 1 H), 6.94 (m, 1 H), 7.07 (m, 1 H) ppm. MS (DCI) m/z 340 (M+H)+.
Example 33 (2S)-l-{(5R/S)-5-((E)-2-(4-hydroxyphenyl)vinyl)-L-prolyl}pyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-hydroxyiodobenzene. 1H NMR (400 MHz, MeOH-d ) δ 2.27 (m, 8 H), 2.76 (m, IH), 3.67 (t, J=6.14 Hz, 2H), 4.51 (m, 1 H), 4.68 (t, J=8.29 Hz, 1 H), 4.85 (dd, J=7.67, 4.30 Hz, 1 H), 6.48 (dd, J=15.96, 8.29 Hz, 1 H), 6.98 (d, J=15.96 Hz, 1 H), 7.70 (m, 4 H) ppm. MS (DCI) m z 312 (M+H)+.
Example 34 (2S)-l-{(5S/i?)-5-((E)-2-(4-methoxyphenyl)vinyl)-L-ρrolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 4-methoxyiodobenzene. 1H NMR (400 MHz, MeOH-d4) δ 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,
J=9.51, 5.52 Hz, 1 H), 4.84 (dd, J=7.83, 4.45 Hz, 1 H), 6.15 and 6.24 (dd, J=15.80, 8.75 Hz, 1 H), 6.80 (d, J-15.34 Hz, 1 H), 6.91 (d, J=8.90 Hz, 2 H), 7.43 (d, J=8.90 Hz, 2 H) ppm. MS (DCI) m/z 326 (M+H)+.
Example 35 (2S)-l-{(5S/ig -5-((E)-2-(3,4-dimethylphenyl)vinyl)-L-prolyl>pyπolidine-2- carbonitrile The title compound was synthesized by substituting 3-methyliodobenzene in Example 23 with 3,4-dimethyliodobenzene. 1H NMR (400 MHz, MeOH-d4) δ 2.06
(m, 4H), 2.23 (m, 8H), 2.38 (m, 2H), 2.56 (m, 1 H), 3.47 (m, 1 H), 3.67 (m, 1 H), 4.61 (m, 1 H), 4.86 (m, 1 H), 6.08 and 6.16 (dd, J 6.11, 5.98 Hz, 1 H), 6.35 and 6.60 (d, J=15.65 Hz, 1 H), 7.16 (m, 3 H) ppm. MS (DCI) m/z 324 (M+H)+.
Example 36 (2S)-l-{(5i^S)-5-(2-(3-memylphenyl)ethyl)-L-prolyllpyπolidine-2-carbonitτile A solution of 2-(2-(S)-cyano-pyπolidine- 1 -carbonyl)-5-(R S)-(2-m-tolyl- vinyl)-pyπolidine-l -carboxylic acid tert-butyl ester (Example 23) (50 mg) and 10% Pd/C(10 mg) in ethanol (5mL) was stiπed under H2 balloon overnight. The catalyst was removed by filtration, and the filtrate was concentrated to provide the desired product. The Boc group of the above compound was removed as described in Example 1G to provide the desired product. 1H NMR (400 MHz, MeOH-dj) δ 1.82 (m, 1 H), 1.98 (m, 2 H), 2.25 (m, 8 H), 2.70 (m, 3 H), 3.64 (t, JM5.60 Hz, 2 H), 3.72 (m, 1 H), 4.57 (t, J=8.29 Hz, 1 H), 4.57 (t, J=8.29 Hz, 1 H), 7.05 (m, 3 H), 7.17 (d, J=7.36 Hz, 1 H) ppm. MS (DCI) m/z 312 (M+H)+.
Example 37 (2S)-l-{(5ig/S)-5-(2-(4-chlorophenyl)ethyl)-L-ρrolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 2-(2-(S)-cyano- pyπolidine-l-carbonyl)-5-(R/S)-(2-m-tolyl-vinyl)-pyπolidine-l -carboxylic acid tert- butyl ester in Example 36 with 2-(2-(S)-cyano-pyπolidine-l-carbonyl)-5-(R/S)-(2-p- chlorophenyl-vinyl)-pyπolidine-l -carboxylic acid tert-butyl ester. 1H NMR (400 MHz, MeOH-d4) δ 1.83 (m, 1 H), 1.98 (m, 2 H), 2.24 (m, 6 H), 2.71 (m, 4 H), 3.64 (t, J=6.60 Hz, 2 H), 3.73 (m, 1 H), 4.59 (t, J=8.29 Hz, 1 H), 7.25 (d, J=8.29 Hz, 2 H), 7.31 (d, J=8.29 Hz, 2 H) ppm. MS (ESI) m/z 332, 334 (M+H)+.
Example 38 (2S)- 1 -((5R/S)-5-(2-ρhenylethyl)-L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 2-(2-(S)-cyano- pyπolidine- 1 -carbonyl)-5-(R S)-(2-m-tolyl-vinyl)-pyπolidine- 1 -carboxylic acid tert- butyl ester in Example 36 with 2-(2-(S)-cyano-pyπolidine-l-carbonyl)-5-(R/S)-(2- phenyl-vinyl)-pyπolidine-l -carboxylic acid tert-butyl ester. 1H NMR (500 MHz, MeOH-d4) δ 1.83 (m, 1 H), 1.99 (m, 2 H), 2.26 (m, 6 H), 2.65 (m, 1 H), 2.77 (m, 2 H), 3.64 (dd, J=7.02, 6.39 Hz, 2 H), 3.76 (m, 1 H), 4.58 (t, J=8.26 Hz, 1 H), 4.83 (dd, J=7.95, 4.52 Hz, 1 H), 7.25 (m, 5 H) ppm. MS (DCI) m/z 298 (M+H)+.
Example 39 (2R,5S)-5- {((2S)-2-cyanopyπolidin- 1 -ypcarbonyl} -N-(3-carboxy)phenylpyπolidine-2-carboxamide
Example 39A 2S-(4-Carboxy-phenylcarbamoyl)-5R-(2S-cyano-pyrrolidine- 1 -carbonyl) -pyπolidine-1 -carboxylic acid tert-butyl ester To a solution of 2S-(2S-cyano-pyπolidine-l-carbonyl)-5R-formyl-pyπolidine- 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% NaH2PO4 solution followed by 5.2 mL of IM KMnO4 solution (5.2 mmol) at room temperature. After 1 hour, ethyl acetate and saturated NaHSO3 were added. Then IN HC1 was added to dissolve the solids. The aqueous layer was saturated with NaCl then extracted with ethyl acetate (2X) and chloroform (IX). The organic extracts were dried with Na2SO4 and concentrated to provide the crude acid (280 mg). MS (ESI) m/z 338 (M+H)+.
Example 39B (2ig,5S)-5-{((2S)-2-cyanopyπolidin-l-yl)carbonyl> -N-(3-carboxy)phenylpyπolidine-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. 1H ΝMR (400 MHz, MeOH-d δ 2.1-2.4 (m, 6 H), 2.65 (m, 2 H), 3.68 (m, 2 H), 4.57 (t, J=7.67 Hz, 1 H), 4.71 (t, J=7.67 Hz, 1 H), 4.89 (dd, J=7.67, 4.30 Hz, 1 H), 7.74 (d, J-8.90 Hz, 2 H), 8.02 (d, J=8.90 Hz, 2 H) ppm. MS (ESI) m/z 347 (M+H)+.
Example 40 (2S)-l-((5R)-5-{(methyl(phenyl)amino)methyl}-L-prolyl)pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-methoxyaniline in Example 9 with N-methylaniline. 1H ΝMR (400 MHz, MeOH-d4) δ 1.89 (m, 1 H), 2.24 (m, 6 H), 2.54 (m, 1 H), 3.03 (s, 3 H), 3.73 (m, 4 H), 4.03 (m, 1 H), 4.61 (dd, J=9.05, 5.98 Hz, 1 H), 4.85 (m, 1 H), 6.79 (m, 1 H), 6.93 (m, 2 H), 7.26 (m, 2 H) ppm. MS (DCI) m/z 313
Figure imgf000091_0001
Example 41 (2S)- 1 - {(5R)-5-(naphthalen- 1 -yloxymethyl)-L-prolyl) -pyπolidine-2-carbonitrile The title compound was synthesized by substituting 4-bromophenol in Example 15 with 1-naphthol. 1H ΝMR (500 MHz, MeOH-d^ δ 2.26 (m, 7 H), 2.64 (m, 1 H), 3.69 (m, 2 H), 4.30 (m, 1 H), 4.56 (m, 2 H), 4.76 (dd, J=9.04, 5.30 Hz, 1 H), 4.87 (dd, J=7.95, 4.52 Hz, 1 H), 7.00 (d, J=7.49 Hz, 1 H), 7.41 (t, J=7.95 Hz, 1 H), 7.50 (m, 3 H), 7.82 (m, 1 H), 8.43 (m, 1 H). MS (ESI) m/z 350 (M+H)+.
Example 42 (2S)-l-{(5R)-5-((4-cyano-2-methoxyphenoxy)-methyl)-L-prolyl}-pyπolidine-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-d4) δ 1.98 - 2.09 (m, 1 H), 2.10 - 2.46 (m, 5
H), 2.55 - 2.65 (m, 1 H), 3.62 - 3.71 (m, 2 H), 3.91 (s, 3 H), 4.15 - 4.24 (m, 1 H), 4.37 - 4.47 (m, 2 H), 4.69 (dd, J=8.89 Hz, 1 H), 4.77 - 4.87 (m, 1 H), 7.16 (d, 1 H), 7.31 - 7.39 (m, 2 H). MS (ESI) m z 355 (M+H)+.
Example 43 (2S)-l-{(5R)-5-((2-cyano-4-trifluoromethylphenoxy)-methyl)-L-prolyl>-pyπolidine- 2-carbonitrile The title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with 2-cyano-4-(trifluoromethyl)phenol. 1H NMR (400 MHz, MeOH- d4> δ 2.25 (m, 7 H), 2.57 (m, 1 H), 3.68 (m, 2 H), 4.29 (m, 1 H), 4.62 (m, 2 H), 4.73 (dd, J=8.75, 5.06 Hz, 1 H), 4.83 (m, 1 H), 7.44 (d, J=8.90 Hz, 1 H), 7.97 (dd, J=8.75, 1.99 Hz, 1 H), 8.05 (d, .
Figure imgf000092_0001
Example 44 (2S)- 1 - {(5R)-5-((2-chloro-4-cyanophenoxy)-methyl)-L-prolyl} -pyπolidine-2- carbonitrile The title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with 2-chloro-4-cyanophenol 1H NMR (500 MHz, MeOH-d4) δ 2.02 - 2.46 (m, 7 H), 2.53 - 2.65 (m, JM3.25, 7.95 Hz, 1 H), 3.62 - 3.74 (m, 2 H), 4.23 - 4.33 (m, 1 H), 4.49 - 4.59 (m, 2 H), 4.72 (dd, J=8.58, 6.08 Hz, 1 H), 4.80 - 4.87 (m, 1 H), 7.30 (d, J=8.73 Hz, 1 H), 7.71 (dd, J=8.58, 2.03 Hz, 1 H), 7.84 (d, J=1.87 Hz, 1 H). MS (ESI) m/z 359 (M+H)+.
Figure imgf000093_0001
Example 45 (2S)- 1 - {(5i?)-5-((2-chloropyridyl-3-oxy)-methyl)-L-prolyl> -pyπolidine-2-carbonitrile The title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with 2-chloro-ρyridin-3-ol. 1H NMR (400 MHz, MeOH-d4) δ 2.01 - 2.46 (m, 7 H), 2.54 - 2.64 (m, 1 H), 3.63 - 3.72 (m, 2 H), 4.21 - 4.31 (m, 1 H), 4.46 - 4.52 (m, 2 H), 4.72 (dd, J=8.59, 5.83 Hz, 1 H), 4.82 - 4.87 (m, 1 H), 7.39 (dd, J=8.13, 4.76 Hz, 1 H), 7.60 (dd, J=8.13, 1.38 Hz, 1 H), 8.02 (dd, J=4.91, 1.53 Hz, 1 H). MS (ESI) m/z 335 (M+H)+.
Example 46 (2S)- 1 - {(5i-)-5-((4-carboxy-2-methoxyphenoxy)-methyl)-L-prolyl} -pyπolidine-2- carbonitrile
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 stiπed 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-{(5iϋ)-5-((4-carboxy-2-methoxyphenoxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile The title compound was synthesized by substituting 2-methoxy-4-cyanophenol in Example 42 with the compound of Example 46A. 1H NMR (500 MHz, MeOH- j) δ 2.03 (m, 1 H), 2.27 (m, 6 H), 2.59 (m, 1 H), 3.68 (m, 2 H), 3.92 (s, 3 H), 4.18 (m, 1 H), 4.41 (m, 2 H), 4.69 (dd, J=8.73, 6.24 Hz, 1 H), 4.84 (dd, J=7.95, 4.52 Hz, 1 H), 7.11 (d, J=8.42 Hz, 1 H), 7.64 (d, J .87 Hz, 1 H), 7.68 (dd, J=8.42, 1.87 Hz, 1 H). MS (ESI) m/z 374 (M+H)+.
Example 47 (2S)- 1 - {(5R)-5-((4-carboxy-2-tert-butylphenoxy)-methyl)-L-prolyl} -pyπolidine-2- carbonitrile
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 CH2C1 and 40 mL of MeOH, then tetrabutylamonium tribromide (7.82 g,
16.22 mmol) was added. After one hour, the mixture was concentrated in vacuo and the residue was taken up in ether. The ether solution was washed with IN HC1 (2X) and brine (IX), then dried with NaSO4. The solution was then concentrated in vacuo and the residue was purified by silica gel chromatography (10% EtOAc/Hexane) to give the titled bromophenol (2.72 g, 88%). MS (ESI) m/z -227 (M+H)".
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), PdCl2(dρρf CH2Cl2 (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%). MS (DCI) m/z 299 (M+H)+.
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. The mixture was extracted with EtOAc (3x) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuum to give the crude 4-benzyloxy-3-tert-butyl-benzoic acid, which was carried on without purification. The above crude acid was mixed with 5 mL of benzene and the mixture was heated to reflux. N,N-dimethylformamide tert-butyl acetal (3.69 mL) was added in batches. After 1.3 hours, the mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0% then 5% EtOAc/Hexane) to give the desired tert-butyl ester (403 mg, 58%). MS (DCI) m/z 341 (M+H)+.
Example 47E 3-tert-Butyl-4-hydroxγ-benzoic acid tert-butyl ester The compound of Example 47D (400 mg, 1.17 mmol) and 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-pyπolidine-l- carbonyl)-pyπolidine-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. Then di-tert-butyl azodicarbonate (DBAD, 265 mg, 1.51 mmol) was added. The mixture was heated to 95 °C. After the reaction was complete, the mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (20%-40% EtOAc/Hexane) to give the titled ether (436 mg, 83%). Example 47G (2S)-l-{(5i-)-5-((4-carboxy-2-tert-butylphenoxy)-methyl)-L-ρrolyl>-pyπolidine-2- carbonitrile The compound of Example 47F was deprotected according to the procedures of Example 1G to give the title compound. 1H NMR (500 MHz, MeOH-c^) δ 1.45 (s,
9 H), 2.02 - 2.11 (m, 1 H), 2.13 - 2.38 (m, 5 H), 2.39 - 2.50 (m, 1 H), 2.55 - 2.65 (m, 1 H), 3.63 - 3.75 (m, 2 H), 4.24 - 4.32 (m, 1 H), 4.40 (dd, J=10.60, 4.68 Hz, 1 H), 4.59 (dd, J=10.60, 7.80 Hz, 1 H), 4.76 (dd, J=8.89, 5.15 Hz, 1 H), 4.78 - 4.89 (m, 1 H), 7.13 (d, J=8.42 Hz, 1 H), 7.92 (dd, J=8.42, 2.18 Hz, 1 H), 8.04 (d, J=2.18 Hz, 1 H). MS (ESI) m/z 400 (M+H)+.
Example 48 (2S)-l-{(5i-)-5-((4-carboxy-2-chlorophenoxy)-methyl)-L-ρrolyl}-pyπolidine-2- carbonitrile The title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 2-chlorophenol. 1H NMR (400 MHz, MeOH-cL*) δ 2.23 (m, 7 H), 2.59 (m, 1 H), 3.68 (m, 2 H), 4.24 (m, 1 H), 4.53 (d, J=5.22 Hz, 2 H), 4.71 (dd, J=8.75, 5.98 Hz, 1 H), 4.83 (overlap with solvent peak, IH), 7.23 (d, J=8.59 Hz, 1 H), 7.98 (dd, J=8.59, 2.15 Hz, 1 H), 8.04 (d, J=2.15 Hz, 1 H). MS (ESI) m/z 378 (M+H)+.
Example 49 (2S)- 1 - {(5i-)-5-((4-carboxy-2-^Q-propylphenoxy)-methyl)-L-prolyl} -pyπolidine-2- carbonitrile The title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 2-iso-propylphenol. 1H NMR (400 MHz, MeOH-ά^) δ 1.23 (d, J=6.75 Hz, 3 H), 1.26 (d, J=6.75 Hz, 3 H), 2.24 (m, 7 H), 2.60 (m, 1 H), 3.51 (m, 1 H), 3.66 (m, 2 H), 4.22 (m, 1 H), 4.45 (d, J=5.22 Hz, 2 H), 4.73 (dd, J=8.90, 5.52 Hz, 1 H), 4.85 (m, 1 H), 7.05 (d, J=8.59 Hz, 1 H), 7.89 (dd, J=8.59, 2.15 Hz, 1 H), 7.94
(d, J=2.15 Hz, 1 H). MS (ESI) m/z 386 (M+H)+.
Example 50 (2S)- 1 - {(5i-)-5-(r4-(tetrazol-5-yl)-2-chloroρhenoxyl-methyl)-L-ρrolyl) -pyπolidine-2- carbonitrile Example 50A 5R-Hydroxymethyl-pyπolidine-l, 2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The compound of Example 9F was reacted according to the procedures of
Example 14A to give the title compound.
Example 5 OB 5R-(2-chloro-4-cyano-phenoxymethyl)-pyπolidine-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-pyπolidine-l,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester NaN3 (145 mg, 0.17 mmol) and NH4C1 (91.8 mg, 0.17 mmol) were added to the compound of Example 50B (520 mg, 0.13 mmol) in DMF (2mL) under N2. The reaction was heated to 110 °C for 48 hours. Saturated NaHCO3 was added and the mixture was extracted with EtOAc (3X). The combined extracts were dried (Na SO4), concentrated and purified by column chromatography to give the product (520 mg, 90 %). MS (ESI) m/z 438, 440 (M+H1"). Example 50D
(2S)-l-{(5i-)-5-([4-(tetrazol-5-yl)-2-chlorophenoxy1-methyl)-L-prolyl)-pyπolidine-2- carbonitrile The compound of Example 50C was processed according to the procedures described in Examples 22C-E to give the title compound. H NMR (500 MHz, MeOH-d4) δ 2.24 (m, 7 H), 2.57 (m, 1 H), 3.67 (m, 2 H), 4.24 (m, 1 H), 4.52 (d,
J=5.30 Hz, 2 H), 4.68 (dd, J=8.73, 5.93 Hz, 1 H), 4.84 (m, 1 H), 7.33 (d, J=8.73 Hz, 1 H), 7.99 (dd, J=8.74, 2.18 Hz, 1 H), 8.11 (d, J=2.18 Hz, 1 H). MS (ESI) m/z 402 (M+H)+.
Example 51 (2S)-l-{(5i-)-5-((5-carboxy-2-chlorophenoxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile The title compound was synthesized by substituting 4-bromo-2-tert-butyl- phenol in Example 47 with 2-chloro-5-bromophenol. 1H NMR (400 MHz, MeOH-d δ ppm 2.25 (m, 7H), 2.62 (m, 1 H), 3.68 (m, 2 H), 4.24 (m, 1 H), 4.50 (m, 2 H), 4.70 (dd, J=8.59, 6.14 Hz, 1 H), 4.86 (m, 1 H), 7.53 (d, J=8.29 Hz, 1 H), 7.68 (dd, J=8.29, 1.84 Hz, 1 H), 7.75 (d, J=1.84 Hz, 1 H). MS (ESI) m/z 378, 380 (M+H)+.
Example 52 (2S)-l-{(5R)-5-((5-carboxy-2-chloropyridyl-3-oxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile
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 stiπed 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 (Na2SO4), 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+H1").
Example 52C (2S)-l-{(5R)-5-((5-carboxy-2-chloropyridyl-3-oxy)-methyl)-N-Boc-L-ρrolyl}- pyπolidine-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}-pyπolidine-2- carbonitrile The Boc group was removed using procedure as described in Example 1G to give the title compound. 1H NMR (500 MHz, MeOH-d4) δ 2.25 (m, 7 H), 2.60 (m, 1 H), 3.68 (m, 2 H), 4.27 (m, 1 H), 4.56 (m, 2 H), 4.72 (dd, J=8.73, 5.93 Hz, 1 H), 4.84 (dd, J=7.96, 4.52 Hz, 1 H), 8.03 (d, J=1.56 Hz, 1 H), 8.60 (d, J=1.56 Hz, 1 H). MS (ESI) m/z 379, 381 (M+H)+.
Example 53 (2S)- 1 - {(5i?)-5-(5-carboxynaphthalen- 1 -yloxymethyl)-L-prolyl> -pyπolidine-2- carbonitrile
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> -pyπolidine-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. !H NMR (500 MHz, MeOH-d4) δ 2.29 (m, 7 H), 2.64 (m, 1 H), 3.70 (m, 2 H), 4.31 (m, 1 H), 4.59 (m, 2 H), 4.74 (m, 1 H), 4.87 (dd, J=7.96, 4.52 Hz, 1 H), 7.08 (d, J=7.49 Hz, 1 H), 7.55 (m, 2 H), 8.21 (dd, J=7.18, 1.25 Hz, 1 H), 8.53 (d, J=8.73 Hz, 1 H), 8.68 (d, J=8.42 Hz, 1 H). MS (ESI) m/z 394 (M+H)+.
Example 54 (2S)- 1 - |(5R)-5-((4-carboxynaphthalen- 1 -yloxy)methyl)-L-prolyl} -pyπolidine-2- carbonitrile The title compound was synthesized by substituting 2-tert-butylphenol in Example 47 with 1 -naphthol. 1H NMR (500 MHz, MeOH-d δ 2.21 (m, 7 H), 2.55
(m, 1 H), 3.70 (m, 2 H), 4.15 (m, 1 H), 4.65 (m, 2 H), 4.76 (m, 1 H), 4.86 (dd, J=7.96, 4.52 Hz, 1 H), 7.04 (d, J=8.24 Hz, 1 H), 7.56 (m, 1 H), 7.62 (m, 1 H), 8.26 (d, J=8.24 Hz, 1 H), 8.48 (d, J=7.93 Hz, 1 H), 9.01 (d, J=8.54 Hz, 1 H). MS (ESI) m/z 394 (M+H)+.
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;
Chem.Abstr.; 86; 121372). 1H NMR (400 MHz, MeOH-c ) δ 2.22 (m, 7 H), 2.58 (m, 1 H), 3.65 (m, 2 H), 4.22 (m, 1 H), 4.68 (dd, J=8.75, 5.98 Hz, 1 H), 4.85 (m, 3 H), 8.32 (d, J=2.15 Hz, 1 H), 8.73 (d, J=2.15 Hz, 1 H). MS (ESI) m/z 379 (M+H)+.
Example 56 (2S)-l-{(5J-)-5-((5-carboxy-2-bromophenoxy)-methyl)-L-prolyl}-pyπolidine-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 stiπed 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} -pyπolidine-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. 1H NMR (400 MHz, MeOH-d4) δ 2.27 (m, 7 H), 2.59 (m, 1 H), 3.67 (m, 2 H), 4.26 (m, 1 H), 4.50 (m, 2 H), 4.71 (dd, J=8.75, 6.29 Hz, 1 H), 4.86 (m, 1 H), 7.60 (dd, J=8.29, 1.53 Hz, 1 H), 7.71 (m, 2 H). MS (ESI) m/z 514, 516 (M+H)+.
Example 57 (2S)-l-({(2S,5R)-5-r(2-methylphenoxy)methynpyπolidin-2-yl}carbonyl)pyπolidine- 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. 1H NMR (400 MHz, MeOH-c ) δ ppm 2.01 - 2.44 (m, 10 H), 2.52 - 2.68 (m, 1 H), 3.60 - 3.77 (m, 2 H), 4.08 - 4.25 (m, 1 H), 4.28 - 4.42 (m, 2 H), 4.71 (dd, J=8.90, 5.83 Hz, 1 H), 4.82 - 4.87 (m, 1 H), 6.86 - 6.92 (m, 1 H), 6.95 (d, J=7.67 Hz, 1 H), 7.11 - 7.21 (m, 2 H). MS (ESI) m/z 330 (M+H)+.
Example 58 (2S)- 1 -( {(2S,5R)-5-r(2-methoxyphenoxy)methyllpyπolidin-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. 1H NMR (300 MHz, MeOH-α ) δ ppm 1.92 - 2.08 (m, 1 H), 2.11 - 2.45 (m, 6 H), 2.52 - 2.66 (m, 1 H), 3.62 - 3.73 (m, 2 H), 3.91 (s, 3 H), 4.06 - 4.21 (m, 1 H), 4.22 - 4.38 (m, 2 H), 4.62 - 4.72 (m, 1 H), 4.84 - 4.88 (m, 1 H), 6.87 - 6.96 (m, 1 H), 7.00 - 7.10 (m, 3 H). MS (ESI) m/z 528 (M+H)+.
Example 59 (2S)-l-({(2S,5R)-5-r(2,4-dichlorophenoxy)methyllρyπolidin-2- yl} carbonyl)pyπolidine-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. 1H NMR (500 MHz, MeOH-d δ ppm 2.01 - 2.11 (m, 1 H), 2.10 - 2.45 (m, 6 H), 2.53 - 2.64 (m, 1 H), 3.59 - 3.74 (m, 2 H), 4.16 - 4.26 (m, 1 H), 4.40 - 4.44 (m, 2 H), 4.70 (dd, J=8.70, 5.95 Hz, 1 H), 4.81 - 4.85 (m, 1 H), 7.15 (d, J=8.85 Hz, 1 H), 7.32 (dd, J=8.85, 2.44 Hz, 1 H), 7.46 (d, J=2.75 Hz, 1 H). MS (ESI) m/z 368, 370 (M+H)+. Example 60 (2S)-l-r((2S,5R)-5-{r2-bromo-4-(trifluoromethyl)phenoxy1methyl>pyπolidin-2- yl)carbonyllpyrrolidine-2-carbonitrile The compound of Example 14A (50 mg, 0.15 mmol) and 3-bromo-4- fluorobenzotrifluoride (30 μL, 0.2 mmol) were stiπed in DMF (ImL) under N2. NaH (13 mg, 0.3 mmol) was added to the mixture. It was stiπed at room temperature for lhour. After the reaction was over, the mixture was purified by reverse-phase HPLC to give the Boc-protected compound (40% yield). MS (ESI) m/z 546, 548 (M+H)+. The Boc group was removed according to Example 1 G to give the title compound. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.05 - 2.44 (m, 7 H), 2.49 - 2.65 (m, 1 H), 3.50 - 3.59 (m, 1 H), 3.62 - 3.74 (m, 1 H), 4.20 - 4.32 (m, 1 H), 4.47 - 4.58 (m, 2 H), 4.68 - 4.76 (m, 1 H), 4.81 - 4.90 (m, 1 H), 7.27 (dd, J=8.42, 4.05 Hz, 1 H), 7.69 (d, J=8.73 Hz, 1 H), 7.85 - 7.94 (m, 1 H). MS (ESI) m/z 446, 448 (M+H)+.
Example 61 (2S)-l-({(2S,5R)-5-r(4-bromo-2-methoxyρhenoxy)methynpyπolidin-2- yl} carbonyl)pyπolidine-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. MS (ESI) m/z 408, 410 (M+H)+.
Example 62 (2S)-l-({(2S,5R)-5-r(2-chloro-4-methoxyρhenoxy)methyllpyπolidin-2- yl> carbonyl)pyπolidine-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. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.97 - 2.11 (m, 1 H), 2.11 - 2.46 (m, 7 H), 2.53 - 2.67 (m, 1 H), 3.62 - 3.71 (m, 2 H), 3.76 (s, 3 H), 4:12 - 4.24 (m, 1 H), 4.29 - 4.39 (m, 2 H), 4.69 (dd, J=8.75, 5.98 Hz, 1 H), 4.82 - 4.90 (m, J=7.83, 4.45 Hz, 1 H), 6.86 (dd, J=8.90, 3.07 Hz, 1 H), 7.01 (d, J=3.07 Hz, 1 H), 7.12 (d, J=9.21 Hz, 1 H). MS (ESI) m/z 364 (M+H)+. Example 63 (2S)-l-({(2S,5R)-5-r(4-bromo-2-chlorophenoxy)methyllpyπolidin-2- yl> carbonyl)pyπolidine-2-carbonitrile
Example 63A 2R-(4-Bromo-2-chloro-phenoxymethyl)-5S-(2S-cyano-pyπolidine-l-carbonyl)- pyπolidine-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)methynpyπolidin-2- yl} carbonyl)pyπolidine-2-carbonifrile The title compound was synthesized after removal of the Boc group described in Example IG. MS (ESI) m/z 412, 414 (M+H)+.
Example 64 (2S)-l-r((2S,5R)-5-{r(4-chloro-l-naρhthyl)oxylmethyl|ρyπolidin-2- yl)carbonyl1pyπolidine-2-carbonitrile 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. 1H NMR (400 MHz, MeOH- d4) δ ppm 2.08 - 2.49 (m, 7 H), 2.57 - 2.71 (m, 1 H), 3.65 - 3.77 (m, 2 H), 4.26 - 4.37 (m, 1 H), 4.53 - 4.59 (m, 2 H), 4.74 - 4.79 (m, 1 H), 4.86 (dd, J=7.83, 4.76 Hz, 1 H), 6.97 (d, J=8.29 Hz, 1 H), 7.53 (d, J=8.29 Hz, 1 H), 7.57 - 7.73 (m, 2 H), 8.19 (d, J=7.98 Hz, 1 H), 8.47 (d, J=7.36 Hz, 1 H). MS (ESI) m z 384 (M+H)+.
Example 65 (2S)-1 -( {(2S,5R)-5-r(quinolin-4-yloxy)methyllpyπolidin-2-yl} carbonyl)pyπolidine- 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. 1H NMR (400 MHz, MeOH-ά ) δ ppm2.10 - 2.51 (m, 7 H), 2.60 - 2.72 (m, 1 H), 3.72 (t, J=7.06 Hz, 2 H), 4.38 - 4.49 (m, 1 H), 4.83 - 4.89 (m, 1 H), 4.91 - 5.00 (m, 2 H), 7.57 (d, J=6.44 Hz, 1 H), 7.91 - 7.99 (m, 2 H), 8.11 - 8.19 (m, 2 H), 8.74 (d, J=8.59 Hz, 1 H), 9.07 (d, J=6.44 Hz, 1 H). MS (ESI) m/z 351 (M+H)+.
Example 66 (2S)- 1 -( {(2S,5R)-5-r(quinolin-5-yloxy)methyl1pyπolidin-2-yl} carbonyl)pyπolidine- 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. 1H NMR (400 MHz, MeOH-d ) δ ppm 2.09 - 2.48 (m, 8 H), 2.59 - 2.72 (m, 1 H), 3.72 (t, J=6.60 Hz, 2 H), 4.29 - 4.40 (m, 1 H), 4.62 - 4.75 (m, 2 H), 4.83 - 4.89 (m, J=4.91 Hz, 1 H), 7.36 (d, J=7.98 Hz, 1 H), 7.79 (d, J=8.59 Hz, 1 H), 7.91 (dd, J=8.59, 4.91 Hz, 1 H), 8.00 (dd, 1 H), 9.08 (dd, J=5.06, 1.38 Hz, 1 H), 9.44 (d, J=8.59 Hz, 1 H). MS (ESI) m/z 351 (M+H)+.
Example 67 (2S)-l-r((2S,5R)-5-{r4-bromo-2-(lH-ρyrazol-3-yl)ρhenoxγ1methyl>ρyπolidin-2- yl)carbonyllpyπolidine-2-carbonixrile The title compound was synthesized by substituting 3-tert-butyl-4-hydroxyl- benzoic acid tert-butyl ester in Example 47F with 4-bromo-2-(lH-pyrazol-3-yl)- phenol followed by removal of the Boc group described in Example IG. 1H NMR (400 MHz, MeOH-d δ ppm 1.93 (dd, J=13.20, 9.21 Hz, 1 H), 2.09 - 2.41 (m, 7 H),
2.52 - 2.62 (m, 1 H), 3.57 - 3.69 (m, 2 H), 4.20 - 4.30 (m, 1 H), 4.61 - 4.71 (m, 3 H), 4.85 (dd, J=7.83, 4.45 Hz, 1 H), 6.85 (d, J=8.59 Hz, 1 H), 6.90 (d, J=2.45 Hz, 1 H), 7.28 (dd, J=8.75, 2.61 Hz, 1 H), 7.83 (d, J=2.45 Hz, 1 H), 7.91 (d, J=2.45 Hz, 1 H). MS (ESI) m/z 444, 446 (M+H)+.
Example 68 (2S)-l-({(2S,5R)-5-r(2-tert-butylphenoxy)methvnpyπolidin-2- yl) carbonyl)pyπolidine-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. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.34 - 1.49 (m, 9 H), 2.00 - 2.11 (m, 1 H), 2.12 - 2.38 (m, 5 H), 2.38 - 2.49 (m, 1 H), 2.53 - 2.67 (m, 1 H), 3.61 - 3.75 (m, 2 H), 4.18 - 4.34 ( , 2 H), 4.49 (dd, J=10.29, 7.48 Hz, 1 H), 4.73 (dd, J=8.73, 5.30 Hz, 1 H), 4.85 (dd, J=7.95, 4.52 Hz, 1 H), 6.95 (t, J=7.49 Hz, 1 H), 7.05 (d, J=8.11 Hz, 1 H), 7.16 - 7.24 (m, 1 H), 7.32 (dd, J=7.80, 1.25 Hz, 1 H). MS (ESI) m/z 356 (M+H)+.
Example 69 (2S)- 1 -( {(2S,5R)-5-r(2-tert-butyl-4-cyanoρhenoxy)methyl1pyπolidin-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(PPh3)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. The mixture was cooled to room temperature, and then water and EtOAc were added. The EtOAc extracts were dried over Na2SO4, concentrated and the resulting residue was purified by flash chromatography (5-10% EtOAc/Hexanes) to give the desired nitrile (64 mg). MS (DCI) m/z 238 (M+H)+.
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. MS (DCI) m/z 193 (M+NH4)+.
Example 69C (2S)-l-({(2S,5R)-5-r(2-tert-butyl-4-cyanoρhenoxy)methyllpyπolidin-2- yl } carbonyl)pyπolidine-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. 1H NMR (500 MHz, MeOH-cLj) δ ppm 1.44 (s, 9 H), 1.99 - 2.39 (m, 6 H), 2.39 - 2.50 (m, 1 H), 2.53 - 2.64 (m, 1 H), 3.61 - 3.75 (m, 2 H), 4.24 - 4.32 (m, 1 H), 4.40 (dd, J=10.60, 4.68 Hz, 1 H), 4.60 (dd, J=10.60, 7.80 Hz, 1 H), 4.75 (dd, J=8.73, 4.99 Hz, 1 H),' .84 (dd, J=7.95, 4.52 Hz, 1 H), 7.20 (d, J=8.42 Hz, 1 H), 7.58 - 7.67 (m, 2 H). MS (ESI) m/z 381(M+H)+. Example 70 (2S -l-({(2S,5R)-5-r(4-bromo-2-tert-butylphenoxy methyllρyπolidin-2- yl) carbonyl)pyπolidine-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)methyllpyπolidin-2- yl} carbonyl)pγπolidine-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. 1H NMR (300 MHz, MeOH-d4) δ ppm 1.41 (s, 9 H), 1.95 - 2.48 (m, 8 H), 2.50 - 2.67 (m, 1 H), 3.62 - 3.76 (m, 2 H), 4.16 - 4.33 ( , 2 H), 4.43 - 4.54 (m, 1 H), 4.72 (dd, J=8.65, 5.26 Hz, 1 H), 4.79 - 4.85 (m, 1 H), 6.99 (d, J=8.82 Hz, 1 H), 7.34 (dd, J=8.65, 2.54 Hz, 1 H), 7.40 (d, J=2.37 Hz, 1 H). MS (ESI) m/z 434, 436 (M+H)+.
Example 71 (2S)-l-({(2S,5R)-5-f(2-isoproρylphenoxy)methyl1ρyπolidin-2- yl } carbonyl)pyπolidine-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. 1H NMR (500 MHz, MeOH-c ) δ ppm 1.21 (d, J=6.86 Hz, 3 H), 1.24 (d, J=6.86 Hz, 3 H), 2.02 - 2.45 (m, 7 H), 2.56 - 2.66 (m, 1 H), 3.43 - 3.53 (m, 1 H), 3.63 - 3.73 (m, 2 H), 4.16 - 4.24 (m, 1 H), 4.36 (d, J=4.99 Hz, 2 H), 4.70 (dd, J=9.04, 5.93 Hz, 1 H), 4.83 - 4.89 (m, 1 H), 6.92 - 7.02 (m, 2 H), 7.12 - 7.20 (m, 1 H), 7.23 - 7.29 (m, 1 H). MS (ESI) m z 342 (M+H)+.
Example 72 ethyl 3-tert-butyl-4-r(,(2R,5S)-5-{r(2S)-2-cyanoρyrrolidin-l-yncarbonyl>pyπolidin-2- vDmethoxylbenzoate
Example 72A 3-tert-Butyl-4-hydroxy-benzoic acid ethyl ester The compound of Example 47A (2.3 g), PdCl2(dppf)«CH2Cl2 (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%). MS (DCI) m/z 223 (M+H)+.
Example 72B ethyl 3-tert-butyl-4-r((2R,5S)-5- {r(2S)-2-cyanoρyπolidin- 1 -yncarbonyl}ργπolidin-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. 1H NMR (500 MHz, MeOH-cU) δ ppm 1.41 - 1.49 (m, 9 H), 2.01 - 2.11 (m, 1 H), 2.12 - 2.37 (m, 5 H), 2.38 - 2.50 (m, 1 H), 2.50 - 2.66 (m, 1 H), 3.60 - 3.76 (m, 1 H), 4.23 - 4.31 (m, 1 H), 4.34 (q, J=7.17 Hz, 2
H), 4.39 (dd, J=10.60, 4.68 Hz, 1 H), 4.59 (dd, J=10.60, 7.80 Hz, 1 H), 4.59 (dd, J=10.60, 7.80 Hz, 1 H), 4.75 (dd, J=8.73, 5.30 Hz, 1 H), 4.84 (dd, J=7.95, 4.52 Hz, 1 H), 7.13 (d, J=8.42 Hz, 1 H), 7.13 (d, J=8.42 Hz, 1 H), 7.92 (dd, J=8.42, 2.18 Hz, 1 H), 7.92 (dd, J=8.42, 2.18 Hz, 1 H), 8.02 (d, J=2.18 Hz, 1 H), 8.02 (d, J=2.18 Hz, 1 H). MS (ESI) m/z 428 (M+H)+.
Example 73 {3-tert-butyl-4-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yncarbonyl}pyπolidin-2- yl)methoxy1phenoxy| acetic acid
Example 73A (3-tert-Butyl-4-hydroxy-phenoxy)-acetic acid tert-butyl ester tert-Butyl-hydroquinone (500 mg, 3.0 mmol) and K2CO3 (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%). MS (DCI) m/z 297 (M+H)+.
Example 73B {3-tert-butyl-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH- j) δ ppm 1.37 - 1.47 (s, 9 H), 1.97 - 2.08 (m, 1 H), 2.09 - 2.48 (m, 6 H), 2.53 - 2.64 (m, 1 H), 3.58 - 3.74 (m, 2 H), 4.16 - 4.28 (m, 2 H), 4.43
(dd, J=10.29, 7.80 Hz, 1 H), 4.59 (s, 2 H), 4.70 (dd, J=8.89, 5.46 Hz, 1 H), 4.82 - 4.88 (m, 1 H), 6.75 (dd, J=8.89, 2.96 Hz, 1 H), 6.96 (d, J=3.12 Hz, 1 H), 6.99 (d, J=8.73 Hz, 1 H). MS (ESI) m/z 446(M+H)+.
Example 74 (2S)-l-r((2S,5R)-5-{r2-methoxy-4-(lH-tetraazol-5-yl)phenoxylmethyl}ρyπolidin-2- yl)carbonyl1pyπolidine-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. 1H NMR (500 MHz, MeOH- j) δ ppm 1.98 - 2.10 (m, 1 H), 2.11 - 2.47 (m, 6 H), 2.61 (m, 1 H), 3.59 - 3.75 (m, 2 H), 3.94 - 4.06 (m, 3 H), 4.13 - 4.27 (m, 1 H), 4.36 - 4.52 (m, 2 H), 4.69 (dd, J=9.04, 6.24 Hz, 1 H), 4.85 (dd, J=7.95, 4.52 Hz, 1 H), 7.24 (d, J=8.11 Hz, 1 H), 7.63 (dd, J=8.42, 1.87 Hz, 1 H), 7.70 (d, J=l .87 Hz, 1 H). MS (ESI) m/z 398 (M+H)+.
Example 75 3-tert-butyl-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-vncarbonyl>pyπolidin-2- yl)methoxy1benzamide
Example 75A 3 -tert-Butyl-4-hydroxy-benzamide The compound of Example 47E (800 mg, 4.1 mmol), DCC (856 mg, 5.4mmol), and HOBt (540 mg, 5.4 mmol) were mixed in DMF (10 mL). Ammonium hydroxide (28 %, 22mL) was added to the mixture at 0 °C. The reaction was stiπed over night and purified by silica gel chromatography (70% - 90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5 %). MS (DCI) m/z 194 (M+H)+.
Example 75B 3-tert-butyl-4-r((2R,5S)-5-{r(2S)-2-cvanoρvπolidin-l-yncarbonyl}ρyπolidin-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. 1H NMR (500 MHz, MeOH-d δ ppm 1.45 (s, 9 H), 2.02 - 2.39 (m, 6 H), 2.39 - 2.49 (m, 1 H), 2.52 - 2.67 (m, 1 H), 3.61 - 3.77 (m, 2 H), 4.21 - 4.32 (m, 1 H), 4.38 (dd, J=10.29, 4.68 Hz, 1 H), 4.57 (dd, J=10.45, 7.64 Hz, 1 H), 4.75 (dd, J=8.73, 5.30 Hz, 1 H), 4.83 - 4.89 (m, 1 H), 7.12 (d, J=8.42 Hz, 1 H), 7.77 (dd, J=8.73, 2.18 Hz, 1 H), 7.89 (d, J=2.18 Hz, 1 H). MS (ESI) m/z 415 (M+H)+.
Example 76
(2S)-l-r((2S,5R)-5-{r2-isoproρyl-4-(lH-tetraazol-5-yl)phenoxy1methyl>ρyπolidin-2- yl)carbonyl1pyπolidine-2-carbonitrile
Example 76A 4-Bromo-2-isopropyl-phenol The title compound was synthesized by substituting 2-tert-butylphenol in Example 47A with 2-isoρropylρhenol. MS (DCI) m/z 215, 217 (M+H)+.
Example 76B 4-cyano-2-isopropyl-phenol 4-Bromo-2-isoρroρyl-ρhenol (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-pyπolidine-l-carbonyl)-5R-r2-isopropyl-4-(lH-tetτazol-5-yl)- phenoxymethyll-pyπolidine-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-isoρroρyl-4-(lH-tetraazol-5-yl)phenoxylmethyl>pyπolidin-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. 1H NMR (500 MHz, MeOH-d-ύ δ ppm 1.30 (dd, J=l 1.85, 6.86 Hz, 6 H), 1.95 - 2.09 (m, 1 H), 2.04 - 2.38 ( , 6 H), 2.43 - 2.54 (m, 1 H), 3.62 - 3.79 (m, 1 H), 3.87 - 4.06 (m, 1 H), 4.29 - 4.42 (m, 3 H), 4.46 - 4.55 (m, 2 H), 4.81 - 4.86 (m, 1 H), 7.09 (d, J=8.74 Hz, 1 H), 7.85 (dd, J=8.58, 2.03 Hz, 1 H), 7.97 (d, J=1.87
Hz, 1 H). MS (ESI) m/z 410 (M+H)+.
Example 77 3-r((2R,5S)-5-{[(2S) -2-cvanoρyπolidin-l-yncarbonyl>ρyπolidin-2- yl)methoxy1pyridine-2-carboxylic acid
Example 77A 3-Hydroxy-pyridine-2-carboxylic acid tert-butyl ester 3-Hydroxypicolinic acid (500 mg, 3.6 mmol) was stiπed 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 stiπed 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 ΝMR (500 MHz, MeOH-d ) δ 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
Hz, 2 H), 4.21 - 4.31 (m, J=7.80, 3.43 Hz, 1 H), 4.38 - 4.48 (m, 1 H), 4.57 (dd, J 0.45, 3.59 Hz, 1 H), 4.74 (dd, J=8.73, 6.24 Hz, 1 H), 4.79 - 4.82 (m, 1 H), 7.68 (dd, J=8.73, 4.68 Hz, 1 H), 7.84 (d, J=8.11 Hz, 1 H), 8.32 (d, J=4.06 Hz, 1 H). MS (ESI) m/z 345 (M+H)+.
Example 78 (2S1-1 -RT2S,5R)-5- {\A-(l -tert-butyl- lH-tetτaazol-5-yl -2- isopropylphenoxylmethyl}pyπolidin-2-yl)carbonyllpyπolidine-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. 1H NMR (400 MHz, MeOH-d ) δ ppm 1.30 (dd, J=11.51, 6.90 Hz, 6 H), 1.80 (s, 9 H), 2.02 - 2.48 (m, 7 H), 2.53 - 2.68 (m, 1 H), 3.50 - 3.63 (m, 1 H), 3.61 - 3.76 (m, 2 H), 4.18 - 4.28 (m, 1 H), 4.46 (d, J=4.91 Hz, 2 H), 4.65 - 4.76 (m, 1 H), 4.83 - 4.90 (m, 1 H), 7.14 (d, J=8.90 Hz, 1 H), 7.90 - 7.97 (m, 1 H), 8.01 (d, J=1.84 Hz, 1 H). MS (ESI) m/z 480 (M+H)+.
Example 79 / (2S)-l-r((2S,5R)-5-{r4-(l-tert-butyl-lH-tetraazol-5-γl)-2- clιlorophenoxylmethyl}pyπolidin-2-yl)carbonyl1pyπolidine-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 50B. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.80 (s, 9 H), 2.01 - 2.48 (m, 7 H), 2.51 - 2.67 (m, 1 H), 3.61 - 3.76 (m, 2 H), 4.20 - 4.33 (m, 1 H), 4.52 (d, J=5.52 Hz, 2 H), 4.66 - 4.75 (m, 1 H), 4.82 - 4.88 (m, 1 H), 7.32 (d, J=8.59 Hz, 1 H), 8.06 (dd, J=8.59, 2.15 Hz, 1 H), 8.14 (d, J=l .84 Hz, 1 H). MS (ESI) m/z 458, 460 (M+H)+.
Example 80 5-chloro-2-r((2R,5S)-5-{r(2S)-2-cyanoρyrrolidin-l-yncarbonyl)pyπolidin-2- yl)methoxy~lbenzoic acid
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-cyanopyπolidin-l-yncarbonyl}ρyπolidin-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. 1H NMR (500 MHz, MeOH-d*) δ ppm 1.97 - 2.07 (m, 1 H), 2.11 - 2.39 (m, 6 H), 2.53 - 2.63 (m, 1 H), 3.61 - 3.72 (m, 2 H), 4.13 - 4.24 (m, 1 H), 4.32 - 4.40 (m, 1 H), 4.46 (dd, J 0.45, 3.59 Hz, 1 H), 4.69 (dd, J=8.73, 5.93 Hz, 1 H), 4.80 - 4.84 (m, 1 H), 7.22 (d, J=8.74 Hz, 1 H), 7.55 (dd, J=8.73, 2.81 Hz, 1 H), 7.84 (d, J=2.81 Hz, 1 H). MS (ESI) m/z 378, 380 (M+H)+.
Example 81 {2-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl>pyπolidin-2- yl)methoxylphenyl} acetic acid
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 stiπed for 16 h and then poured into aqueous pH 7 buffer solution. Extraction with ethyl acetate followed by chromatography on silica gel (hexane/ethyl acetate = 4/1) gave desired product (66 mg, 30%). MS (DCI) m/z 330 (M+H)+.
Example 8 IB {2-|Y(2R,5S)-5- {r(2S)-2-cyanoρyπolidin- 1 -yll carbonyl }pyπolidin-2- yl)methoxγ1phenyl} acetic acid 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. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.98 - 2.45 (m, 7 H), 2.50 - 2.64 (m, 1 H), 3.61 - 3.76 (m, 4 H), 4.08 - 4.20 (m, 1 H), 4.33 - 4.44 (m, 2 H), 4.69 (dd, J=9.21, 5.52 Hz, 1 H), 4.82 - 4.88 (m, 1 H), 6.92 - 7.10 (m, 2 H), 7.20 - 7.34 (m, 2 H). MS (ESI) m/z 358 (M+H)+.
Example 82 3-IY(2R,5S)-5- {r(2S)-2-cyanopyπolidin- 1 -yl1carbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 0.66 - 0.77 (m, 1 H), 0.81 - 1.14 (m, 6 H), 1.22 - 1.34 (m, 1 H), 2.30 - 2.41 (m, 2 H), 2.84 - 2.95 (m, 1 H), 3.13 - 3.22 (m, 2 H), 3.39 (dd, J=9.00, 5.95 Hz, 1 H), 3.50 - 3.55 (m, 2 H), 5.95 (dd, J=10.98, 8.54 Hz, 1 H), 6.38 - 6.45 (m, 1 H), 6.51 (dd, J=8.09, 1.98 Hz, 1 H) . MS (ESI) m/z 362 (M+H)+.
Example 83 3-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-vncarbonyl}ρyπolidin-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,
MeOH-d4) δ ppm 1.26 (dd, J=15.91, 6.86 Hz, 6 H), 2.07 - 2.45 (m, 7 H), 2.56 - 2.66 (m, 1 H), 3.49 - 3.59 (m, 1 H), 3.62 - 3.74 (m, 2 H), 4.17 - 4.27 (m, 1 H), 4.44 (d, J=4.99 Hz, 2 H), 4.71 (dd, J=9.05, 5.62 Hz, 1 H), 4.85 (dd, J=7.80, 4.37 Hz, 1 H), 7.38 (d, J=8.11 Hz, 1 H), 7.61 (d, J=1.56 Hz, 1 H), 7.69 (dd, J=7.80, 1.56 Hz, 1 H). MS (ESI) m/z 386 (M+H)+.
Example 84 2-r5-(2-Cyano-pyπolidine- 1 -carbonyl)-pyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.98 - 2.07 (m, 1 H), 2.10 - 2.45 (m, 6 H), 2.53 - 2.64 (m, 1 H), 3.60 - 3.75 (m, 2 H), 4.10 - 4.25 (m, 1 H), 4.51 - 4.61 (m, 2 H), 4.70 (dd, J=8.89, 5.77 Hz, 1 H), 4.84 (dd, J=7.80, 4.37 Hz, 1 H), 7.42 - 7.49 (m, 1 H), 7.51 (d, J=9.05 Hz, 1 H),
7.53 - 7.59 (m, 1 H), 7.91 (dd, J=l 1.23, 8.42 Hz, 2 H), 8.03 (d, J=9.05 Hz, 1 H). MS (ESI) m/z 394 (M+H)+.
Example 85 3-chloro-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl|ρvπolidin-2- yl)methoxyl -N,N-dimethylbenzamide 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), and HOBt (540 mg, 5.4 mmol) were mixed in DMF (10 mL). N,N- dimethyl amine (2M in THF, 4.6 mL) was added to the mixture at 0 °C. The reaction was stiπed over night and purified by silica gel chromatography (70% - 90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5 %). MS (DCI) m/z 200, 202 (M+H)+.
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. 1H ΝMR (400 MHz, MeOH-c ) δ ppm 2.01 - 2.47 (m, 7 H), 2.53 - 2.64 (m, 1 H), 2.97 - 3.13 (m, 6 H), 3.61 - 3.74 (m,
2 H), 4.18 - 4.29 (m, 1 H), 4.46 - 4.51 (m, 2 H), 4.70 (dd, J=8.59, 5.83 Hz, 1 H), 4.83 (dd, J=7.83, 4.45 Hz, 1 H), 7.22 (d, J=8.59 Hz, 1 H), 7.41 (dd, J=8.44, 1.99 Hz, 1 H), 7.53 (d, J=2.15 Hz, 1 H). MS (ESI) m/z 405, 407 (M+H)+.
Example 86 (2S)-l-r((2S,5R)-5-{r(2-chloro-l-oxidopyridin-3-yl)oxylmethyl}pyπolidin-2- yl)carbonyr|pyπoιidine-2 -carbonitrile Example 86A 2S-(2-Chloro-pyridin-3-yloxymethyl)-5R-(2S-cyano-pyπolidine-l-carbonyl)- pyπolidine-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. 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 435, 437 (M+H). Example 86B (2S)-l-r((2S,5R)-5-{r(2-chloro-l-oxidopyridin-3-yl)oxylmethyl)pyπolidin-2- yl)carbonyllpyπolidine-2-carbonitrile The above compound (77 mg, 0.14 mmol) and mCPBA (96 mg, 77%, 0.35 mmol) were mixed in CH C12. The reaction was stiπed over night and purified by reverse phase HPLC to provide the coπesponding N-oxide. (51 mg, 64 %). MS (ESI) m/z 451, 453 (M+H)+. The Boc group was removed according to Example IG to give the title compound. 1H ΝMR (500 MHz, MeOH-α ) δ ppm 2.01 - 2.46 (m, 7 H), 2.51 - 2.69 (m, 1 H), 3.61 - 3.75 (m, 2 H), 4.19 - 4.33 (m, 1 H), 4.51 - 4.63 (m, 2 H), 4.73 (dd, J=8.73, 5.62 Hz, 1 H), 4.81 - 4.86 (m, 1 H), 7.36 - 7.48 (m, 2 H), 8.21 (dd, J=6.40, 1.40 Hz, 1 H). MS (ESI) m/z 351, 353 (M+H)+.
Example 87 (2S)-l-({(2S,5R)-5-r(2-chloro-4-moφholin-4-ylρhenoxy)methyllρyπolidin-2- yl} carbonyl)pyπolidine-2-carbonitrile The oven dried flask was charged with Pd2(dba)3 (5 mg, 0.005 mmol), (o- biρhenyl)P(t-Bu)2 (3 mg, 0.01 mmol) and ΝaH (11 mg, 0.27 mmol) and filled with argon. Toluene (1 mL), compound of Example 63A (45 mg, 0.088 mmol) and mophline (40 μL) were added. The mixture was heated to 80 °C for 1 hour. The mixture was then cooled to room temperature, filtered, and purified by reverse phase HPLC to give the product. (40 mg, 87 %). MS (ESI) m/z 519, 521 (M+H)+. The Boc group was removed according to Example IG to give the title compound. 1H ΝMR (400 MHz, MeOH-d^) δ ppm 1.94 - 2.44 (m, 7 H), 2.49 - 2.66 (m, 1 H), 3.05 - 3.11 (m, 4 H), 3.63 - 3.71 (m, 1 H), 3.77 - 3.86 (m, 5 H), 4.12 - 4.20 (m, 1 H), 4.31 - 4.37 (m, 2 H), 4.64 - 4.73 (m, 1 H), 4.83 (dd, J=7.98, 3.68 Hz, 1 H), 6.92 (dd, J=9.05, 2.92 Hz, 1 H), 7.06 (d, J=2.76 Hz, 1 H), 7.10 (dd, J=8.90, 3.38 Hz,
1 H). MS (ESI) m/z 419, 421 (M+H)+.
Example 88 (2S)-l-({(2S,5R)-5-r(4-amino-2-chlorophenoxy)methynpyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile
Example 88 A 2S-(2S-Cyano-pyπolidine-l-carbonyl)-5R-(2-chloro-4-nitro-phenoxymethyl)- pyπolidine-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-phenoχymethyl)-5S-(2S-cyano-ρyπolidine-l-carbonyl)- pyπolidine-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/H2O (ImL : 0.2 mL). Iron powder (25 mg, 0.98 mmol) was added to the mixture and it was heated to 50 °C for 1 hour. It was filtered and ethyl acetate (25 mL) was added to the mixture. The solution was washed with brine (2X), then dried with NaSO4. The solution was then concentrated in vacuo to give the titled analine.
(48 mg, 100%). MS (ESI) m/z 449, 451 (M+H)+.
Example 88C (2S)-l-({(2S,5R)-5-r(4-amino-2-chloroρhenoxy)methyllpyπolidin-2- yl) carbonyl)pyπolidine-2-carbonitrile The Boc group was removed according to Example IG to give the title compound. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.97 - 2.47 (m, 7 H), 2.53 - 2.66 (m, 1 H), 3.58 - 3.75 (m, 2 H), 4.16 - 4.26 (m, 1 H), 4.34 - 4.43 (m, 2 H), 4.69 (dd, J=8.89, 6.08 Hz, 1 H), 4.83 (dd, J=7.96, 4.52 Hz, 1 H), 7.04 - 7.08 (m, J=2.50 Hz, 1 H), 7.17 (d, J=8.74 Hz, 1 H), 7.20 (d, J=2.50 Hz, 1 H).
Example 89 3-chloro-4-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl>pyπolidin-2- yl)methoxy"l-l-naphthoic acid
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. MS (ESI) m/z 245
(M+H)+.
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. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.96 - 2.50 (m, 7 H), 2.58 - 2.80 (m, 1 H), 3.63 - 3.76 (m, 2 H), 4.32 - 4.51 (m, 2 H), 4.61 (dd, J=10.59, 8.13 Hz, 1 H), 4.75 - 4.79 (m, 1 H), 4.89 (dd, J=7.98, 4.60 Hz, 1 H), 7.62 - 7.77 (m, 2 H), 8.25 (s, 1 H), 8.29 - 8.39 (m, 1 H), 8.94 - 9.07 (m, 1 H). MS (ESI) m/z 428, 430 (M+H)+.
Example 90 3-bromo-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl>pyπolidin-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. 1H NMR (300 MHz, MeOH-d4) δ ppm 2.02 - 2.49 (m, 7 H), 2.49 - 2.64 (m, 1 H), 3.61 - 3.77 (m, 2 H), 4.20 - 4.34 (m, 1 H), 4.52 (d, J=5.42 Hz, 2 H), 4.64 - 4.73 (m, 1 H), 4.77 - 4.82 (m, 1 H), 7.20 (d, J=8.81 Hz, 1 H), 8.03 (dd, J=8.81, 2.03 Hz, 1 H), 8.21 (d, J=2.37 Hz, 1 H). MS (ESI) m/z 422, 424 (M+H)+.
Example 91 6-chloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yncarbonyl}pyπolidin-2- yl)methoxy1nicotinic acid 1 -oxide The title compound was synthesized by substituting 2S-(2-chloro-pyridin-3- yloxymethyl)-5R-(2S-cyano-pyπolidine- 1 -carbonyl)-pyπolidine- 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}-pyπolidine-2-carbonixrile (Example 52C). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.85 - 1.96 (m, 1 H), 1.98 - 2.10 (m, 4 H), 2.11 - 2.22 (m, 1 H), 2.21 - 2.36 (m, 4 H), 4.49 - 4.67 (m, 4 H), 4.84 (dd, J=7.80, 4.99 Hz, 1 H), 7.57 (s, 1 H), 8.47 (s, 1 H), 8.78 (s, 1 H), 9.99 (s, 1 H). MS (ESI) m/z 395, 397 (M+H)+.
Example 92 6-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl>pyπolidin-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. 1H NMR (400 MHz, MeOH-d δ ppm 1.93 - 2.48 (m, 7 H), 2.55 - 2.70 (m, 1 H), 3.61 - 3.76 (m, 2 H), 4.16 - 4.32 (m, 1 H), 4.50 - 4.59 (m, 2 H), 4.72 (dd, J=8.90, 5.83 Hz, 1 H), 4.85 (dd, J=7.67, 4.60 Hz, 1 H), 7.33 (dd, J=8.90, 2.46 Hz, 1 H), 7.42 (d, J=2.15 Hz, 1 H), 7.86 (d, J=8.59 Hz, 1 H), 7.96 (d, J=8.90 Hz, 1 H), 8.02 (dd, J=8.75, 1.38 Hz, 1 H), 8.55 (s, 1 H). MS (ESI) m/z 394 (M+H)+.
Example 93 (2S)-l-r((2S,5R)-5-{r2-chloro-4-(methylsulfonyl)phenoxylmethyl}ρyπolidin-2- yl)carbonyllpyπolidine-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 KClO3 (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. The resulting residue was purified by reverse-phase HPLC to give both l-chloro-2-methanesulfonyl-4-methoxy- benzene and 2-chloro-l-methanesulfonyl-3-methoxy-benzene. MS (DCI) m/z 224 (M+NH4)+.
Example 93B (2S)-l-r((2S,5R)-5-{r2-chloro-4-(methylsulfonyl)phenoxy1methyl>pyπolidin-2- yl)carbonyllpyπolidine-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. IH NMR (500 MHz, MeOH-d4) δ ppm 2.04 - 2.37 (m, 6 H), 2.37 - 2.45 (m, 1 H), 2.55 - 2.64 (m, J=13.27, 8.09 Hz, 1 H), 3.13 (s, 3 H), 3.63 - 3.72 (m, 2 H), 4.21 - 4.31 (m, 1 H), 4.54 - 4.58 (m, 2 H), 4.72 (dd, J=8.85, 5.80 Hz, 1 H), 4.83 (dd, J=7.93, 4.58 Hz, 1 H), 7.37 (d, J=8.85 Hz, 1 H), 7.91 (dd, J=8.54, 2.14 Hz, 1 H), 8.00 (d, J=2.44 Hz, 1 H). MS (ESI) m/z 412 (M+H)+.
Example 94 (2S)-l-r((2S,5R)-5-{r4-chloro-2-(hydroxymethyl)phenoxy1methyl}ρyπolidin-2- yl)carbonyl1pyπolidine-2-carbonitrile
Example 94A 2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-chloro-phenol 4-Chloro-2-hydroxymethyl-ρhenol (100 mg, 0.6 mmol), TBSC1 (104 mg, 0.66 mmol) and imidazol (51.2 mg, 0.72 mmol) were mixed in CH2C12. The mixture was stiπed for 1 hour and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane/ethyl acetate = 5/1) to give the desired product (225 mg, 100%). MS (DCI) m z 273, 275 (M+H)+.
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-(hydroxγmethyl)ρhenoxy1methγ pyπolidin-2- yl)carbonyllpyπolidine-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. MS (ESI) m/z 464, 466 (M+H)+. The Boc group was removed according to Example IG to give the title compound. 1H NMR (400 MHz, MeOH- j) δ ppm 1.97 - 2.09 (m, 1 H), 2.09 - 2.43 (m, 6 H), 2.52 - 2.65 (m, 1 H), 3.62 - 3.71 (m, 2 H), 4.09 - 4.22 (m, 1 H), 4.29 - 4.42 (m, 2 H), 4.65 - 4.73 (m, 3 H), 4.84 (dd, J=7.67, 4.60 Hz, 1 H), 7.02 (d, J=8.90 Hz, 1 H), 7.27 (dd, J=8.75, 2.61 Hz, 1 H), 7.39 (d, J=2.76 Hz, 1 H). MS (ESI) m/z 380, 382 (M+H)+.
Example 95 5-chloro-6-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yl1carbonyl}pyπolidin-2- yl)methoxy~l-2-naphthoic acid The title compound was synthesized using the same reaction sequence of
Example 89 by substituting 4-hydroxy-naphthalene-l -carboxylic acid in Example 89A with 6-hydroxy-naphthalene-2-carboxylic acid. 1H NMR (400 MHz, MeOH-d δ ppm 2.03 - 2.51 (m, 7 H), 2.56 - 2.69 (m, 1 H), 3.63 - 3.75 (m, 2 H), 4.22 - 4.35 (m, 1 H), 4.58 - 4.66 (m, 2 H), 4.73 (dd, J=8.75, 5.98 Hz, 1 H), 4.85 (dd, J=7.52, 4.45 Hz, 1 H), 7.60 (d, J=9.21 Hz, 1 H), 8.06 (d, J=8.90 Hz, 1 H), 8.15 (dd, J=8.90, 1.53 Hz, 1 H), 8.27 (d, J=8.90 Hz, 1 H), 8.63 (d, J=1.23 Hz, 1 H). MS (ESI) m/z 428, 430 (M+H)+.
Example 96 (2S)-l-r((2S,5R)-5-{r(6-chloro-l,3-benzodioxol-5-yl)oxylmethyl>pyπolidin-2- yl)carbonyllpyπolidine-2-carbonitrile
Example 96A 6-Chloro-benzo|T ,31dioxol-5-ol 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}ρyπolidin-2- yl)carbonyl1pyπolidine-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. 1H NMR (400 MHz, MeOH-d ) δ ppm 1.96 - 2.48 (m, 7 H), 2.46 - 2.66 (m, 1 H), 3.56 - 3.74 (m, 2 H), 4.10 - 4.22 (m, 1 H), 4.26 - 4.37 (m, 2 H), 4.68 (dd, J=8.75, 5.98 Hz, 1 H), 4.85 (dd, J=7.83, 4.45 Hz, 1 H), 5.97 (s, 2 H), 6.89 (d, J=17.18 Hz, 1 H). MS (ESI) m/z 378, 380 (M+H)+.
Example 97 N-{4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl)pyπolidin-2-yl)methoxyl- 1 -naphthyllmethanesulfonamide
Example 97A 2-(4-Amino-naphthalen-l-yloxymethyl)-5-(2-cyano-pyπolidine-l-carbonyl)- pyπolidine-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-cyanopyπolidin- 1 -yl1carbonyl}pyπolidin-2-yl)methoxyl- l-naphthyl}methanesulfonamide The compound of Example 97A (32 mg, 0.07 mmol) was dissolved in CH2C12 (ImL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride
(6.0 μL, 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 give the desired sulfonamide. The title compound was obtained after removal of the Boc group as described in Example 1 G. 1H NMR (400 MHz, MeOH-dj) δ ppm 1.98 - 2.45 (m, 7 H), 2.03 (s, 3
H), 2.51 - 2.67 (m, 1 H), 3.59 - 3.71 (m, 2 H), 3.78 (d, J=6.75 Hz, 2 H), 4.10 - 4.26 (m, 1 H), 4.65 (dd, J=9.21, 5.52 Hz, 1 H), 4.86 (dd, J=7.67, 4.60 Hz, 1 H), 6.71 (d, J=8.29 Hz, 1 H), 7.33 - 7.66 (m, 3 H), 8.08 (d, J=8.29 Hz, 1 H), 8.15 (d, J=7.98 Hz, 1 H). MS (ESI) m/z 443 (M+H)+. ,
Example 98 (2S)-l-r((2S,5R)-5-{r2-bromo-4-(methylsulfonyl)phenoxylmethyl>pyπolidin-2- yl)carbonyl1pyπoιidine-2-carboniτrile 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}pyπolidin-2- yl)carbonyl1pyπolidine-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,
MeOH-d4) δ ppm 2.06 - 2.48 (m, 7 H), 2.60 (dd, J=13.35, 7.83 Hz, 1 H), 3.13 (s, 3 H), 3.63 - 3.73 (m, 2 H), 4.24 - 4.34 (m, 1 H), 4.53 - 4.59 (m, 2 H), 4.73 (dd, J=8.44, 5.98 Hz, 1 H), 4.82 - 4.87 (m, 1 H), 7.33 (d, J=8.90 Hz, 1 H), 7.95 (dd, J=8.75, 2.30 Hz, 1 H), 8.15 (d,1 j=2.46 Hz, 1 H). MS (ESI) m/z 456, 458 (M+H)+.
Example 99 (2S)-l-r((2S,5R)-5-{r(6-bromo- 3-benzodioxol-5-yl)oxylmethyl>pyrrolidin-2- yl)carbonyllpyπolidine-2-carbonitrile Example 99A 6-bromo-benzori,31dioxol-5-ol The title compound was synthesized by substituting 3-hydroxy-benzoic acid in
Example 52A with sesamol.
Example 99 (2S)-l-r((2S,5R)-5-{r(6-bromo-l,3-benzodioxol-5-yl)oxy1methyl}pyπolidin-2- yl)carbonyl1pyπolidine-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. 1H NMR (500 MHz, MeOH-cU) δ ppm 1.98 - 2.06 (m, 1 H), 2.12 - 2.39 (m, 6 H), 2.51 - 2.62 (m, 1 H), 3.62 - 3.72 (m, 2 H), 4.08 - 4.14 (m, 1 H), 4.25 - 4.32 (m, 2 H), 4.61 (dd, J=8.73, 6.24 Hz, 1 H), 4.84
(dd, J=7.80, 4.37 Hz, 1 H), 5.97 (s, 2 H), 6.85 (s, 1 H), 7.04 (s, 1 H). MS (ESI) m/z 422, 424 (M+H)+.
Example 100 2-chloro-N-{3-chloro-4-r((2i-,5S)-5-{r(2S)-2-cyanopyπolidin-l- yl1carbonyl}pyπOlidin-2-yl)methoxy1phenyl}benzenesulfonamide
Example 100A 2R-r2-Chloro-4-(2-chloro-benzenesulfonylamino)-phenoxymethγll-5S-(2S-cyano- pyπolidine-l-carbonyl)-pyπolidine-l -carboxylic acid tert-butyl ester The compound of Example 88B (32 mg, 0.07 mmol) was dissolved in CH2C12 (ImL) and pyridine (0.5 mL) in a microwave reaction tube. 2-Chloro-benzenesulfonyl chloride (6.0 μL, 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}ρyπolidin-2- yl)carbonyl1pyπolidine-2-carbonitrile The Boc group was removed according to Example IG to give the title compound. 1H ΝMR (400 MHz, MeOH-d) δ ppm 1.92 - 2.05 (m, 1 H), 2.07 - 2.45 (m, 6 H), 2.49 - 2.60 (m, 1 H), 3.58 - 3.71 (m, 2 H), 4.09 - 4.18 (m, 1 H), 4.31 (d, J=6.14 Hz, 2 H), 4.64 (dd, J=8.75, 5.98 Hz, 1 H), 4.81 - 4.85 (m, 1 H), 6.97 - 7.03 (m, 1 H), 7.06 - 7.12 (m, 1 H), 7.22 (d, J=2.45 Hz, 1 H), 7.36 - 7.44 (m, 1 H), 7.51 - 7.59 (m, 2 H), 7.99 (dd, J=7.83, 1.38 Hz, 1 H). MS (ESI) m/z 523, 525 (M+H)+.
Example 101 N-{3-chloro-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yncarbonyl}pyπolidin-2- yl)methoxylphenyl}methanesulfonamide The title compound was synthesized by substituting 2-chloro-benzenesulfonyl chloride in Example 100A with methanesulfonyl chloride. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.99 - 2.11 (m, 1 H), 2.11 - 2.44 (m, 6 H), 2.53 - 2.64 (m, 1 H), 3.43 (s, 3 H), 3.60 - 3.73 (m, 2 H), 4.16 - 4.28 (m, 1 H), 4.50 (d, J=5.80 Hz, 2 H), 4.70 (dd, J=8.70, 5.95 Hz, 1 H), 4.81 - 4.84 (m, J=4.88 Hz, 1 H), 7.24 (d, J=8.85 Hz, 1 H), 7.42 (dd, J=8.70, 2.59 Hz, 1 H), 7.57 (d, J=2.44 Hz, 1 H). MS (ESI) m/z 427, 429 (M+H)+.
Example 102 N-{3-chloro-4-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}pyπolidin-2- yl)methoxylphenyl} acetamide 2R-(4-Anιino-2-chloro-phenoxymethyl)-5S-(2S-cyano-pyπolidine-l- carbonyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (Example 88B) (32 mg, 0.07 mmol) was dissolved in CH2C12 (ImL). Acetyl chloride (6.0 μL, 0.21 mmol) and triethylamine (30 μL, 0.21 mmol) were added. After the reaction was over, it was purified by reverse phase HPLC to provide the desired amide (25 mg, 78 %). MS (ESI) m/z 491, 493 (M+H)+. The Boc group was removed according to Example IG to give the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.97 - 2.09 (m, 1 H), 2.10 (s, 3 H), 2.13 - 2.45 (m, 6 H), 2.59 (dd, J=12.58, 8.59 Hz, 1 H), 3.60 - 3.73 (m, 2 H), 4.13 - 4.26 (m, 1 H), 4.39 (d, J=5.22 Hz, 2 H), 4.68 (dd, J=8.59, 6.44 Hz, 1 H), 4.84 (dd,
J=7.67, 4.60 Hz, 1 H), 7.12 (d, J=9.21 Hz, 1 H), 7.42 (dd, J=8.90, 2.45 Hz, 1 H), 7.72 (d, J=2.45 Hz, 1 H). MS (ESI) m/z 523, 525 (M+H)+.
Example 103 (2S)-l-({(2S,5R)-5-r(l-benzothien-4-yloxy)methyllρyπolidin-2- yl} carbonyl)pyπolidine-2-carbonitrile Example 103 A 2R-(Benzo|'bltlιiophen-4-yloxymethyl)-5S-(2S-cvano-pyπolidine-l-carbonyl)- pyπolidine-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 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)pyπolidine-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% CH3CN/H2O with 0.1% trifluoroacetic acid (TFA) in aq. eluent] gave the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 2.06 - 2.46 (m, 8 H), 2.56 - 2.69 (m, 1 H), 3.63 - 3.75 (m, 2
H), 4.20 - 4.31 (m, 1 H), 4.49 - 4.56 (m, J=5.52 Hz, 2 H), 4.74 (dd, J=8.90, 5.52 Hz, 1 H), 4.87 (dd, J=7.83, 4.45 Hz, 1 H), 6.92 (d, J=7.98 Hz, 1 H), 7.31 (t, J=7.98 Hz, 1 H), 7.48 (d, J=5.52 Hz, 1 H), 7.54 (d, J=7.98 Hz, 1 H), 7.67 (d, J=5.52 Hz, 1 H). MS (ESI) m/z 356 (M+H)+.
Example 104 (2S)-l-r((2S,5R)-5-{r4-bromo-2-(methylsulfonyl)ρhenoxy1methyl>ρyπolidin-2- yl)carbonyllpyπolidine-2-carboniιrile
Example 104A 2-Methanesulfonyl-phenol 2-Methylsulfanyl-ρhenol (lg, 7.1 mmol) and mCPBA (8 g, 77%, 35.5 mmol) were mixed in CH2C12. The reaction was stiπed 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)ρyπolidin-2- yl)carbonyllpyπolidine-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.07 - 2.43 (m, 7 H), 2.54 - 2.68 (m, 1 H), 3.31 (s, 3 H), 3.61 - 3.72 (m, 2 H), 4.21 - 4.32 (m, 1 H), 4.46 - 4.53 (m, 1 H), 4.61 (dd, J=10.61, 3.43 Hz, 1 H), 4.73 (dd, J=9.05, 5.62 Hz, 1 H), 4.82 (dd, J=7.80, 4.37 Hz, 1 H), 7.31 (d, J=9.05 Hz, 1 H), 7.86 (dd, J=8.89, 2.65 Hz, 1 H), 8.02 (d, J=2.50 Hz, 1 H). MS (ESI) m/z 456, 458 (M+H)+.
Example 105 6-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.00 - 2.12 (m, 1 H), 2.11 - 2.45 (m, 6 H), 2.56 - 2.68 (m, 1 H), 3.62 - 3.74 (m, 2 H), 4.18 - 4.26 (m, 1 H), 4.50 -
4.54 (m, 2 H), 4.72 (dd, J=9.05, 5.62 Hz, 1 H), 4.85 (dd, J=7.95, 4.52 Hz, 1 H), 7.35 (dd, J=9.51, 2.65 Hz, 1 H), 7.43 (d, J=2.50 Hz, 1 H), 7.51 (dd, J=8.11, 7.49 Hz, 1 H), 8.02 (d, J=8.42 Hz, 1 H), 8.09 (dd, J=7.33, 1.40 Hz, 1 H), 8.89 (d, J=9.67 Hz, 1 H). MS (ESI) m/z 394 (M+H)+.
Example 106 N- {3-bromo-4-r((2R,5S)-5- { r(2S)-2-cyanoρyπolidin- 1 -yncarbonyl>ρyπolidin-2- ypmethoxylphenyl} acetamide
Example 106A 2R-(4-Amino-2-bromo-phenoxymethyl)-5S-(2S-cyano-pyπolidine-l-carbonyl)- pyπolidine-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-pyπolidine-l-carbonyl)-pyπolidine-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. 1H NMR (500 MHz, MeOH-cLj) δ ppm 2.03 - 2.10 (m, 1 H), 2.09 - 2.12 (s, 3 H), 2.12 - 2.46 (m, 6 H), 2.52 - 2.65 (m, 1 H), 3.56 - 3.77 (m, 2 H), 4.14 - 4.26 (m, 1 H), 4.35 - 4.43 (m, 2 H), 4.68 (dd, J=8.54, 6.10 Hz, 1 H), 4.80 - 4.87 (m, 1 H), 7.10 (d, J=8.85 Hz, 1 H), 7.48 (dd, J=8.85, 2.75 Hz, 1 H), 7.88 (d, J=2.44 Hz, 1 H). MS (ESI) m/z 435, 437 (M+H)+.
Example 107 N-{3-bromo-4-r((2R,5S)-5-{r(2S)-2-cvanopyπolidin-l-yncarbonyl}pyπolidin-2- yl)methoxylphenyl}methanesulfonamide
Example 107A The compound of Example 106A (34 mg, 0.07 mmol) was dissolved in CH2C12 (ImL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride (6.0 μL, 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-cγanoρyπolidin-l-yllcarbonyl}pyπolidin-2- yl)methoxylphenyl}methanesulfonamide The Boc group was removed according to Example IG to give the title compound. 1H NMR (500 MHz, MeOH-d^ δ ppm 2.01 - 2.44 (m, 7 H), 2.54 - 2.67 (m, 1 H), 2.93 (s, 3 H), 3.61 - 3.73 (m, 2 H), 4.14 - 4.28 (m, 1 H), 4.35 - 4.46 (m, 2 H), 4.70 (dd, J=8.89, 6.08 Hz, 1 H), 4.84 (dd, J=7.80, 4.37 Hz, 1 H), 7.13 (d, J=8.73
Hz, 1 H), 7.27 (dd, J=8.73, 2.50 Hz, 1 H), 7.51 (d, J=2.50 Hz, 1 H). MS (ESI) m/z 471, 473 (M+H)+.
Example 108 N-{3-bromo-4-r((2R,5S)-5-(r(2S)-2-cyanopyπolidin-l-yncarbonyl}ρyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.00 - 2.08 (m, 1 H), 2.10 - 2.39 (m, 6 H), 2.52 - 2.63 (m, 1 H), 3.61 - 3.72 (m, 2 H), 4.14 - 4.21 (m, 1 H), 4.30 - 4.37 (m, 2 H), 4.66 (dd, J=8.58, 6.08 Hz, 1 H), 4.83 (dd, J=7.96, 4.52 Hz, 1 H), 6.98 - 7.02 (m, 1 H), 7.07 (dd, J=8.73, 2.50 Hz, 1 H), 7.29 (d, J=2.81 Hz, 1 H), 7.49 (t, J=7.64 Hz, 2 H), 7.58 (t, J=7.33 Hz, 1 H), 7.72 (dd, J=8.42, 1.25 Hz, 2 H). MS (ESI) m/z 533, 535 (M+H)+.
Example 109 N-{3-bromo-4-r((2R,5S)-5-{r(2S)-2-cvanoρyπolidin-l-yllcarbonyl}ρyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.00 - 2.06 (m, 1 H), 2.10 - 2.38 (m, 6 H), 2.50 - 2.61 (m, J=12.95, 7.96 Hz, 1 H), 3.59 - 3.70 (m, 2 H), 4.09 - 4.20 (m, 1 H), 4.27 - 4.35 (m, 2 H), 4.65 (dd, J=8.74, 6.24 Hz, 1 H), 4.82 (dd, J=7.95, 4.52 Hz, 1 H), 6.98 (d, J=8.73 Hz, 1 H), 7.14 (dd, J=8.89, 2.65 Hz, 1 H), 7.36 - 7.44 (m, 2 H), 7.51 - 7.61 (m, 2 H), 7.98 (dd, J=7.95, 1.40 Hz, 1
H). MS (ESI) m/z 567, 569 (M+H)+.
Example 110 methyl 2,3-dichloro-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l- yllcarbonyl}pyπolidin-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
-219, -211 (M-Hy.
Example HOB methyl 2,3-dichloro-4-r((2R,5S)-5-{r(2S)-2-cyanopyrrolidin-l- yncarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-d^) δ ppm 2.03 - 2.37 (m, 6 H), 2.37 - 2.45 (m, 1 H), 2.54 - 2.63 (m, J=13.26, 7.96 Hz, 1 H), 3.63 - 3.72 (m, 2 H), 3.90 (s, 3 H), 4.22 - 4.30 (m,
J=6.71, 6.71 Hz, 1 H), 4.51 - 4.56 (m, 2 H), 4.71 (dd, J=8.73, 5.93 Hz, 1 H), 4.84 (dd, J=7.95, 4.21 Hz, 1 H), 7.20 (d, J=9.05 Hz, 1 H), 7.84 (d, J=8.73 Hz, 1 H). MS (ESI) m/z 426 (M+H)+.
Example 111 3-r((2R,5S)-5-ir(2S)-2-cyanopyπolidin-l-yllcarbonyl}ρyπolidin-2-yl)methoxyl-4- methoxybenzoic acid
Example 111A 3-hydroxy-4-methoxy-benzoic acid tert-butyl ester The title compound was synthesized by substituting 3-hydroxypicolinic acid in
Example 77A with 4-methoxy-3-hydroxy-benzoic acid. MS (DCI) m/z 225(M+H)+.
Example 11 IB 3-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl}ρyπolidin-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. 1H NMR (400 MHz, MeOH-d4) δ ppm 1.98 - 2.09 (m, 1 H), 2.11 - 2.41 (m, 7 H), 2.53 - 2.67 (m, J=12.73, 8.75 Hz, 1 H), 3.63 - 3.72 (m, 2 H), 3.96 (s, 3 H), 4.12 - 4.22 (m, 1 H), 4.30 - 4.44 (m, 2 H), 4.68 (dd, J=8.90, 6.44 Hz, 1 H), 4.85 (dd, J=7.98, 4.30 Hz, 1 H), 7.08 - 7.15 (m, 1 H), 7.68 (d, J=2.15 Hz, 1 H), 7.78 (dd, J=8.44, 1.99 Hz, 1 H). MS (ESI) m/z 374 (M+H)+.
Example 112 2,3-dichloro-4-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yncarbonyl}pyπolidin-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
2R-(4-tert-butoxycarbonyl-2,3-dichloro-phenoxymethyl)-5S-(2S-cyano-pyπolidine-l- carbonyl)-pyπolidine-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 tert-butyl ester.
Example 112C 2,3-dichloro-4-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}ρyπolidin-2- yl)methoxylbenzoic acid The Boc and tert-butyl groups were removed by procedure described in Example 103B. 1H NMR (500 MHz, MeOH- δ ppm 2.03 - 2.12 (m, 1 H), 2.13 - 2.45 (m, 6 H), 2.55 - 2.64 (m, 1 H), 3.62 - 3.74 (m, 2 H), 4.22 - 4.30 (m, 1 H), 4.50 - 4.55 (m, J=1.25 Hz, 2 H), 4.72 (dd, J=8i73, 5.93 Hz, 1 H), 4.84 (none, 1 H), 7.19 (d,
J=8.73 Hz, 1 H), 7.87 (d, J=8.74 Hz, 1 H). MS (ESI) m/z 412 (M+H)+.
Example 113 (2S)-l-({(2S,5R)-5-r(2,4-dichloro-5-nifroρhenoxy)methynpyπolidin-2- yl} carbonyl)pyπolidine-2-carboniτrile Example 113 A 2S-(2S-Cyano-pyπolidine-l-carbonyl)-5R-(2,4-dichloro-5-nitro-phenoxymethyl)- pyπolidine-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)methynpγπolidin-2- yl}carbonyl)pyπolidine-2-carboniτrile The Boc group of the above ether was removed according to Example 103B. 1H NMR (400 MHz, MeOH-α ) δ ppm 2.03 - 2.45 (m, 8 H), 2.54 - 2.66 (m, 1 H), 3.63 - 3.72 (m, 2 H), 4.21 - 4.31 (m, 1 H), 4.48 - 4.57 (m, 2 H), 4.72 (dd, J=8.59, 6.14 Hz, 1 H), 4.81 - 4.87 (m, 1 H), 7.80 (d, J=1.23 Hz, 2 H). MS (ESI) m/z 413 (M+H)+.
Example 114 tert-butyl 2,3-dichloro-4-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l- yl1carbonyl>pyπolidin-2-yl)methoxylbenzoate The title compound was synthesized when only the Boc group in Example
112B was removed. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.59 (s, 9 H), 2.04 - 2.11 (m, J=13.26, 8.27 Hz, 1 H), 2.13 - 2.45 (m, 6 H), 2.59 (dd, J=13.26, 7.64 Hz, 1 H), 3.62 - 3.72 (m, 2 H), 4.22 - 4.30 (m, 2 H), 4.52 (d, J=4.99 Hz, 1 H), 4.71 (dd, J=8.73, 5.93 Hz, 1 H), 4.84 (dd, J=7.95, 4.21 Hz, 1 H), 7.18 (d, J=8.73 Hz, 1 H), 7.70 (d, J=8.74 Hz, 1 H). MS (ESI) m z 468(M+H)+.
Example 115 ethyl 4-chloro-3-r((2R,5S)-5-{r(2S -2-cyanopyπolidin-l-yncarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-c ) δ ppm 1.39 (t, J=7.18 Hz, 3 H), 2.06 - 2.45 (m, 7 H), 2.56 - 2.65 (m, J=13.26, 8.27 Hz, 1 H), 3.63 - 3.72 (m, 2 H), 4.21 - 4.29 (m, J=8.42, 4.06 Hz, 1 H), 4.38 (q, J=7.18 Hz, 2 H), 4.47 - 4.55 (m, 2 H), 4.70 (dd, J=8.73, 6.24 Hz, 1 H), 4.84 (dd, J=7.95, 4.21 Hz, 1 H), 7.54 (d, J=8.11 Hz, 1 H), 7.68 (dd, J=8.42, 1.87 Hz, 1 H), 7.74 (d, J .56 Hz, 1 H). MS (ESI) m/z 406 (M+H)+.
Example 116 isopropyl 4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yllcarbonyl}pyπolidin- 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-cyanopyπolidin-l-yl1carbonyl)pyπolidin- 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. 1H NMR (500 MHz, MeOH-d^) δ ppm 1.37 (d, J=6.24 Hz, 6 H), 2.05 - 2.46 (m, 7 H), 2.56 - 2.63 (m, 1 H), 3.63 - 3.72 (m, 2 H), 4.22 - 4.29 (m, 1 H), 4.47 - 4.55 (m, 2 H), 4.71 (dd, J=8.73, 5.93 Hz, 1 H), 4.84 (dd, J=7.96, 4.52 Hz, 1 H), 5.18 - 5.27 (m, J=6.24, 6.24, 6.24, 6.24, 6.24, 6.24 Hz, 1 H), 7.53 (d, J=8.42 Hz, 1 H), 7.66 (dd, J=8.27, 1.72 Hz, 1 H), 7.72 (d, J .87 Hz, 1 H). MS (ESI) m/z 420 (M+H)+.
Example 117 N- {2,4-dichloro-5-r((2R,5S)-5- {r(2S)-2-cyanopyπolidin- 1 -yllcarbonyl}ρyπolidin-2- yl)methoxylphenyl| acetamide Example 117A 2-(5-Amino-2,4-dichloro-phenoxymethyl)-5-(2-cyano-pyπolidine-l-carbonyl)- pyrrolidine-1 -carboxylic acid tert-butyl ester 2S-(2S-Cyano-pyπolidine- 1 -carbonyl)-5R-(2,4-dichloro-5-nitro- phenoxymethyl)-pyπolidine-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 mmol) were mixed in 5.5: 1.9 mL of EtOH:H2O and the mixture was heated to 70 °C. After 2 hours, EtOAc was added and the mixture was filtered through Celite. The filtrate was concentrated in vacuum and the resulting residue was used directly in the next step. MS (ESI) m/z 483 (M+H)+.
Example 117B 2-(5-Acetylamino-2,4-dichloro-phenoxymethyl)-5-(2-cyano-pyπolidine-l-carbonyl)- pyπolidine-1 -carboxylic acid tert-butyl ester To the above amine (0.1 mmol) and Et3N (0.4 mmol) in dichloromethane was added acetyl chloride (0.25 mmol). After the reaction was complete, the mixture was quenched by water (50 μL) and acetonitrile (c.a. 1 mL) was added. The mixture was then purified by reverse-phase HPLC to give the desired product, which is used in the next step without characterization. Example 117C
N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yncarbonyl}ρyπolidin-2- yl)methoxylphenyl} acetamide The Boc group was removed as described in Example 103B to give the title compound. 1H NMR (500 MHz, MeOH-d;) δ ppm 2.01 - 2.10 (m, 1 H), 2.12 - 2.19 (m, 1 H), 2.21 (s, 3 H), 2.22 - 2.44 (m, 5 H), 2.53 - 2.64 (m, 1 H), 3.61 - 3.72 (m, 2 H), 4.17 - 4.25 (m, 1 H), 4.39 - 4.46 (m, 2 H), 4.68 (dd, J=8.85, 6.10 Hz, 1 H), 4.81 - 4.84 (m, 1 H), 7.53 (s, 1 H), 7.74 (s, 1 H). MS (ESI) m/z 425 (M+H)+. Example 118 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-vncarbonyl)pyπolidin-2- ypmethoxylphenyl} acrylamide The title compound was synthesized by substituting acetyl chloride in 117B with acryloyl chloride. 1H NMR (500 MHz, MeOH- δ ppm 2.02 - 2.44 (m, 7 H),
2.54 - 2.64 (m, J=13.10, 8.42 Hz, 1 H), 3.63 - 3.72 (m, 2 H), 4.19 - 4.26 (m, 1 H), 4.42 - 4.48 (m, 2 H), 4.69 (dd, J=8.73, 6.24 Hz, 1 H), 4.84 (dd, J=7.80, 4.37 Hz, 1 H), 5.85 (dd, J=10.29, 1.56 Hz, 1 H), 6.43 (ddd, 1 H), 6.59 (dd, J=17.00, 10.14 Hz, 1 H),
7.55 (s, 1 H), 7.85 (s, 1 H). MS (ESI) m/z 437 (M+H)+.
Example 119 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yncarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.04 - 2.46 (m, 7 H), 2.55 - 2.65 (m, 1 H), 3.63 - 3.73 (m, 2 H), 4.20 - 4.29 (m, 1 H), 4.44 - 4.53 (m, 2 H), 4.70 (dd, J=8.74, 6.24 Hz, 1 H), 4.84 (dd, J=7.80, 4.37 Hz, 1 H), 7.55 (t, J=7.64 Hz, 2 H), 7.58 - 7.67 (m, 2 H), 7.78 (s, 1 H), 7.98 (d, J=7.18 Hz, 2 H). MS (ESI) m/z 487 (M+H)+.
Example 120 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-c ) δ ppm 2.02 - 2.44 (m, 7 H), 2.54 - 2.63 (m, J=13.26, 8.27 Hz, 1 H), 3.54 (s, 3 H), 3.62 - 3.71 (m, 2 H), 4.10 (s, 2 H), 4.19 - 4.26 (m, J=8.42, 4.37 Hz, 1 H), 4.41 - 4.49 (m, 2 H), 4.69 (dd, J=8.74, 6.24 Hz, 1 H), 4.84 (dd, J=7.95, 4.21 Hz, 1 H), 7.55 (s, 1 H), 8.09 (s, 1 H). MS (ESI) m/z 455 (M+H)+. Example 121 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cvanopyπolidin-l-yllcarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-d^) δ ppm 2.07 (dd, J=13.12, 8.54 Hz, 1 H), 2.12 - 2.44 (m, 7 H), 2.54 - 2.63 (m, J=13.27, 8.39 Hz, 1 H), 3.39 (s, 3 H), 3.62 - 3.65 (m, 2 H), 3.65 - 3.72 (m, 2 H), 3.78 - 3.82 (m, 2 H), 4.20 (s, 2 H), 4.21 - 4.25 (m, 1 H), 4.41 - 4.48 (m, 2 H), 4.69 (dd, J=8.70, 5.95 Hz, 1 H), 4.81 - 4.84 (m, 1 H), 7.56 (s, 1 H), 8.11 (s, 1 H). MS (ESI) m/z 499 (M+H)+.
Example 122 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-c^) δ ppm 0.89 - 0.95 (m, 2 H), 0.96 - 1.02 (m, 2 H), 1.92 - 1.99 (m, 1 H), 2.01 - 2.11 (m, 1 H), 2.12 - 2.43 (m, 6 H), 2.54 - 2.63 (m, 1 H), 3.63 - 3.71 (m, 2 H), 4.18 - 4.24 (m, 1 H), 4.39 - 4.45
(m, 2 H), 4.69 (dd, J=8.73, 6.24 Hz, 1 H), 4.84 (dd, J=7.95, 4.52 Hz, 1 H), 7.52 (s, 1 H), 7.76 (s, 1 H). MS (ESI) m/z 451(M+H)+.
Example 123 ethyl 2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbony pyπolidin- 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. 1H NMR (500 MHz, MeOH-d^ δ ppm 1.33 (t, J=7.02 Hz, 3 H), 2.07 (dd, J=13.12, 8.24 Hz, 1 H), 2.13 - 2.44 (m, 6 H), 2.54 - 2.63 (m, J=13.12, 8.24 Hz, 1 H), 3.62 - 3.71 (m, 2 H), 4.18 - 4.21 (m, 1 H), 4.24 (q, J=7.22 Hz, 2 H), 4.40 - 4.47 (m, 2 H), 4.69 (dd, J=8.70, 6.26 Hz, 1 H), 4.82 - 4.83 (m, 1 H), 7.48 (s, 1 H), 7.78 (s, 1 H). MS (ESI) m/z 455 (M+H)+.
Example 124 (2S)-l-({(2S,5R)-5-r(5-(bis(methanesulfonyl))amino-2,4- dichlorophenoxy)methyllpyπolidin-2-yl)carbonyl)pyπolidine-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. 1H NMR (500 MHz, MeOH-d^) δ ppm 2.02 - 2.12 (m, 1 H), 2.13 - 2.44 (m, 6 H), 2.59 (ddd, J=16.25, 13.20, 8.39 Hz, 1 H), 3.53 and 3.57 (s, 6 H), 3.62 - 3.72 (m, 2 H), 4.20 - 4.28 (m, J=6.87, 6.87 Hz, 1 H), 4.51 (d, J=5.80 Hz, 2 H), 4.71 (dd, J=8.70, 5.95 Hz, 1 H), 4.81 - 4.83 (m, 1 H), 7.39 (s, 1 H), 7.73 (s, 1 H). MS (ESI) m/z 539 (M+H)+.
Example 125 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-vncarbonyl>ρyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.03 (s, 2 H), 2.04 - 2.09 (m, 1 H), 2.12 - 2.43 (m, 6 H), 2.53 - 2.62 (m, J=13.12, 8.24 Hz, 1 H), 3.62 - 3.73 (m, 2 H), 4.14 - 4.25 (m, 2 H), 4.52 (s, 2 H), 4.70 (dd, J=8.70, 5.95 Hz, 1 H), 4.82 - 4.84 (m, 1 H), 6.94 (s, 1 H), 7.32 - 7.41 (m, 5 H), 7.48 (s, 1 H). MS (ESI) m/z 537(M+H)+.
Example 126 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}pyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.04 - 2.45 (m, 8 H), 2.54 - 2.64 (m, 1 H), 3.61 - 3.73 (m, 2 H), 4.22 (dd, J=8.39, 4.42 Hz, 1 H), 4.42 - 4.51 (m, 2 H), 4.68 (dd, J=8.54, 6.41 Hz, 1 H), 4.81 - 4.82 (m, 1 H), 7.06 (t, J=7.48 Hz, 1 H), 7.31 (t, J=7.93 Hz, 2 H), 7.43 - 7.51 (m, 3 H), 8.14 (s, 1 H). MS (ESI) m/z 502 (M+H)+.
Example 127
N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yncarbonyl}pyπolidin-2- yl)methoxylphenyl} -N'-(3 ,5-dimethoxyphenyl)urea The title compound was synthesized by substituting acetyl chloride in Example 107B with 3,5-dimethoxyphenylisocyanate followed by removal of the Boc group described in Example 103B. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.04 - 2.45 (m, 8 H), 2.54 - 2lό3 (m, 1 H), 3.62 - 3.73 (m, 2 H), 3.77 (s, 6 H), 3.87 (d, J=2.14 Hz, 1 H), 4.18 - 4.26 (m, 1 H), 4.43 - 4.51 (m, 2 H), 4.69 (dd, J=8.70, 6.26 Hz, 1 H), 4.80 - 4.84 (m, 1 H), 6.22 (t, J=2.14 Hz, 1 H), 6.69 (d, J=1.83 Hz, 2 H), 7.47 (s, 1 H), 8.13 (s, 1 H). MS (ESI) m/z 562 (M+H)+.
Example 128 N-{2,4-dichloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl>pyπolidin-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^ δ ppm 2.06 - 2.46 (m, 8
H), 2.55 - 2.65 (m, 1 H), 3.62 - 3.73 (m, 2 H), 4.19 - 4.27 (m, 1 H), 4.44 - 4.53 (m, 2 H), 4.69 (dd, J=8.70, 6.26 Hz, 1 H), 4.82 - 4.84 (m, 1 H), 7.50 (s, 1 H), 7.54 (t, J=8.09 Hz, 1 H), 7.65 (dd, J=7.93, 1.22 Hz, 1 H), 7.90 (dd, J=8.09, 1.37 Hz, 1 H), 8.19 (s, 1 H), 8.66 (t, J=2.14 Hz, 1 H). MS (ESI) m/z 547 (M+H)+.
Example 129 (2S)-l-({(2S,5R)-5-r(5-amino-2,4-dichlorophenoxy)methynpyπolidin-2- yl> carbonyl)pyπolidine-2-carbonitrile The Boc group in 2R-(5-amino-2,4-dichloro-phenoxymethyl)-5S-(2S-cyano- pyπolidine-l-carbonyl)-pyπolidine-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.97 - 2.07 (m, 1 H), 2.11 - 2.44 (m, 7 H), 2.51 - 2.63 (m, 1 H), 3.61 - 3.71 (m, 2 H), 4.15 - 4.23 (m, 1 H), 4.32 - 4.36 (m, 2 H), 4.69 (dd, J=8.70, 5.95 Hz, 1 H), 4.81 - 4.84 (m, 1 H), 6.61 (s, 1 H), 7.21 (s, 1 H). MS (ESI) m/z 383 (M+H)+.
Example 130 isopropyl 6-chloro-5-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yl1carbonyl>pyπolidin- 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-cyanopyπolidin-l-yl1carbonyl}pyπolidin- 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. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.39 (d, J=6.10 Hz, 6 H), 2.05 - 2.46 (m, 7 H), 2.55 - 2.65 (m, 1 H), 3.63 - 3.73 (m, 2 H), 4.23 - 4.31 (m, 1 H), 4.52 - 4.61 (m, 2 H), 4.73 (dd, J=8.70, 5.95 Hz, 1 H), 4.81 - 4.85 (m, 1 H), 5.23 - 5.32 (m, 1 H), 7.99 (d,
J=1.83 Hz, 1 H), 8.58 (d, J=1.83 Hz, 1 H). MS (ESI) m/z 421(M+H)+.
Example 131 (2S)-l-r((2S,5R)-5-{r4-chloro-3-(methylsulfonyl)ρhenoxy1methyl}ρyπolidin-2- yl)carbonyllpyrrolidine-2-carbomtrile
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 BBr3 solution (IM in CH2C12, 1.9 mL) was added slowly. The reaction was stiπed 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 Na2SO4 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+NH4)+.
Example 131 C (2S)-l-r((2S,5R)-5-{r4-chloro-3-(methylsulfonyl)phenoxylmethyl}pyπolidin-2- yl)carbonyllpyπolidine-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. !H NMR (500 MHz, MeOH-d4) δ ppm 2.02 (dd, J=13.04, 8.75 Hz, 1 H), 2.10 - 2.45 (m, 7 H), 2.61
(dd, J=13.35, 8.44 Hz, 1 H), 3.31 (overlaps with solvent peak, 3 H), 3.63 - 3.71 (m, 2 H), 4.12 - 4.23 (m, 1 H), 4.38 - 4.50 (m, 2 H), 4.71 (dd, J=9.05, 5.68 Hz, 1 H), 4.82 - 4.85 (m, J=4.30 Hz, 1 H), 7.35 (dd, J=8.59, 3.07 Hz, 1 H), 7.61 (d, J=8.59 Hz, 1 H), 7.74 (d, J=3.07 Hz, 1 H). MS (ESI) m/z 412 (M+H)+.
Example 132 (2S)-l-r((2S,5R)-5-{r2-chloro-3-(methylsulfonyl)ρhenoxylmethyl}pyπolidin-2- yl)carbonyl1pyπolidine-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 2.05 - 2.46 (m, 7 H), 2.56 - 2.66 (m, 1 H), 3.31 (overlaps with solvent peak, 3 H), 3.64 - 3.72 (m, 2 H), 4.27 (dd, J=8.29, 3.99 Hz, 1 H), 4.46 - 4.57 (m, 2 H), 4.72 (dd, J=8.59, 6.14 Hz, 1 H), 4.82 - 4.86 (m, 1
H), 7.49 - 7.54 (m, 1 H), 7.57 (t, J=7.98 Hz, 1 H), 7.79 (dd, J=7.67, 1.53 Hz, 1 H). MS (ESI) m/z 412(M+H)+.
Example 133 ethyl 3-r((2R,5S)-5-{r(2S)-2-cyanopyπolidin-l-yllcarbonyl}ρyπolidin-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. MS (DCI) m z 220 (M+NIL;)+.
Example 133B ethyl 3-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}ρyπolidin-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. 1H NMR (500 MHz, MeOH-d4) δ ppm 1.39 (t, J=7.21 Hz, 3 H), 1.97 - 2.09 (m, J=13.20, 8.59 Hz, 1 H), 2.10 - 2.45 (m, 6 H), 2.60 (ddd, J=16.65, 13.27, 8.44 Hz, 1 H), 3.62 - 3.71 (m, 2 H), 4.17 - 4.27 (m, 1 H), 4.38 (q, J=7.06 Hz, 2 H), 4.48 - 4.57 (m, 2 H),
4.71 (dd, J=8.90, 5.83 Hz, 1 H), 4.82 - 4.86 (m, 1 H), 7.54 - 7.62 (m, 1 H), 7.62 - 7.68 (m, J=7.06, 1.84 Hz, 1 H). MS (ESI) m/z 408 (M+H)+.
Example 134 3-r((2R,5S)-5-{r(2S)-2-cyanoρvπolidin-l-yncarbonyl}ρyπolidin-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+NH4)+.
Example 134B 2R-(5-tert-butoxycarbonyl-2,3-difluoro-phenoxymethyl)-5S-(2S-cyano-pyπolidine-l- carbonyl)-pyπolidine-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-cvanoρvπolidin-l-yncarbonyl}ρyπolidin-2-yl)methoxy1-4,5- difluorobenzoic acid Both Boc and tert-butyl groups were removed using procedure described in Example 103B. 1H NMR (400 MHz, MeOH-d4) δ ppm 2.03 (ddd, J=17.49, 13.20, 8.59 Hz, 1 H), 2.11 - 2.44 (m, 6 H), 2.60 (ddd, J=16.80, 13.27, 8.59 Hz, 1 H), 3.62 - 3.72 (m, 2 H), 4.17 - 4.26 (m, 1 H), 4.48 - 4.56 (m, 2 H), 4.71 (dd, J=8.90, 5.83 Hz, 1 H), 4.83 - 4.87 (m, 1 H), 7.55 - 7.62 (m, 1 H), 7.63 - 7.68 (m, J=5.37, 1.69 Hz, 1 H). MS (ESI) m/z 380 (M+H)+.
Example 135 tert-butyl 3-r((2R,5S)-5-{r(2S)-2-cyanoρyπolidin-l-yllcarbonyl}ρyπolidin-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^) δ ppm 1.59 (s, 9 H), 2.03 (ddd, J=17.18, 13.04, 8.44 Hz, 1 H), 2.11 - 2.44
(m, 6 H), 2.60 (ddd, J=16.80, 13.27, 8.59 Hz, 1 H), 3.62 - 3.72 (m, 2 H), 4.16 - 4.27
(m, 1 H), 4.48 - 4.56 (m, 2 H), 4.71 (dd, J=8.90, 5.83 Hz, 1 H), 4.83 - 4.86 (m, 1 H),
7.51 (dt, J=10.28, 6.90, 1.84 Hz, 1 H), 7.55 - 7.60 (m, 1 H). MS (ESI) m/z 436
(M+H)+.
The following additional compounds, representative of formula (I), may be prepared by one skilled in the art using known synthetic methodology or by using synthetic methodology described in the Schemes and Examples contained herein;
4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-3- methylbenzenesulfonamide;
3-bromo-4-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]benzenesulfonamide;
3-cyano-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]benzenesulfonamide; 4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-N,3- dimethylbenzenesulfonamide;
3-bromo-4-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N-methylbenzenesulfonamide;
3-cyano-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N-methylbenzenesulfonamide;
3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}ρyπolidin-2-yl)methoxy]-4- methyl-N-phenylbenzenesulfonamide; 4-chloro-3-[((2i-,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N-phenylbenzenesulfonamide;
3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- methoxy-N-phenylbenzenesulfonamide; N-({3-[((2Λ,5S)-5-{[(2S)-2-cyanQpyπolidm-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-
4-methylphenyl}sulfonyl)acetamide;
N-({4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl}sulfonyl)acetamide;
N-({3-[((2i?,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 4-methoxyphenyl} sulfonyl)acetamide;
3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- methylbenzamide;
4-bromo-3-[((2i?,5S)-5-{[(2S)-2-cyanopyrrolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]benzamide; 4-cyano-3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]benzamide;
3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-N,4- dimethylbenzamide;
4-bromo-3-[((2i?,5S)-5-{[(2S)-2-cyanopynolidin-l-yl]carbonyl}pynolidin-2- yl)methoxy]-N-methylbenzamide;
4-cyano-3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N-methylbenzamide;
3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- methyl-N-phenylbenzamide; 4-bromo-3-[((2i?,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]-N-phenylbenzamide;
4-cyano-3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N-phenylbenzamide;
N-{4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} acetamide;
N-{4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} -2-furamide;
3-[({4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} amino)carbonyl]benzoic acid; 6-[({4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]phenyl} amino)carbonyl]pyridine-2-carboxylic acid;
N-{4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl}benzenesulfonamide;
2-{4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenoxy} -2-methylpropanoic acid;
({4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]phenyl}amino)(oxo)acetic acid;
3-[((2i-,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4-
(trifluoromethyl)benzoic acid;
3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- ethoxybenzoic acid; 4-chloro-3-[((2i?,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]-N,N-dimethylbenzamide;
4-chloro-3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N-pyridin-4-ylbenzamide;
3-chloro-4-[((2i?,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]benzenesulfonamide;
4-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-3- methoxybenzenesulfonamide;
4-[((2R,5S)-5- { [(2S)-2-cyanopyπolidin- 1 -yl]carbonyl}ρyπolidin-2-yl)methoxy]-3- isopropylbenzenesulfonamide; 3-chloro-4-[((2i?,5S)-5- { [(2S -2-cyanoρyrrolidin- 1 -yl]carbonyl}pyπolidin-2- yl)methoxy]-N-methylbenzenesulfonamide;
4-[((2R,5S)-5- { [(2S)-2-cyanoρyπolidin- 1 -yl]carbonyl}pyπolidin-2-yl)methoxy]-3- methoxy-N-methylbenzenesulfonamide;
4-[((2R,5S)-5- {[(2S)-2-cyanopyπolidin- 1 -yljcarbonyl}pyπolidin-2-yl)methoxy]-3- isopropyl-N-methylbenzenesulfonamide;
3-[((2i?,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- isopropyl-N-phenylbenzenesulfonamide;
4-bromo-3-[((2i-,5S)-5- { [(2S)-2-cyanopyπolidin- 1 -yl]carbonyl}pyπolidin-2- yl)methoxy]-N-phenylbenzenesulfonamide; 4-cyano-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]-N-phenylbenzenesulfonamide;
N-({3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-
4-isopropylphenyl}sulfonyl)acetamide;
N-({4-bromo-3-[((2i-,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} sulfonyl)acetamide;
N-({4-cyano-3-[((2R,5S)-5-{[(2S)-2-cyanoρyrrolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl}sulfonyl)acetamide; 4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]benzamide;
3-[((2i-,5iS)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- methoxybenzamide; 3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2-yl)methoxy]-4- isopropylbenzamide;
4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyrrolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]-N-methylbenzamide;
3-[((2Λ,5S)-5-{[(2S -2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- methoxy-N-methylbenzamide;
3-[((2i-,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- isopropyl-N-methylbenzamide;
4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy] -N-phenylbenzamide; 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}ρyπolidin-2-yl)methoxy]-4- methoxy-N-phenylbenzamide;
3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4- isopropyl-N-phenylbenzamide;
N-{4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} -2-methoxyacetamide;
N-{4-chloro-3-[((2i-,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]phenyl}benzamide;
N-{4-chloro-3-[((2i-,5S)-5-{[(2S)-2-cyanoρyrrolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} nicotinamide; N-{4-chloro-3-[((2i-,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]phenyl}methanesulfonamide;
(2S)-l-[((2S,5R)-5-{[5-(benzylamino)-2-chlorophenoxy]methyl}pyπolidin-2- yl)carbonyl]pyπolidine-2-carbonixrile;
{4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenoxy} acetic acid;
4-({4-chloro-3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} amino)-4-oxobutanoic acid;
3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]-4-
(lH-pyrazol-3-yl)benzoic acid; 3-[((2R,5S)-5- {[(2S)-2-cyanopyπolidin- 1 -yl]carbonyl}ρyπolidin-2-yl)methoxy]-4- isopropoxybenzoic acid; and
4-chloro-3-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}ρyπolidin-2- yl)methoxy]-N-phenylbenzamide.

Claims

We Claim:
1. A compound of Formula (I)
Figure imgf000144_0001
(I), or a therapeutically acceptable salt or prodrug thereof, wherein A is selected from the group consisting of
Figure imgf000144_0002
or therapeutically suitable salt, ester or prodrug, thereof, wherein R\ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R\ and R2> 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, pyπole, thiazole, thiophene, triazine, 1,2,3-triazole or unsubstituted pyridine; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; l^t is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; with the proviso that if Rt and R2 and the carbon atoms to which they are attached form a benzene ring, then R4 is not carboxylic acid; Ra and 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; Rπ is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaR Ncarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R12 and R13 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, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole; Rι4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2ι is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, Ra bN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, 95 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl,
100 thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl,
105 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl,
110 tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R23 and R24 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-
115 dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole; R31 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,
120 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, oxazolyl,
125 pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R32 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsxilfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
130 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,
135 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R33 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
140 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,
145 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R34 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaR N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
150 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,
155 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 1 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
160 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, 165 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R42 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
170 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,
175 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; Rt3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
180 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,
185 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R44 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RgRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
190 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,
195 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,
200 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, oxazolyl,
205 pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R52 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
210 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,
215 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl5ι tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R51 and R52 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,
220 cyclopentene, cyclohexene, furan, imidazole, isothiazole, isoxazole, 1,3-dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl,
225 RaRbNsulfonyl, 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
230 consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; Re2, Rs3, R^ and R^ are each independently selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl,
235 RaRbNcarbonylalkyl, RaRbNsulfonyl, 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 240 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, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein A is selected from the group consisting of
Figure imgf000151_0001
the nitrogen of the pyridine group of A may be optionally substituted with an Noxide; provided that exactly one of u or μ is hydrogen.
2. The compound according to claim 1, wherein 250 A is
Figure imgf000151_0002
. Ri is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,
255 alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, 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,
260 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,
265 alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, 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,
270 oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RgRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaR Nsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,
275 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, oxazolyl,
280 pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; B^ is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycyano, cyanoalkyl, hydroxy,
285 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,
290 oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, alkenylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylalkylsulfonyl,
295 arylsulfonyl, arylNHC(O), alkylsulfonyl, cycloalkylcarbonyl, heteroaryl, and heteroarylcarbonyl.
3. The compound according to claim 1, wherein A is
Figure imgf000153_0001
Ri is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle,
305 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, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R2 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy,
310 RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl,
315 oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy,
320 alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
325 Rt is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the group consisting of
330 furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, alkenylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, 335 alkoxyalkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylalkylsulfonyl, arylsulfonyl, arylNHC(O), alkylsulfonyl, cycloalkylcarbonyl, heteroaryl, and heteroarylcarbonyl.
4. The compound according to claim 1, wherein
340 A is
Figure imgf000154_0001
Ri is selected from the group consisting of halo, alkoxy, cyano, alkyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylsulfonyl, heteroaryl and hydroxyalkyl, wherein the heteroaryl is pyrazolyl; 345 R2 is selected from the group consisting of hydrogen, halo and alkylsulfonyl; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, αRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, carboxy, carboxyalkoxy, alkylsulfonyl, heteroaryl and heterocycle, wherein the heteroaryl is tetrazolyl; R4 is selected from the group consisting of hydrogen, RgRbN, alkoxycarbonyl, 350 cyano, carboxy, alkylsulfonylNH and nitro; and Ra and R 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 355 heteroarylcarbonyl.
5. The compound according to claim 1, wherein A is
Figure imgf000154_0002
360 R\ and R2, 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-
365 dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyrimidine, pyπole, thiazole, thiophene, triazine, 1,2,3-triazole or unsubstituted pyridine; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRb -, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,
370 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, oxazolyl,
375 pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy cyano, cyanoalkyl, hydroxy,
380 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,
385 oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; with the proviso that if Ri and R2 and the carbon atoms to which they are attached form a benzene ring, then R4 is not carboxylic acid; and Ra and Rb are independently selected from the group consisting of hydrogen,
390 alkyl, aryl, alkenylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylalkylsulfonyl, arylsulfonyl, arylNHC(O), alkylsulfonyl, cycloalkylcarbonyl, heteroaryl, and heteroarylcarbonyl.
395 6. The compound according to claim 1, wherein A is
Figure imgf000156_0001
Ri and R2 together with the carbon atoms to which they are attached, form a
400 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, pyπole, thiazole, thiophene, triazine, 1,2,3-triazole or unsubstituted pyridine;
405 R is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the group consisting of
410 furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R_ι is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, alkoxy cyano, hydroxy, hydroxyalkyl,
415 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
420 with the proviso that if Ri and R2 and the carbon atoms to which they are attached form a benzene ring, then R4 is not carboxylic acid; and Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, alkenylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylalkylsulfonyl,
425 arylsulfonyl, arylNHC(O), alkylsulfonyl, cycloalkylcarbonyl, heteroaryl, and heteroarylcarbonyl.
7. The compound according to claim 1, wherein A is
Figure imgf000157_0001
Ri and R2, 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 435 pyridine; R3 is selected from the group consisting of hydrogen, halo, haloalkyl, R^N-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, carboxy, carboxyalkoxy, alkylsulfonyl, heteroaryl, heterocycle, wherein the heteroaryl is tetrazolyl; t is selected from the group consisting of hydrogen, RaRbN-, alkoxycarbonyl, 440 alkoxy cyano, alkylsulfonylNH and nitro; and Raand Rb 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 445 heteroarylcarbonyl.
8. The * compound according to claim 1. , wherein A is
Figure imgf000157_0002
450 Rn is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl,
455 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl,
460 thiophenyl, triazinyl and 1,2,3-triazolyl; R12 and R13 together with the carbon atoms to which they are attached, form a substimted 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,
465 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole; and Rι4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, ly^N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl,
470 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,
475 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
9. The compound according to claim 1, wherein A is
Figure imgf000158_0001
Rπ is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl,
485 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, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; Rι2 and R13 together with the carbon atoms to which they are attached, form a
490 substimted or unsubstituted heterocycle or a substimted 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, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole;
495 R1 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the
500 group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
10. The compound according to claim 1, wherein
505 A is
Figure imgf000159_0001
Rii is selected from the group consisting of halo, alkoxy, cyano and carboxy; Rι2 and R13 together with the carbon atoms to which they are attached, form a substimted or unsubstituted benzene; and 510 R14 is hydrogen.
11. The compound according to claim 1 , wherein A is
Figure imgf000159_0002
515 R21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaR N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl,
520 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,
525 thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RgRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl,
530 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl,
535 tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R 3 and R24 together with the carbon atoms to which they are attached, form a substimted or unsubstituted heterocycle or a substimted or unsubstituted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, naphthalene, furan, imidazole, isothiazole, isoxazole, 1,3-
540 dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazolyl.
12. The compound according to claim 1, wherein A is
Figure imgf000160_0001
R21 is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, 550 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, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R22 is selected from the group consisting of hydrogen, halo, haloalkyl, 555 haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
560 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R23 and R24 together with the carbon atoms to which they are attached, form a substimted or unsubstimted heterocycle or a substituted or unsubstimted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane,
565 cyclopentene, cyclohexene, naphthalene, furan, imidazole, isothiazole, isoxazole, 1,3- dioxolane, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazolyl.
13. The compound according to claim 1, wherein
570 A is
Figure imgf000161_0001
R21 is selected from the group consisting of halo and carboxy; R22 is selected from the group consisting of hydrogen and halo; and R23 and R24 together with the carbon atoms to which they are attached, form 1,3-
575 dioxolane.
14. The compound according to claim 1, wherein A is
Figure imgf000161_0002
580 R31 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, 585 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
590 R32 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl,
595 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
600 R33 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RgRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl,
605 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
610 R34 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaR N-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl,
615 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein
620 the nitrogen of the pyridine group of A may be optionally substituted with an oxide.
15. The compound according to claim 1, wherein A is
Figure imgf000163_0001
R31 is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl,
630 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, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R32 is selected from the group consisting of hydrogen, halo, haloalkyl,
635 haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
640 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R33 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl,
645 alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
650 R3 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the 655 group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide.
660 16. The compound according to claim 1, wherein A is
Figure imgf000164_0001
665 R31 is halo; R32 is hydrogen; R33 is hydrogen,; R34 is hydrogen; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an
670 oxide.
17. The compound according to claim 1, wherein A is
Figure imgf000164_0002
675 R_n is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl,
680 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,
685 pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R« is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl,
690 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl,
695 tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R« is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl,
700 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl,
705 tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; Rzj4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl,
710 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl,
715 tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of u or }4 is hydrogen.
720 18. The compound according to claim 1, wherein A is
Figure imgf000166_0001
R^ is selected from the group consisting of hydrogen, halo, haloalkyl,
725 haloalkoxy, RaRbN-, RaRbNcarbonyl, 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,
730 pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R42 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl,
735 alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl;
740 R43 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, nitro, wherein the heteroaryls are selected from the
745 group consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; I^4 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy,
750 hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, oxazolyl, pyrazinyl, pyridazinyl, 755 pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein the nitrogen of the pyridine group of A may be optionally substituted with an oxide; provided that exactly one of π or μ is hydrogen.
760 19. The compound according to claim 1, wherein A is
Figure imgf000167_0001
765 R41 is selected from the group consisting of hydrogen, halo and carboxy; t2 is hydrogen; R 3 is selected from the group consisting of hydrogen, halo, alkoxycarbonyl and carboxy; R^ is hydrogen; and wherein 770 the nitrogen of the pyridine group of A may be optionally substimted with an oxide; provided that exactly one of n or μ is hydrogen
20. The compound according to claim 1, wherein
775 A is
Figure imgf000167_0002
R51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaR Ncarbonylalkyl, RaR Nsulfonyl, alkoxy, 780 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,
785 imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R52 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl,
790 RaRbNsulfonyl, 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
795 consisting of furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R51 and R52 together with the carbon atoms to which they are attached, form a substituted or unsubstimted heterocycle or a substimted or unsubstituted aryl, heteroaryl
800 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, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl,
805 haloalkoxy, haloalkylthio, RgRbN-, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, 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,
810 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, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein the nitrogen of the pyridine group of A may be optionally substimted with an
815 oxide.
21. The compound according to claim 1, wherein A is
Figure imgf000169_0001
820 R51 is selected from the group consisting of halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, 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
825 furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; R52 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy,
830 hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl,
835 tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; or R51 and R52 together with the carbon atoms to which they are attached, form a substimted or unsubstimted heterocycle or a substimted or unsubstimted aryl, heteroaryl or cycloalkyl selected from the group consisting of benzene, cyclopentane, cyclohexane, cyclopentene, cyclohexene, furan, imidazole, isothiazole, isoxazole, 1,3-dioxolane,
840 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyπole, thiazole, thiophene, triazine and 1,2,3-triazole; R53 is selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, RaRbN-, RaRbNcarbonyl, alkoxy, alkoxycarbonyl, cyano, hydroxy, hydroxyalkyl, alkyl, alkenyl, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl,
845 alkylsulfonyl, aryl, heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, 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, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl; and wherein
850 the nitrogen of the pyridine group of A may be optionally substituted with an oxide.
22. The compound according to claim 1, wherein A is
Figure imgf000170_0001
R51 and R52 together with the carbon atoms to which they are attached, form a benzene; R53 is hydrogen.
860 23. The compound according to claim 1, wherein A is
Figure imgf000170_0002
865 Rg2, Res, Rβ and Rgs are each independently selected from the group consisting of hydrogen, halo, haloalkyl, haloalkoxy, haloalkylthio, RaRb -, RaRbNcarbonyl, RaRbNcarbonylalkyl, RaRbNsulfonyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkylthio, carboxy, carboxyalkyl, carboxyalkoxy, alkylcarbonyl, alkylsulfonyl, aryl,
870 heteroaryl, heterocycle, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, formyl, formylalkyl, nifro, 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, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyπolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl
875 and 1,2,3-triazolyl.
24. The compound according to claim 1, wherein A is
Figure imgf000171_0001
880 R62, Ra, Re4 and Res are hydrogen.
25. The compound according to claim 1, that is selected from the group consisting of 885 (2S)-l-{(5i?)-5-((2-chlorophenoxy)methyl)-L-prolyl}pyπolidine-2-carbonitrile; (2S)-l-{(5i-)-5-(naphthalen-l-yloxymethyl)-L-prolyl}-pyπolidine-2-carbonitrile; (2S)-l-{(5i?)-5-((4-cyano-2-methoxyphenoxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile; (2S)-l-{(5i-)-5-((2-cyano-4-trifluoromethylphenoxy)-methyl)-L-prolyl}- 890 pyπolidine-2-carbonitrile; (2S)-l-{(5i?)-5-((2-chloro-4-cyanophenoxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile; (25)-l-{(5i-)-5-((2-chloropyridyl-3-oxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile; 895 (2S)- 1 - {(5i-)-5-((4-carboxy-2-methoxyphenoxy)-methyl)-L-prolyl} -pyπolidine-2- carbonitrile; (2S)-l-{(5i?)-5-((4-carboxy-2-tert-butylphenoxy)-methyl)-L-prolyl}-pyπolidine- 2-carbonitrile; (2S)-l-{(5i?)-5-((4-carboxy-2-chlorophenoxy)-methyl)-L-prolyl}-pyπolidine-2- 900 carbonitrile; (2S)-l-{(5i?)-5-((4-carboxy-2-t50-propylphenoxy)-methyl)-L-prolyl}-pynolidine- 2-carbonitrile; (2S)-l-{(5i?)-5-([4-(tetrazol-5-yl)-2-chlorophenoxy]-methyl)-L-prolyl}- pyπolidine-2-carbonitrile; 905 (2S)-l-{(5i?)-5-((5-carboxy-2-chlorophenoxy)-methyl)-L-prolyl}-pyπolidine-2- carbonitrile; (2S)-l-{(5i?)-5-((5-carboxy-2-chloropyridyl-3-oxy)-methyl)-L-prolyl}- pyπolidine-2-carbonixrile; (2S)-l-{(5i?)-5-(5-carboxynaphthalen-l-yloxymethyl)-L-prolyl}-pyπolidine-2- 910 carbonitrile; (26)- 1 - {(5i-)-5-((4-carboxynaphthalen- 1 -yloxy)methyl)-L-prolyl} -pyπolidine-2- carbonitrile; (25)-l-{(5i-)-5-((5-carboxy-3-chloropyridyl-2-oxy)-methyl)-L-prolyl}- pyπolidine-2-carbonitrile;
915 (25)- 1 - {(5i-)-5-((5-carboxy-2-bromophenoxy)-methyl)-L-prolyl} -ρyπolidine-2- carbonitrile; (2S)-l-({(2S,5R)-5-[(2-methylphenoxy)methyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(2-methoxyphenoxy)methyl]pyπolidin-2-
920 yl} carbonyl)pyπolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(2,4-dichlorophenoxy)methyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile; (2S)-l-[((2S,5R)-5-{[2-bromo-4-(trifluoromethyl)phenoxy]methyl}pyπolidin-2- yl)carbonyl]pyπolidine-2-carbonitrile;
925 (2S)- 1 -( {(2S,5R)-5-[(4-bromo-2-methoxyphenoxy)methyl]pyπolidin-2- yl}carbonyl)pyrrolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(2-chloro-4-methoxyphenoxy)methyl]pyπolidin-2- yl } carbonyl)pyπolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(4-bromo-2-chlorophenoxy)methyl]pyπolidin-2-
930 yl} carbonyl)pyπolidine-2-carbonitrile; (2S)-l-[((2S,5R)-5-{[(4-chloro-l-naphthyl)oxy]methyl}pyπolidin-2- yl)carbonyl]pyπolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(quinolin-4-yloxy)methyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile;
935 (2S)-l-({(2S,5R)-5-[(quinolin-5-yloxy)methyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile; (2S)-l-[((2S,5R)-5-{[4-bromo-2-(lH-pyrazol-3-yl)phenoxy]methyl}pyπolidin-2- yl)carbonyl]pyπolidine-2 -carbonitrile; (2S)-l-({(2S,5R)-5-[(2-tert-butylphenoxy)methyl]pyπolidin-2-
940 yl} carbonyl)pyπolidine-2-carbonitrile; (2S> 1 -( {(2S, 5R)-5-[(2-tert-butyl-4-cyanophenoxy)methyl]pyπolidin-2- yl}carbonyl)ρyπolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(4-bromo-2-tert-butylphenoxy)me1hyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonixrile; 945 (2S)-l-({(2S,5R)-5-[(2-isopropylρhenoxy)methyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile; ethyl 3-tert-butyl-4-[((2R,5S)-5- {[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]benzoate; {3-tert-butyl-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolimn-l-yl]carbonyl}ρyπolidin-2- 950 yl)methoxy]phenoxy} acetic acid; (2S)-l-[((2S,5R)-5-{[2-methoxy-4-(lH-tetraazol-5- yl)phenoxy]methyl}pyπolidm-2-yl)carbonyl]pyπolidine-2-carbonitrile; 3-tert-butyl-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl}carbonyl}pyπolidin-2- yl)methoxy]benzamide; 955 (2S)-l-[((2S,5R)-5-{[2-isopropyl-4-(lH-tetraazol-5- yl)phenoxy]memyl}pyτolidm-2-yl)carbonyl]pyπolidine-2-carbonitrile; 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]pyridine-2-carboxylic acid; (2S)-l-[((2S,5R)-5-{[4-(l-tert-butyl-lH-tetraazol-5-yl)-2- 960 isopropylphenoxy]memyl}pyπolidm-2-yl)carbonyl]pyπolidme-2-carbonitrile; (2S)-l-[((2S,5R)-5-{[4-(l-tert-butyl-lH-tefraazol-5-yl)-2- cWorophenoxy]methyl}pyπolidin-2-yl)carbonyl]pyπolidine-2-carbonitrile; 5-cmoro-2-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]benzoic acid; 965 {2-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} acetic acid; 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 4-fluorobenzoic acid; 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 970 4-isopropylbenzoic acid; 2-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 1-naphthoic acid; 3-cωoro-4-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-N,N-dimethylbenzamide; 975 (2S)-l-[((2S,5R)-5-{[(2-cmoro-l-oxidopyridin-3-yl)oxy]methyl}pyπolidin-2- yl)carbonyl]pyπolidine-2-carbonitrile; (2S)-l-({(2S,5R)-5-[(2-chloro-4-mo holin-4-ylphenoxy)methyl]pyπolidin-2- yl} carbonyl)pyπolidine-2-carborιitrile; (2S)-l-({(2S,5R)-5-[(4-amino-2-chlorophenoxy)methyl]pyπolidin-2- 980 yl} carbonyl)pyπolidine-2-carbonitrile; 3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanoρyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]benzoic acid; 6-chloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]nicotinic acid 1 -oxide; 985 6-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 2-naphthoic acid; (2S)-l-[((2S,5R)-5-{[2-chloro-4-(methylsulfonyl)phenoxy]me%l}pyπolidin-2- yl)carbonyl]pyπolidine-2 -carbonitrile; (2S)-l-[((2S,5R)-5-{[4-chloro-2-(hydroxymethyl)phenoxy]methyl}pyπolidin-2- 990 yl)carbonyl]pyπolidine-2-carbonitrile; 5-chloro-6-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy] -2-naphthoic acid; (2S)-l-[((2S,5R)-5-{[(6-chloro-l,3-benzodioxol-5-yl)oxy]me l}pyπolidin-2- yl)carbonyl]pyπolidine-2 -carbonitrile; 995 N-{4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]-l-naphthyl}methanesulfonamide; (2S)- 1 -[((2S,5R)-5- { [2-bromo-4-(methylsulfonyl)phenoxy]methyl}pyπolidin-2- yl)carbonyl]pyπolidine-2-carbonixrile; (2S)-l-[((2S,5R)-5-{[(6-bromo-l,3-benzodioxol-5-yl)oxy]methyl}pyπolidin-2- 1000 yl)carbonyl]pyπolidine-2-carbonitrile; 2-cMoro-N-{3-cMoro-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidm-2-yl)memoxy]phenyl}benzenesulfonarnide; N-{3-chloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl}methanesulfonamide; 1005 N-{3-chloro-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl}acetamide; (2S)-l-({(2S,5R)-5-[(l-benzothien-4-yloxy)methyl]pyrτolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile; (2S)-l-[((2S,5R)-5-{[4-bromo-2-(methylsulfonyl)phenoxy]methyl}pyπolidin-2- 1010 yl)carbonyl]pyπolidine-2-carbonitrile; N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl} acetamide; N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl } methanesulfonamide; 1015 N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidm-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl}benzenesulfonamide; N-{3-bromo-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidm-l-yl]carbonyl}pyπolidin-2- yl)methoxy]phenyl } -2-chlorobenzenesulfonamid; methyl 2,3-dichloro-4-[((2R,5S)-5- { [(2S)-2-cyanopyπolidin- 1 - 1020 yl]carbonyl}pyπolidin-2-yl)methoxy]benzoate; 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 4-methoxybenzoic acid; 2,3-dicMoro-4-[((2R,5S)-5-{[(2S)-2-cyanopyπolidm-l-yl]carbonyl}pyπolidin-2- yl)methoxy]benzoic acid; 1025 (2S)-l-({(2S,5R)-5-[(2,4-dichloro-5-nitrophenoxy)methyl]pyπolidin-2- yl}carbonyl)pyπolidine-2-carbonitrile; tert-butyl 2,3-dichloro-4-[((2R,5S)-5- { [(2S)-2-cyanopyπolidin- 1 - yl]carbonyl}pyπolidin-2-yl)methoxy]benzoate; ethyl 4-chloro-3-[((2R,5S)-5- { [(2S)-2-cyanopyπolidin- 1 -yl]carbonyl}pyπolidin- 1030 2-yl)methoxy]benzoate; isopropyl 4-chloro-3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]benzoate; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}acetamide; 1035 N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}acrylamide; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}benzamide; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- 1040 yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl} -2-methoxyacetamide; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidm-2-yl)methoxy]phenyl}-2-(2-mexhoxyethoxy)acetamide; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}cyclopropanecarboxamide; 1045 ethyl 2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenylcarbamate; &w-[N-{2,4-dichloro-5-[((2i?,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}]methanesulfonamide; Ν-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- 1050 yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl} - 1 -phenylmethanesulfonamide; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}-N'-phenylurea; N-{2,4-dichloro-5-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l- yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}-N'-(3,5-dimethoxyphenyl)urea; 1055 N- {2,4-dichloro-5-[((2R,5S)-5- {[(2S)-2-cyanopyπolidin-l - yl]carbonyl}pyπolidin-2-yl)methoxy]phenyl}-N,-(4-nitrophenyl)urea; (2S)-l-({(2S,5R)-5-[(5-amino-2,4-dichloroρhenoxy)methyl]pyπolidin-2- yl} carbonyl)pyπolidine-2-carbonitrile; isopropyl 6-chloro-5-[((2R,5S)-5- { [(2S)-2-cyanopyπolidin- 1 - 1060 yl]carbonyl}pyπolidin-2-yl)methoxy]nicotinate; (2S)-l-[((2S,5R)-5-{[2-chloro-3-(methylsulfonyl)phenoxy]methyl}pyπolidin-2- yl)carbonyl]ρyπolidine-2-carbonitrile; ethyl 3-[((2R,5S)-5- {[(2S)-2-cyanopyπolidin-l -yl]carbonyl}pyπolidin-2- yl)methoxy]-4,5-difluorobenzoate; I "
1065 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyπolidin-2-yl)methoxy]- 4,5-difluorobenzoic acid; and tert-butyl 3-[((2R,5S)-5-{[(2S)-2-cyanopyπolidin-l-yl]carbonyl}pyrrolidin-2- yl)methoxy]-4,5-difluorobenzoate.
1070 26. A method of treating diabetes, comprising administering of a therapeutically effective amount of a compound of formula (I).
27. A method of treating type II diabetes, comprising administering of a therapeutically effective amount of a compound of formula (I).
1075 28. A method of treating hyperglycemia, comprising administering of a therapeutically effective amount of a compound of formula (I).
29. A method of treating Syndrome X, comprising administering of a therapeutically 1080 effective amount of a compound of formula (I) .
30. A method of treating hyperinsulinemia, comprising administering of a therapeutically effective amount of a compound of formula (I).
1085 31. A method of treating β-cell failure, comprising administering of a therapeutically effective amount of a compound of formula (I).
32. A method of treating obesity, comprising administering of a therapeutically effective amount of a compound of formula (I).
1090 33. A method of treating satiety disorders, comprising aάrninistering of a therapeutically effective amount of a compound of formula (I).
34. A pharmaceutical composition comprising a therapeutically effective amount of a 1095 compound of formula (I) and a pharmaceutically suitable carrier.
35. A method of treating inflammatory bowel syndrome, including Crohn's disease and ulcerative colitis, comprising aclπiinistration of a therapeutically effective amount of a compound of formula (I).
1100
36. A method of treating short bowel disease, comprising adtninistration of a therapeutically effective amount of a compound of formula (I).
37. A method of increasing bone maπow transplant efficiency, comprising
1105 administration of a therapeutically effective amount of a compound of formula (I).
38. 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).
1110
PCT/US2004/028886 2003-09-04 2004-09-07 Pyrrolidine-2-carbonitrile derivatives and their use as inhibitors of dipeptidyl peptidase-iv (dpp-iv) WO2005023762A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65542803A 2003-09-04 2003-09-04
US10/655,428 2003-09-04

Publications (1)

Publication Number Publication Date
WO2005023762A1 true WO2005023762A1 (en) 2005-03-17

Family

ID=34273460

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/028886 WO2005023762A1 (en) 2003-09-04 2004-09-07 Pyrrolidine-2-carbonitrile derivatives and their use as inhibitors of dipeptidyl peptidase-iv (dpp-iv)

Country Status (1)

Country Link
WO (1) WO2005023762A1 (en)

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006040625A1 (en) 2004-10-12 2006-04-20 Glenmark Pharmaceuticals S.A. Novel dipeptidyl peptidase iv inhibitors, pharmaceutical compositions containing them, and process for their preparation
US7230002B2 (en) 2004-02-03 2007-06-12 Glenmark Pharmaceuticals Ltd. Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
WO2007120702A2 (en) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
US7291618B2 (en) 2004-05-12 2007-11-06 Pfizer Inc Therapeutic compounds
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
JP2009057299A (en) * 2007-08-30 2009-03-19 Nippon Soda Co Ltd Substituted phenoxyazabicyclooctane derivative and method for producing the same
EP2116235A1 (en) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
US7838525B2 (en) 2003-07-11 2010-11-23 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
TWI385171B (en) * 2009-03-13 2013-02-11 Pyrrolidine compounds
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
CN110294748A (en) * 2019-07-25 2019-10-01 浙江沙星科技有限公司 A kind of synthetic method for Ge Lieting key intermediate
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10633384B2 (en) 2012-06-13 2020-04-28 Hoffmann-La Roche Inc. Diazaspirocycloalkane and azaspirocycloalkane
US10640472B2 (en) 2015-09-04 2020-05-05 Hoffman-La Roche Inc. Phenoxymethyl derivatives
US10647719B2 (en) 2015-09-24 2020-05-12 Hoffmann-La Roche Inc. Bicyclic compounds as dual ATX/CA inhibitors
US10654857B2 (en) 2014-03-26 2020-05-19 Hoffman-La Roche Inc. Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
US10669268B2 (en) 2012-09-25 2020-06-02 Hoffmann-La Roche Inc. Bicyclic derivatives
US10669285B2 (en) 2014-03-26 2020-06-02 Hoffmann-La Roche Inc. Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
US10676446B2 (en) 2015-04-10 2020-06-09 Hoffmann-La Roche Inc. Bicyclic quinazolinone derivatives
US10738053B2 (en) 2015-09-24 2020-08-11 Hoffmann-La Roche Inc. Bicyclic compounds as dual ATX/CA inhibitors
US10787459B2 (en) 2015-09-24 2020-09-29 Hoffmann-La Roche Inc. Bicyclic compounds as ATX inhibitors
US10800786B2 (en) 2015-09-24 2020-10-13 Hoffman-La Roche Inc. Bicyclic compounds as ATX inhibitors
US10849881B2 (en) 2013-11-26 2020-12-01 Hoffmann-La Roche Inc. Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl
US10882857B2 (en) 2017-03-16 2021-01-05 Hoffmann-La Roche Inc. Bicyclic compounds as ATX inhibitors
US10913745B2 (en) 2013-03-12 2021-02-09 Hoffmann-La Roche Inc. Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11059794B2 (en) 2017-03-16 2021-07-13 Hoffmann-La Roche Inc. Heterocyclic compounds useful as dual ATX/CA inhibitors
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096295A2 (en) * 2000-06-13 2001-12-20 Novartis Ag 2-cyanopyrrolidine derivatives and their use as medicaments
WO2004016587A1 (en) * 2002-08-19 2004-02-26 Ono Pharmaceutical Co., Ltd. Nitrogen-containing compounds
WO2004026822A2 (en) * 2002-09-19 2004-04-01 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-iv (dpp-iv)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096295A2 (en) * 2000-06-13 2001-12-20 Novartis Ag 2-cyanopyrrolidine derivatives and their use as medicaments
WO2004016587A1 (en) * 2002-08-19 2004-02-26 Ono Pharmaceutical Co., Ltd. Nitrogen-containing compounds
WO2004026822A2 (en) * 2002-09-19 2004-04-01 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-iv (dpp-iv)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ASHWORTH D M ET AL: "2-Cyanopyrrolidides as potent, stable inhibitors of dipeptidyl peptidase IV", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 6, no. 10, 21 May 1996 (1996-05-21), pages 1163 - 1166, XP004134889, ISSN: 0960-894X *
VILLHAUER E B ET AL: "1-ÄÄ(3-HYDROXY-1-ADAMANTYL)AMINOÜACETYLÜ-2-CYANO-(S)-PYRROLIDINE: A POTENT, SELECTIVE, AND ORALLY BIOAVAILABLE DIPEPTIDYL PEPTIDASE IV INHIBITOR WITH ANTIHYPERGLYCEMIC PROPERTIES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 46, no. 13, 24 May 2003 (2003-05-24), pages 2774 - 2789, XP001165747, ISSN: 0022-2623 *

Cited By (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US8546429B2 (en) 2003-07-11 2013-10-01 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7838525B2 (en) 2003-07-11 2010-11-23 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7230002B2 (en) 2004-02-03 2007-06-12 Glenmark Pharmaceuticals Ltd. Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
US7291618B2 (en) 2004-05-12 2007-11-06 Pfizer Inc Therapeutic compounds
US7465732B2 (en) 2004-05-12 2008-12-16 Pfizer Inc (2S,4S)-4-(piperazin-1-yl)pyrrolidine-2-methanone derivatives
WO2006040625A1 (en) 2004-10-12 2006-04-20 Glenmark Pharmaceuticals S.A. Novel dipeptidyl peptidase iv inhibitors, pharmaceutical compositions containing them, and process for their preparation
US7205323B2 (en) 2004-10-12 2007-04-17 Glenmark Pharmaceuticals S.A. Dipeptidyl peptidase IV inhibitors pharmaceutical compositions containing them, and process for their preparation
US7524844B2 (en) 2004-10-12 2009-04-28 Glenmark Pharmaceuticals S.A. Dipeptidyl peptidase IV inhibitors, process for their preparation and compositions containing them
US7538128B2 (en) 2004-10-12 2009-05-26 Glenmark Pharmaceuticals S.A. Dipeptidyl peptidase IV inhibitors, process for their preparation and compositions containing them
EP2116235A1 (en) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
EP2253311A2 (en) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto
WO2007120702A2 (en) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
JP2009057299A (en) * 2007-08-30 2009-03-19 Nippon Soda Co Ltd Substituted phenoxyazabicyclooctane derivative and method for producing the same
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
TWI385171B (en) * 2009-03-13 2013-02-11 Pyrrolidine compounds
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
EP3323818A1 (en) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
EP3243385A1 (en) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US10633384B2 (en) 2012-06-13 2020-04-28 Hoffmann-La Roche Inc. Diazaspirocycloalkane and azaspirocycloalkane
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US10669268B2 (en) 2012-09-25 2020-06-02 Hoffmann-La Roche Inc. Bicyclic derivatives
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10913745B2 (en) 2013-03-12 2021-02-09 Hoffmann-La Roche Inc. Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US10849881B2 (en) 2013-11-26 2020-12-01 Hoffmann-La Roche Inc. Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl
US10654857B2 (en) 2014-03-26 2020-05-19 Hoffman-La Roche Inc. Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
US10669285B2 (en) 2014-03-26 2020-06-02 Hoffmann-La Roche Inc. Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
US11098048B2 (en) 2014-03-26 2021-08-24 Hoffmann-La Roche Inc. Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10676446B2 (en) 2015-04-10 2020-06-09 Hoffmann-La Roche Inc. Bicyclic quinazolinone derivatives
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US10640472B2 (en) 2015-09-04 2020-05-05 Hoffman-La Roche Inc. Phenoxymethyl derivatives
US11352330B2 (en) 2015-09-04 2022-06-07 Hoffmann-La Roche Inc. Phenoxymethyl derivatives
US10647719B2 (en) 2015-09-24 2020-05-12 Hoffmann-La Roche Inc. Bicyclic compounds as dual ATX/CA inhibitors
US10738053B2 (en) 2015-09-24 2020-08-11 Hoffmann-La Roche Inc. Bicyclic compounds as dual ATX/CA inhibitors
US10889588B2 (en) 2015-09-24 2021-01-12 Hoffmann-La Roche Inc. Bicyclic compounds as dual ATX/CA inhibitors
US10800786B2 (en) 2015-09-24 2020-10-13 Hoffman-La Roche Inc. Bicyclic compounds as ATX inhibitors
US10787459B2 (en) 2015-09-24 2020-09-29 Hoffmann-La Roche Inc. Bicyclic compounds as ATX inhibitors
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11059794B2 (en) 2017-03-16 2021-07-13 Hoffmann-La Roche Inc. Heterocyclic compounds useful as dual ATX/CA inhibitors
US10882857B2 (en) 2017-03-16 2021-01-05 Hoffmann-La Roche Inc. Bicyclic compounds as ATX inhibitors
US11673888B2 (en) 2017-03-16 2023-06-13 Hoffmann-La Roche Inc. Bicyclic compounds as ATX inhibitors
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
CN110294748A (en) * 2019-07-25 2019-10-01 浙江沙星科技有限公司 A kind of synthetic method for Ge Lieting key intermediate

Similar Documents

Publication Publication Date Title
WO2005023762A1 (en) Pyrrolidine-2-carbonitrile derivatives and their use as inhibitors of dipeptidyl peptidase-iv (dpp-iv)
US7205409B2 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US8119664B2 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20040121964A1 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
CA2497725C (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-iv (dpp-iv)
US7238724B2 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
EP1406872B1 (en) Dipeptidyl peptidase inhibitors for the treatment of diabetes
US7834012B2 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US7671076B2 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
CA2493339A1 (en) 2-cyano-4-fluoropyrrolidine derivative or salt thereof
AU2002344820A1 (en) Dipeptidyl peptidase inhibitors for the treatment of diabetes
EP1385508A1 (en) Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20050215603A1 (en) Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20070238753A1 (en) Pharmaceutical Compositions as Inhibitors of Dipeptidyl Peptidase-IV (DPP-IV)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application