WO2010011917A1 - SEH AND 11β-HSD1 DUAL INHIBITORS - Google Patents

SEH AND 11β-HSD1 DUAL INHIBITORS Download PDF

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WO2010011917A1
WO2010011917A1 PCT/US2009/051678 US2009051678W WO2010011917A1 WO 2010011917 A1 WO2010011917 A1 WO 2010011917A1 US 2009051678 W US2009051678 W US 2009051678W WO 2010011917 A1 WO2010011917 A1 WO 2010011917A1
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Prior art keywords
methyl
phenyl
trifluoromethyl
triazol
oct
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PCT/US2009/051678
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French (fr)
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WO2010011917A8 (en
Inventor
Joseph Paul Marino
Carl A. Brooks
Patrick Eidam
John Jeffrey Mcatee
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Glaxosmithkline Llc
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Publication of WO2010011917A1 publication Critical patent/WO2010011917A1/en
Publication of WO2010011917A8 publication Critical patent/WO2010011917A8/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the invention is directed to bicycle[2.2.2]oct-1-yl compounds, pharmaceutical compositions containing them and their use in the treatment of a variety of conditions mediated by the sEH enzyme and/or the 1 1 ⁇ -HSD1 enzyme.
  • Epoxide functional groups may be found in drugs, xenobiotic materials, and endogenous biomolecules.
  • Epoxide hydrolases found in both plants and animals, are enzymes that convert epoxides to diols by hydrolysis.
  • soluble epoxide hydrolase (“sEH") is primarily responsible for the metabolism of arachidonic acid derivatives known as epoxyeicosatrienoic acids ("EETs").
  • EETs epoxyeicosatrienoic acids
  • DHETs dihydroxyeicosatrienoic acids
  • microsomal epoxide hydrolase catalyzes the hydrolysis of a broad range of epoxide substrates including carcinogenic polycyclic aromatic hydrocarbons and reactive epoxides, thus it provides an important detoxification pathway.
  • Polymorphisms in mEH may lead to differences in bioactivation of pro-carcinogens and several human epidemiological studies suggest that mEH genotype is associated with altered cancer risk. Fretland & Omiecinski, Chemico-Biol. Int., 129, 41-59, 2000.
  • EET levels are protective in numerous disorders including hypertension [Ce// Biochem Biophys., 47, 87-98, 2007], heart failure [Xu et al., Proc. Natl Acad. Sc/._l/.S.A,103, 18733-18738, 2006], renal dysfunction / end organ damage [Zhao et al., J. Am. Soc. Nephrol., 15, 1244-1253, 2004; Imig et al., Hypertension, 46, 975-981 , 2005], stroke [Koerner et al., J.
  • 11 beta-hvdroxysteroid dehydrogenase type 1 11 beta-hydroxysteroid dehydrogenase type 1 (“11 ⁇ -HSD1") is an intracellular enzyme that converts inactive glucocorticoids (e.g. cortisone) to active glucocorticoids (e.g. Cortisol).
  • glucocorticoids activate both glucocorticoid receptors and mineralocorticoid receptors in multiple tissues they can affect endocrine, metabolic, cardiovascular, and immune function. See E.g.
  • 11 ⁇ -HSD2 is highly expressed in epithelial tissues and protects the mineralocorticoid receptor from active glucocorticoids (Draper et al., J Endo, 186, 251-271 , 2005). Mutations in the gene that encodes 11 ⁇ -HSD2 cause a decrease in 11 ⁇ -HSD2 activity and are associated with hypertension and metabolic disorders in humans (White et al., Endocr Rev 18, 135-156, 1997).
  • the invention is directed to bicycle[2.2.2]oct-1-yl compounds. Specifically, the invention is directed to compounds according to Formula I and pharmaceutically acceptable salts thereof:
  • the compounds of the invention are sEH and 1 1 ⁇ -HSD1 dual inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme or the 1 1 ⁇ -HSD1 enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH or 11 ⁇ -HSD1 and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • this invention provides for the use of the compounds of
  • the compounds of this invention may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of may be administered alone or in conjunction with one or more other therapeutic agents, eg.
  • agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and ⁇ -
  • ACE angiotensin converting enzyme
  • the invention is directed to compounds according to Formula (I):
  • A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four or five Ri groups;
  • Ri is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc,
  • R 2 and R 3 are independently hydrogen or C 1-3 alkyl; m is O, 1 or 2;
  • R 4 and R 5 are independently hydrogen or C 1-6 alkyl;
  • R 6 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
  • n is 1 or 2;
  • x is 0 - 5;
  • R ⁇ is phenyl unsubstituted or substituted by one to five substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O 2 )Ra, SRb, S(O 2 )Ra, and S(O 2 )NRcRc;
  • R 8 and R 9 are hydrogen or methyl, provided only one may be methyl; each Ra is independently Ci -6 alkyl or Ci -6 haloalkyl; each Rb is independently H, Ci -6 alkyl or Ci -6 haloalkyl; and each Rc is independently H or Ci -6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • C1-C8 alkyl refers to an alkyl group having from 1 to 8 member atoms.
  • Alkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • Cycloalkyl refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms.
  • C 3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms.
  • Unsaturated Cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically pure refers to products whose enantiomeric excess is 99% ee or greater.
  • Hydrof-life refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
  • Halo refers to the halogen radical fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an alkyl group that is substituted with one or more halo substituents. Haloalkyl includes trifluoromethyl.
  • Member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
  • compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • suitable acids include pharmaceutically acceptable inorganic acids and organic acids.
  • Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
  • the compounds according to Formula I may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
  • compounds according to Formula I may contain an acidic functional group and are therefore capable of forming pharmaceutically-acceptable base addition salts by treatment with a suitable base.
  • compounds according to Formula I may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid.
  • pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula.
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the term "compounds of the invention” means both the compounds according to Formula I and the pharmaceutically-acceptable salts thereof.
  • a compound of the invention also appears herein and refers to both a compound according to Formula I and its pharmaceutically-acceptable salts.
  • compounds of the invention can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof.
  • pharmaceutically-acceptable solvates of a compound of the invention may be formed wherein solvent molecules are incorporated into the solid-state structure during crystallization.
  • Solvates may involve water or nonaqueous solvents, or mixtures thereof.
  • the solvent content of such solvates can vary in response to environment and upon storage. For example, water may displace another solvent over time depending on relative humidity and temperature.
  • Solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "hydrates.”
  • Solvates wherein more than one solvent is incorporated into the solid-state structure are typically referred to as “mixed solvates”.
  • Solvates include "stoichiometric solvates” as well as compositions containing variable amounts of solvent (referred to as “non-stoichiometric solvates”).
  • Stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as “stoichiometric hydrates", and non-stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as “non-stoichiometric hydrates”.
  • the invention includes both stoichiometric and non- stoichiometric solvates.
  • crystalline forms of a compound of the invention may contain solvent molecules, which are not incorporated into the solid-state structure.
  • solvent molecules may become trapped in the crystals upon isolation.
  • solvent molecules may be retained on the surface of the crystals.
  • the invention includes such forms.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline packing arrangements). These different crystalline forms are typically known as “polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different IR spectra and X-ray powder diffraction patterns, which may be used for identification. Polymorphs may also exhibit different melting points, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in the production of different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four or five R 1 groups;
  • R 1 is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O 2 )Ra, SRb, S(O 2 )Ra, S(O 2 )NRcRc, piperdinyl, pyrrolidinyl, morpholinyl, and phenyl; R 2 and R 3 are independently hydrogen or C 1-3 alkyl; m is O, 1 or 2; X is
  • R 4 and R 5 are independently hydrogen or C 1-6 alkyl
  • R 6 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; n is 1 or 2; x is O - 5;
  • R 7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc,
  • Re and Rg are hydrogen or methyl, provided only one may be methyl; each Ra is independently C 1-6 alkyl or C 1-6 haloalkyl; each Rb is independently H, C 1-6 alkyl or C 1-6 haloalkyl; and each Rc is independently H or C 1-6 alkyl.
  • A is phenyl which is or substituted by one or two R 1 groups;
  • R 1 is selected from the group consisting of: halo, Ra, and ORb,;
  • R 2 and R 3 are hydrogen;
  • m is O or 1 ;
  • X is
  • R 4 and R 5 are hydrogen;
  • R 6 is C 1-6 alkyl; n is 1 ;
  • R 7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O 2 )Ra, SRb, S(O 2 )Ra, and S(O 2 )NRcRc;
  • R 8 and R 9 are hydrogen; each Ra is independently Ci -6 alkyl or Ci -6 haloalkyl;
  • each Rb is independently H, Ci -6 alkyl or Ci -6 haloalkyl; and each Rc is independently H or Ci -6 alkyl.
  • Suitable protecting groups and methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Scheme 1 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 1.7).
  • Compounds such as 1.2 were prepared from a requisite amide, such as 1.1, and a tetrazole. Hydrolysis of intermediate 1.2 with an aqueous base provides intermediate 1.3. Treatment of intermediate 1.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (1.4). Nitrile 1.5 was then formed by treatment of the amide 1.4 with TFAA. The nitrile was then reduced to the primary amine 1.6. Finally, ureas such as 1.7 were formed by condensing the amine 1.6 with an isocyanate.
  • Scheme 2 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.7).
  • Compounds such as 2.2 were prepared from a requisite amide, such as 2.1, and a tetrazole. Hydrolysis of intermediate
  • intermediate 2.3 Treatment of intermediate 2.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (2.4). Nitrile 2.5 was then formed by treatment of the amide 2.4 with TFAA. The nitrile was then reduced to the primary amine 2.6. Finally, ureas such as 2.7 were formed by condensing the amine 2.6 with an isocyanate, which was formed in situ from triphosgene and an appropriate amine.
  • Scheme 3 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 3.7).
  • Compounds such as 3.2 were prepared from a requisite amide, such as 3.1, and a tetrazole. Reduction of methylester
  • intermediate 3.3 Treatment of intermediate 3.3 with sulfonylchloride and a trialkylamine base furnished the desired mesylate (3.4). Displacement of the mesylate with a nitrile was accomplished using sodium cyanide to provide the desired nitrile 3.5. The nitrile was then hydrolyzed to the carboxylic acid 3.6 using aqueous acid. Finally, amides such as 3.7 were formed by treatment of acid 3.6 with an amine, a trialkylamine base and a coupling reagent such as BOP.
  • Scheme 4 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 4.7).
  • Compounds such as 4.2 were prepared from a requisite amide, such as 4.1, and a tetrazole. Hydrolysis of intermediate
  • intermediate 4.2 with an aqueous base provides intermediate 4.3.
  • Nitrile 4.5 was then formed by treatment of the amide 4.4 with TFAA. The nitrile was then reduced to the primary amine 4.6.
  • amides such as 4.7 were formed by treatment of amine 4.6 with a carboxylic acid, a trialkylamine base and a coupling reagent such as BOP.
  • the naming program used is ACD Name Pro 6.02.
  • BOP is an abbreviation for (Benzotriazol-i-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate
  • 0 C is an abbreviation for degrees Celsius
  • HATU is an abbreviation for Dimethylsulfoxide
  • L is an abbreviation for liter or liters
  • LC-MS is an abbreviation for Liquid chromatography-Mass spectrometry
  • mmol is an abbreviation for millimole or millimolar
  • N is an abbreviation for Normal and refers to the number of equivalents of reagent per liter of solution
  • Ph is an abbreviation for phenyl
  • St is an abbreviation for saturated
  • THF trifluoroacetic acid
  • THF tetrahydrofuran
  • Intermediate 1 Methyl 4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl ⁇ bicyclo[2.2.2]octane-1 -carboxylate
  • Hexafluorophosphate (1.079 g, 2.440 mmol) were added and the resultant mixture was stirred for 30 minutes.
  • the reaction mixture was concentrated to 20% original volume and then partitioned between water and dichloromethane. The layers were separated and the aqueous extracted twice more. The combined organic layers were washed with 2 x water, brine and concentrated in vacuo to afford a red oil.
  • the oil was purified by 2 x 2Og SCX SPE. 4 Volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions combined and concentrated to afford the title compound as a light orange solid. (750mg, 1.982 mmol, 97 % yield)
  • Example 6 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ).
  • Example 7 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ). (24 mg, 0.033 mmol, 8 % yield)
  • Example 9 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
  • Example 10 was prepared using the general procedure similar to that described above in
  • Example 11 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ). (27mg, 0.041 mmol, 19 % yield)
  • Example 12 was prepared using the general procedure similar to that described above in
  • Example 13 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ). (58mg, 0.085 mmol, 39 % yield)
  • Example 14 was prepared using the general procedure similar to that described above in
  • Example 15 was prepared using the general procedure similar to that described above in
  • Example 16 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
  • Example 17 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
  • Example 20 was prepared using the general procedure similar to that described above in
  • Example 22 was prepared using the general procedure similar to that described above in
  • Example 25 was prepared using the general procedure similar to that described above in
  • Example 26 was prepared using the general procedure similar to that described above in
  • Example 27 was prepared using the general procedure similar to that described above in
  • Example 28 was prepared using the general procedure similar to that described above in
  • Example 29 was prepared using the general procedure similar to that described above in
  • Example 30 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of ⁇ [2- (trifluoromethyl)phenyl]methyl ⁇ amine (Scheme 2).
  • Example 31 was prepared using the general procedure similar to that described above in
  • Example 32 was prepared using the general procedure similar to that described above in
  • Example 33 was prepared using the general procedure similar to that described above in
  • Example 34 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of ⁇ [2- (trifluoromethyl)phenyl]methyl ⁇ amine (Scheme 2). (23mg, 0.030 mmol, 1 1 % yield)
  • Example 35 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of ⁇ [2- (trifluoromethyl)phenyl]methyl ⁇ amine (Scheme 2). (37mg, 0.052 mmol, 19 % yield)
  • Example 36 was prepared using the general procedure similar to that described above in
  • Example 37 was prepared using the general procedure similar to that described above in
  • Example 38 was prepared using the general procedure similar to that described above in
  • Example 39 was prepared using the general procedure similar to that described above in
  • Example 40 was prepared using the general procedure similar to that described above in
  • Example 48 2-(4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl ⁇ bicyclo[2.2.2]oct-1 - yl)- ⁇ /-(phenylmethyl)acetamide
  • Example 48 was prepared using the general procedure similar to that described above in
  • Example 49 was prepared using the general procedure described above in Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
  • Example 50 was prepared using the general procedure similar to that described above in
  • Example 52 was prepared using the general procedure similar to that described above in
  • Example 54 ⁇ /-[(2-chloro-4-cyanophenyl)methyl]-2-(4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl ⁇ bicyclo[2.2.2]oct-1 -yl)acetamide
  • Example 54 was prepared using the general procedure similar to that described above in
  • Example 56 was prepared using the general procedure similar to that described above in
  • Example 62 ⁇ /-[(4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl ⁇ bicyclo[2.2.2]oct-1 - yl)methyl]-W-[2-(trifluoromethyl)phenyl]urea
  • the compounds according to Formula I are sEH inhibitors and 11 ⁇ -HSD1 inhibitors.
  • the compounds according to Formula I therefore, are useful in the treatment of conditions involving sEH activity and/or 1 1 ⁇ -HSD1 activity.
  • the biological activity of the compounds according to Formula I against sEH, mEH, 1 1 ⁇ -HSD1 and / or 11 ⁇ -HSD2 can be determined using any suitable assay for determining the relevant activity of a candidate compound, as well as suitable tissue and / or in vivo models. Suitable assays for determining sEH, mEH, 1 1 ⁇ -HSD1 and 1 1 ⁇ -HSD2 inhibitory activity are provided below.
  • the compounds according to Formula I are sEH inhibitors and 11 ⁇ -HSD1 inhibitors.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 0,000 nM and an IC 50 against 1 1 ⁇ -HSD1 from 0.1 nM to 10,000 nM.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC 50 against sEH from 0.1 nM to 1 ,000 nM and an IC 50 against 1 1 ⁇ - HSD1 from 0.1 nM to 1 ,000 nM.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC 50 against sEH from 0.1 nM to 100 nM and an IC 50 against 11 ⁇ -HSD1 from 0.1 nM to 100 nM.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 10 nM and an IC50 against 1 1 ⁇ -HSD1 from 0.1 nM to 10 nM.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) equal to or greater than 10:1 for sEH over mEH.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) equal to or greater than 100:1 for sEH over mEH.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) equal to or greater than 1000:1 for sEH over mEH.
  • 1 1 ⁇ -HSD2 catalyzes the conversion of active glucocorticoids to an inactive form in mammals.
  • Compounds that exhibit pharmacological selectivity for 11 ⁇ -HSD1 over 11 ⁇ -HSD2 therefore are desirable in the methods of treatment described below.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) equal to or greater than 10:1 for 11 ⁇ -HSD1 over 11 ⁇ -HSD2.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) equal to or greater than 100:1 for 11 ⁇ -HSD1 over 11 ⁇ -HSD2. In another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) equal to or greater than 1000:1 for 11 ⁇ -HSD1 over 11 ⁇ -HSD2.
  • Inhibition of sEH or mEH activity can be measured in a fluorescent assay based upon the format described by Wolf et al. (Analytical Biochemistry Vol. 355 (2006) pp. 71- 80).
  • PHOME (3-Phenyl-oxiranyl)-acetic acid cyano-(6- methoxy-naphthalen-2-yl)-methyl ester
  • Production of 6-methoxy-2-naphthaldehyde is monitored at excitation of 360 nm and an emission of 465 nm.
  • the assay is used in a quenched assay format by sequentially adding enzyme (5 ⁇ L; 200 pM sEH or 150 nM mEH in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v); 10 minute ambient pre-incubation after addition) then PHOME substrate (5 ⁇ L; 10 uM PHOME substrate in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v)) to a 384 well assay plate (Greiner 784076) pre-stamped with 25-100 nl_ compound at the desired concentration.
  • enzyme 5 ⁇ L; 200 pM sEH or 150 nM mEH in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v); 10 minute ambient pre-incubation after addition
  • PHOME substrate 5 ⁇ L; 10 u
  • the reaction is incubated for 30 minutes (sEH assay) or 60 minutes (mEH assay) at room temperature, then quenched by the addition of stop solution (5 ⁇ L; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water.
  • Stop solution 5 ⁇ L; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water.
  • Microtiter plates are centrifuged after each addition for 30 seconds at 500 rpm.
  • the fluorescence is measured on an EnVision plate reader platform (Perkin Elmer) using a 360 nm excitation filter, 460 nm emission filter, and 400 nm dichroic filter.
  • Compounds are first prepared in neat DMSO at a concentration of 10 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 50 ⁇ M-0.8 nM or 25 ⁇ M-0.42 nM or 2.5 ⁇ M to 42 pM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values. Cell-based sEH inhibitor assay Cell based sEH inhibition is measured using the 14,15-DHET immunoassay ELISA kit available from Detroit R&D (Cat. No. DH1 ), according to the following procedure:
  • sample dilution buffer ex. Add 220 ⁇ l_
  • Inhibition of 1 1 ⁇ -HSD1 activity can be measured in a scintillation proximity assay (SPA) based format described by Mundt et al. (ASSAY and Drug Development Technologies Vol. 3 No. 4 (2005) pp. 367-375).
  • the assay measures the ⁇ -NADPH dependent reductase activity of Human 1 1 ⁇ -HSD1 upon cortisone substrate to yield the active glucocorticoid Cortisol.
  • Microsomal membranes are prepared from frozen cell pellets of Super 9 (in-house generated variant of Sf9 insect cells) infected for approximately 72 hours with baculovirus encoding for human 11 B-HSD1.
  • the homogenate is centrifuged at 600xg for 10 minutes at 4 0 C; the supernatant from this spin is transferred to ultracentrifuge tubes which are spun at 100000xg for one hour at 4 0 C.
  • the cell pellet is resuspended in ice-cold 4OmM phosphate buffer, pH7.5 with 5% glycerol and 1 mM EDTA, aliquoted, and stored at -8O 0 C.
  • the total protein recovered is determined with commercial protein assay kit using bovine albumin as the standard.
  • Assays are initiated by incubating 0.5 ⁇ l_ of compound sample in the presence of 15 ugs/mL of Sf9 microsomes, 1 mM ⁇ -NADPH, and 16 nM [ 3 H]cortisone ([S]/K m ⁇ 10) in buffer containing 50 mM HEPES, 100 mM KCI, 5 mM NaCI, 2 mM MgCI 2 , 0.02% Brij-35 (w/v) pH 7.4 in a reaction volume of 50 ⁇ l_.
  • the assay is incubated for 3 hours at 37 °C before quenching the reaction with 25 ⁇ l_ of 10 ⁇ M 18 ⁇ -glycyrrhetinic acid, a potent natural product inhibitor of 1 1 ⁇ -HSD1 , and 8 mg/ml_ Protein-A-coated Yttrium silicate SPA beads pre-absorbed with 2.1 ug/mL monoclonal Cortisol antibody in the presence of Superblock ® Blocking Buffer (Pierce, Rockford, IL). Microtiter plates are sealed and incubated overnight before detection of scintillation on a ViewLux Plate Imager for 10 minutes using a clear filter.
  • Compounds are first prepared in neat DMSO at a concentration of 10 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 50 ⁇ M-0.8 nM or 25 ⁇ M-0.42 nM or 2.5 ⁇ M to 42 pM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
  • Compounds (0 - 100 ⁇ M) are pre-incubated with recombinant microsomal human 11 ⁇ -HSD2 (10 ⁇ g/ml) and 1 mM NAD + in assay buffer (50 mM Hepes, pH 7.4, 100 mM KCI, 5 mM NaCI, 0.2 mM MgCI 2 , and 2% DMSO) at ambient temperature for 20 min.
  • Reactions are initiated with the addition of 10 nM [ 3 H]- cortisol (36.5 nCi; [cortisol]/K m ⁇ 1 ), incubated at ambient temperature for 60 min (which is within the linear response time of the assay), and quenched with the addition of 20 ⁇ M glycyrrhetinic acid. Remaining [ 3 H]-cortisol is assayed by addition of 0.7 mg (to a final concentration of 0.6 mg/ml) Protein A-YSi SPA beads (GE Healthcare) pre-complexed with a murine anti-cortisol monoclonal antibody (East Coast Bio, East Berwick, ME).
  • Reaction mixtures are incubated with SPA beads for at least 16 hours at ambient temperature, and cpm is measured on a Microbeta Trilux scintillation plate counter (PerkinElmer, Waltham, MA). Percent inhibition (%/) is calculated at each compound concentration using Equation 1 : where cpm, min, and max refer to counts per minute of reaction in presence of compound,
  • Example 44 All of the tested compounds, except Example 44, were found to have an IC 50 against sEH from 0.1 nM to 2,512 nM.
  • Example 44 was found to have an IC 50 greater than 3,981 nM. It is not known whether or not Example 44 would inhibit sEH activity at concentrations above 3,981 nM.
  • the compounds of the invention inhibit the sEH enzyme and the 11 ⁇ -HSD1 enzyme and can be useful in the treatment of conditions wherein the underlying pathology is (at least in part) attributable to sEH and/or 1 1 ⁇ -HSD1 involvement or in conditions wherein sEH and/or 11 ⁇ -HSD1 inhibition offers some clinical benefit even though the underlying pathology is not (even in part) attributable to sEH and/or 11 ⁇ -HSD1 involvement.
  • Such conditions include hypertension, organ failure / damage (including heart failure, renal failure, and liver failure), peripheral vascular disease (including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g.
  • the invention is directed to methods of treating such conditions.
  • Essential hypertension is commonly associated with the development of significant end organ damage such as renal, endothelial, myocardial, and erectile dysfunction. Such conditions occur “secondary" to the elevated systemic arterial blood pressure. Secondary conditions may be prevented by treatment of the underlying ("primary") cause. Accordingly, in another aspect the invention is directed to methods of preventing such secondary conditions.
  • sEH is indirectly involved in the regulation of platelet function through its effect on EETs. Drugs that inhibit platelet aggregation are believed to decrease the risk of atherthrombotic events, such as myocardial infarction and stroke, in patients with established cardiovascular atherosclerotic disease.
  • the invention is directed to methods of preventing atherothrombotic events, such as myocardial infarction and stroke in patients with a history of recent myocardial infarction, stroke, transient ischemic attacks, unstable angina, or atherosclerosis.
  • treatment in reference to a condition means: (1 ) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound of the invention will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient being treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 mg.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the compounds of this invention may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and ⁇ -
  • compositions The compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient.
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically- acceptable.
  • the compound of the invention and the pharmaceutically-acceptable excepient or excepients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as suppositories
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

Abstract

The invention is directed to bicycle[2.2.2]oct-1-yl compounds, pharmaceutical compositions containing them and their use in the treatment of a variety of conditions mediated by the sEH enzyme and/or the 11β-HSD1 enzyme.

Description

sEH AND 11 β-HSD1 DUAL INHIBITORS
FIELD OF THE INVENTION
The invention is directed to bicycle[2.2.2]oct-1-yl compounds, pharmaceutical compositions containing them and their use in the treatment of a variety of conditions mediated by the sEH enzyme and/or the 1 1 β-HSD1 enzyme.
BACKGROUND OF THE INVENTION
Soluble Epoxide Hydrolase Epoxide functional groups may be found in drugs, xenobiotic materials, and endogenous biomolecules. Epoxide hydrolases, found in both plants and animals, are enzymes that convert epoxides to diols by hydrolysis. In mammals, soluble epoxide hydrolase ("sEH") is primarily responsible for the metabolism of arachidonic acid derivatives known as epoxyeicosatrienoic acids ("EETs"). sEH converts EETs into dihydroxyeicosatrienoic acids ("DHETs"). Several publications have described the beneficial vasodilatory, anti-inflamatory, and anti-thrombotic effects of EETs. See E.g. Spector et al., Prog. Lipid Res., 43, 55-90, 2004; Imig, Cardiovasc. Drug Rev., 24, 169- 188, 2006. DHETs are generally inactive and thus do not exhibit the beneficial effects of EETs. Conversely, microsomal epoxide hydrolase ("mEH") catalyzes the hydrolysis of a broad range of epoxide substrates including carcinogenic polycyclic aromatic hydrocarbons and reactive epoxides, thus it provides an important detoxification pathway. Polymorphisms in mEH may lead to differences in bioactivation of pro-carcinogens and several human epidemiological studies suggest that mEH genotype is associated with altered cancer risk. Fretland & Omiecinski, Chemico-Biol. Int., 129, 41-59, 2000.
Pharmacological, knockout mouse phenotype and genetic polymorphism studies suggest that elevated EET levels are protective in numerous disorders including hypertension [Ce// Biochem Biophys., 47, 87-98, 2007], heart failure [Xu et al., Proc. Natl Acad. Sc/._l/.S.A,103, 18733-18738, 2006], renal dysfunction / end organ damage [Zhao et al., J. Am. Soc. Nephrol., 15, 1244-1253, 2004; Imig et al., Hypertension, 46, 975-981 , 2005], stroke [Koerner et al., J. Neurosci., 27; 4642-4649, 2007], atherosclerosis and thrombosis [Wei et al., Atherosclerosis, 190, 26-34, 2007; Krotz et al., Arterioscler. Thromb. Vase. Biol., 24; 595-600, 2004] and inflammation [Inceoglu et al., Life Sci., 79, 2311-2319, 2006]. One approach to the treatment of such conditions designed to take advantage of the beneficial effect of EETs has been to search for compounds that inhibit sEH thereby preventing EET degradation.
11 beta-hvdroxysteroid dehydrogenase type 1 11 beta-hydroxysteroid dehydrogenase type 1 ("11 β-HSD1") is an intracellular enzyme that converts inactive glucocorticoids (e.g. cortisone) to active glucocorticoids (e.g. Cortisol). Draper et al., J Endocrin 186, 251-271 , 2005. Because glucocorticoids activate both glucocorticoid receptors and mineralocorticoid receptors in multiple tissues they can affect endocrine, metabolic, cardiovascular, and immune function. See E.g. Dallman et al, Endocrinol 145, 2633-2638, 2004; Stulnig et al., Diabetol 47, 1-1 1 , 2004; Wang, Nutrit Metabol 2, 1-14, 2005; Young et al., CHn Sc/ 112, 467-475, 2007; Hadoke et al., Cell MoI Life Sci, 63, 565-578, 2006; and Perez de Prada et al., Athero, 191, 333-339, 2007.
Studies suggest that overexpression of the gene that encodes 11 β-HSD1 can lead to cardiovascular and metabolic disorders. For example, liver-specific overexpression of 11 β-HSD1 in mice leads to insulin resistance, dyslipidemia and hypertension [Paterson et al., Proc Natl Acad U.S.A., 101, 7088-7093, 2004]. Conversely, 1 1 beta-hydroxysteroid dehydrogenase type 2 ("1 1 β-HSD2") catalyzes the pre-receptor dehydrogenation of active glucocorticoids to an inactive form. 11 β-HSD2 is highly expressed in epithelial tissues and protects the mineralocorticoid receptor from active glucocorticoids (Draper et al., J Endo, 186, 251-271 , 2005). Mutations in the gene that encodes 11 β-HSD2 cause a decrease in 11 β-HSD2 activity and are associated with hypertension and metabolic disorders in humans (White et al., Endocr Rev 18, 135-156, 1997).
Several publications suggest that inhibition of 11 β-HSD1 represents a worthwhile approach to the treatment of the following disorders: metabolic disorders including diabetes, metabolic syndrome, hyperglycemia, and obesity [See E.g. Andrews et al., J CHn Endo Metab 88, 285-291 , 2003; and Tomlinson et al Nat CHn Prac Endo Metab, 1 , 92-99, 2005]; cardiovascular disorders including atherosclerosis, hyperlipidemia, and hypertension [See E.g. Hermanowski-Vosatka et al., J Exp Med, 202, 517-527, 2005; Berthiaume et al., Am J Physiol Endocrinol Metab, 293, E1045-E1052, 2007; and Hatakeyama et al., Hypertens 33, 1179-1184, 1999; Krozowski et al. Endo J, 50, 485-489, 2003]; cognitive disorders including cognitive impairment, dementia, and depression [See E.g. Sandeep et al., Proc Natl Acad Sci, 101, 6734-6739, 2004 and Belanoff et al., J Psych Res, 35, 127-145, 2001]; glaucoma; osteoporosis; inflammation [See E.g. Chrousos, Proc Nat Acad Sci, 101, 6329-6330, 2004]; and polycystic ovary syndrome [See E.g. Gambineri et al., J CHn Endo Metab, 91, 2295-2302, 2006 and Draper et al., J Endocrin 186, 251-271 , 2005].
Combined Approach In light of the role sEH plays in the degradation of EETs and the role 1 1 β-HSD1 plays in the conversion of inactive glucocorticiods to active glucocorticoids, it is desirable to prepare compounds that inhibit sEH activity and 11 β-HSD1 activity. Thus, there is a need to identify compounds that inhibit sEH activity and 11 β-HSD1 activity, which can be used in the treatment of a variety of conditions mediated by the sEH enzyme or the 11 β- HSD1 enzyme.
SUMMARY OF THE INVENTION
The invention is directed to bicycle[2.2.2]oct-1-yl compounds. Specifically, the invention is directed to compounds according to Formula I and pharmaceutically acceptable salts thereof:
Figure imgf000004_0001
(I)
The compounds of the invention are sEH and 1 1 β-HSD1 dual inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme or the 1 1 β-HSD1 enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH or 11 β-HSD1 and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
In yet another aspect, this invention provides for the use of the compounds of
Formula (I) for the treatment or prevention of hypertension, heart failure, renal failure, liver failure, peripheral vascular disease, coronary artery disease, myocardial ischemia, angina, hyperlipidemia, diabetes, hypergylcemia, metabolic syndrome, obesity, myocardial infarction, diabetic nephropathy, diabetic heart failure, dyslipidemia, and preventing stroke. The compounds of this invention may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective β-adrenoceptor and α-| - adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to compounds according to Formula (I):
Figure imgf000005_0001
(I) wherein: A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four or five Ri groups;
Ri is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc,
NRcRc, NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, S(O2)NRcRc, piperdinyl, pyrrolidinyl, morpholinyl, and phenyl; R2 and R3 are independently hydrogen or C1-3 alkyl; m is O, 1 or 2;
X is
Figure imgf000005_0002
R4 and R5 are independently hydrogen or C 1-6 alkyl; R6 is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; n is 1 or 2; x is 0 - 5;
Rγ is phenyl unsubstituted or substituted by one to five substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, and S(O2)NRcRc; R8 and R9 are hydrogen or methyl, provided only one may be methyl; each Ra is independently Ci-6 alkyl or Ci-6 haloalkyl; each Rb is independently H, Ci-6 alkyl or Ci-6 haloalkyl; and each Rc is independently H or Ci-6 alkyl; or a pharmaceutically acceptable salt thereof.
"Alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms. For example, C1-C8 alkyl refers to an alkyl group having from 1 to 8 member atoms. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
"Cycloalkyl" refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms. For example, C3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Unsaturated Cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
"Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
"Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or greater. "Half-life" refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
"Halo" refers to the halogen radical fluoro, chloro, bromo, or iodo.
"Haloalkyl" refers to an alkyl group that is substituted with one or more halo substituents. Haloalkyl includes trifluoromethyl. "Member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
"Substituted" in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
The meaning of any functional group or substituent thereon at any one occurrence in Formula I, or any subformula thereof, is independent of its meaning, or any other functional group's or substituent's meaning, at any other occurrence, unless stated otherwise.
In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
The compounds according to Formula I may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
The compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
In certain embodiments, compounds according to Formula I may contain an acidic functional group and are therefore capable of forming pharmaceutically-acceptable base addition salts by treatment with a suitable base. In certain other embodiments, compounds according to Formula I may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula.
As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
As used herein, the term "compounds of the invention" means both the compounds according to Formula I and the pharmaceutically-acceptable salts thereof. The term "a compound of the invention" also appears herein and refers to both a compound according to Formula I and its pharmaceutically-acceptable salts.
In the solid state, compounds of the invention can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof. The skilled artisan will appreciate that pharmaceutically-acceptable solvates of a compound of the invention may be formed wherein solvent molecules are incorporated into the solid-state structure during crystallization. Solvates may involve water or nonaqueous solvents, or mixtures thereof. In addition, the solvent content of such solvates can vary in response to environment and upon storage. For example, water may displace another solvent over time depending on relative humidity and temperature. Solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "hydrates." Solvates wherein more than one solvent is incorporated into the solid-state structure are typically referred to as "mixed solvates". Solvates include "stoichiometric solvates" as well as compositions containing variable amounts of solvent (referred to as "non-stoichiometric solvates"). Stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "stoichiometric hydrates", and non-stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "non-stoichiometric hydrates". The invention includes both stoichiometric and non- stoichiometric solvates.
In addition, crystalline forms of a compound of the invention, including solvates thereof, may contain solvent molecules, which are not incorporated into the solid-state structure. For example, solvent molecules may become trapped in the crystals upon isolation. In addition, solvent molecules may be retained on the surface of the crystals. The invention includes such forms.
The skilled artisan will further appreciate that compounds of the invention, including solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline packing arrangements). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different IR spectra and X-ray powder diffraction patterns, which may be used for identification. Polymorphs may also exhibit different melting points, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in the production of different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
Representative Embodiments
In one embodiment:
A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four or five R1 groups;
R1 is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, S(O2)NRcRc, piperdinyl, pyrrolidinyl, morpholinyl, and phenyl; R2 and R3 are independently hydrogen or C1-3 alkyl; m is O, 1 or 2; X is
Figure imgf000011_0001
R4 and R5 are independently hydrogen or C 1-6 alkyl;
R6 is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; n is 1 or 2; x is O - 5;
R7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc,
NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, and S(O2)NRcRc;
Re and Rg are hydrogen or methyl, provided only one may be methyl; each Ra is independently C1-6 alkyl or C1-6 haloalkyl; each Rb is independently H, C1-6 alkyl or C1-6 haloalkyl; and each Rc is independently H or C1-6 alkyl.
In another embodiment:
A is phenyl which is or substituted by one or two R1 groups; R1 is selected from the group consisting of: halo, Ra, and ORb,; R2 and R3 are hydrogen; m is O or 1 ; X is
Figure imgf000011_0002
R4 and R5 are hydrogen; R6 is C1-6 alkyl; n is 1 ; R7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, and S(O2)NRcRc; R8 and R9 are hydrogen; each Ra is independently Ci-6 alkyl or Ci-6 haloalkyl; each Rb is independently H, Ci-6 alkyl or Ci-6 haloalkyl; and each Rc is independently H or Ci-6 alkyl.
Specific examples of compounds of the present invention include the following:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-(phenylmethyl)urea;
N-[(2,4-dichlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-phenylurea; Λ/-(4-fluorophenyl)-Λ/'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-[4-(trifluoromethyl)phenyl]urea;
N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^Joct-i-y^methylJurea;
4-[({[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]amino}carbonyl)amino]benzoic acid; N-(3,4-dichlorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(3-cyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(4-cyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea; N-(4-chloro-3-nitrophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(3-chloro-2-fluorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-
3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea; N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-(3,5-dichlorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[3-(methyloxy)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[4-(methyloxy)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(3,4-dicyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea; N-^-cyano-S-^rifluoromethylJphenylJ-N'-^^-methyl-δ-p-^rifluoromethylJphenylJ^H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[4-(methyloxy)-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-
4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-(3-cyano-4-methylphenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol- 3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[3-cyano-4-(1 H-pyrrol-1-yl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}urea; N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[3-(trifluoromethyl)phenyl]methyl}urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[4-(trifluoromethyl)phenyl]methyl}urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-({2-[(trifluoromethyl)oxy]phenyl}methyl)urea;
N-[1-(2,4-dichlorophenyl)ethyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-yOmethylJurea;
N-[(2-chlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea; N-{[4-chloro-2-(methylthio)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea; N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[4-(trifluoromethyl)-3-pyridinyl]methyl}urea;
N-[(2,3-dichlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-y^methyllurea; N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-
4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-{[2-chloro-4-(methylsulfonyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethyOurea;
N-{[4-chloro-2-(methylsulfonyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2- (trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethyOurea;
N-[(2-chloro-4-cyanophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-y^methyllurea;
N-[4-{[({[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]amino}carbonyl)amino]methyl}-3-(trifluoromethyl)phenyl]methanesulfonamide; N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-(2-pyridinylmethyl)urea;
N-(2-biphenylylmethyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{1-[3-(trifluoromethyl)phenyl]ethyl}urea;
N-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethyOurea;
N-[2-(2,4-dichlorophenyl)ethyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^loct-i-yOmethyOurea; (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl {[2-(trifluoromethyl)phenyl]methyl}carbamate;
(2-chlorophenyl)methyl[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]carbamate;
2-chlorophenyl[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1 -yl)methyl]carbamate;
3-(2-chlorophenyl)-N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- ylJbicyclop^^loct-i-yOmethyOpropanamide;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}sulfamide; 2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/- phenylacetamide; 2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/-
(phenylmethyl)acetamide;
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/-
{[2-(trifluoromethyl)phenyl]methyl}acetamide; 2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/-
{[3-(trifluoromethyl)phenyl]methyl}acetamide;
Λ/-{[2-chloro-4-(methylsulfonyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-
4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide;
Λ/-[(2,4-dichlorophenyl)methyl]-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide;
Λ/-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-
(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide;
Λ/-[(2-chloro-4-cyanophenyl)methyl]-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide; Λ/-({2-chloro-4-[(methylsulfonyl)amino]phenyl}methyl)-2-(4-{4-methyl-5-[2-
(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide;
Λ/-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-
4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide;
Λ/-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide;
2-(3-chlorophenyl)-Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]acetamide;
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-2-[4-(trifluoromethyl)phenyl]acetamide; N'-[(2,4-dichlorophenyl)methyl]-N-methyl-N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
4-fluoro-Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-
1 -yl)methyl]benzamide;
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-Λ/'-[2-(trifluoromethyl)phenyl]urea; and
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-2-(trifluoromethyl)benzamide
Compound Preparation The compounds according to Formula I are prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction schemes. All functional groups are as defined in Formula I unless otherwise defined. Starting materials and reagents depicted below in the general reaction schemes are commercially available or can be made from commercially available starting materials using methods known by those skilled in the art. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
Schemel
Figure imgf000016_0001
Figure imgf000016_0002
Scheme 1 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 1.7). Compounds such as 1.2 were prepared from a requisite amide, such as 1.1, and a tetrazole. Hydrolysis of intermediate 1.2 with an aqueous base provides intermediate 1.3. Treatment of intermediate 1.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (1.4). Nitrile 1.5 was then formed by treatment of the amide 1.4 with TFAA. The nitrile was then reduced to the primary amine 1.6. Finally, ureas such as 1.7 were formed by condensing the amine 1.6 with an isocyanate.
Scheme 2
Figure imgf000017_0001
NH4CI, TEA, BOP DMF
H2N ^^ N^-R7 ^-t N^-R7
R6 R6
24 2 5
Figure imgf000017_0002
Scheme 2 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.7). Compounds such as 2.2 were prepared from a requisite amide, such as 2.1, and a tetrazole. Hydrolysis of intermediate
2.2 with an aqueous base provides intermediate 2.3. Treatment of intermediate 2.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (2.4). Nitrile 2.5 was then formed by treatment of the amide 2.4 with TFAA. The nitrile was then reduced to the primary amine 2.6. Finally, ureas such as 2.7 were formed by condensing the amine 2.6 with an isocyanate, which was formed in situ from triphosgene and an appropriate amine.
Scheme 3
Figure imgf000018_0001
3 2 3 3
Figure imgf000018_0002
3 6 3 7
Scheme 3 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 3.7). Compounds such as 3.2 were prepared from a requisite amide, such as 3.1, and a tetrazole. Reduction of methylester
3.2 provides intermediate 3.3. Treatment of intermediate 3.3 with sulfonylchloride and a trialkylamine base furnished the desired mesylate (3.4). Displacement of the mesylate with a nitrile was accomplished using sodium cyanide to provide the desired nitrile 3.5. The nitrile was then hydrolyzed to the carboxylic acid 3.6 using aqueous acid. Finally, amides such as 3.7 were formed by treatment of acid 3.6 with an amine, a trialkylamine base and a coupling reagent such as BOP.
Scheme 4
WvW° oxa'y'Chlor'd8 VftWi LIOH WΛ I
R 66 \ / N R6 R6
N=N
4 2 43
Figure imgf000019_0001
4 7
Scheme 4 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 4.7). Compounds such as 4.2 were prepared from a requisite amide, such as 4.1, and a tetrazole. Hydrolysis of intermediate
4.2 with an aqueous base provides intermediate 4.3. Treatment of intermediate 4.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (4.4). Nitrile 4.5 was then formed by treatment of the amide 4.4 with TFAA. The nitrile was then reduced to the primary amine 4.6. Finally, amides such as 4.7 were formed by treatment of amine 4.6 with a carboxylic acid, a trialkylamine base and a coupling reagent such as BOP.
Examples The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements. Abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical and biological arts. Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad). Flash column chromatography was performed on silica gel.
The naming program used is ACD Name Pro 6.02.
The following abbreviations and terms have the indicated meanings throughout:
"aq" is an abbreviation for aqueous
"BOP" is an abbreviation for (Benzotriazol-i-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate "0C" is an abbreviation for degrees Celsius
"DMF" is an abbreviation for dimethylformamide
"HATU" is an abbreviation for Dimethylsulfoxide
"equiv" is an abbreviation for equivalent "HPLC" is an abbreviation for High Pressure Liquid Chromatography
"g" is an abbreviation for gram or grams
"L" is an abbreviation for liter or liters
"LC-MS" is an abbreviation for Liquid chromatography-Mass spectrometry
"mL" is an abbreviation for milliliter or milliliters "min" is an abbreviation for minute or minutes
"mmol" is an abbreviation for millimole or millimolar
"N" is an abbreviation for Normal and refers to the number of equivalents of reagent per liter of solution
"Ph" is an abbreviation for phenyl "sat" is an abbreviation for saturated
"TFA" is an abbreviation for trifluoroacetic acid "THF" is an abbreviation for tetrahydrofuran Intermediate 1 : Methyl 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]octane-1 -carboxylate
Figure imgf000021_0001
To a stirred solution of methyl 4-[(methylamino)carbonyl]bicyclo[2.2.2]octane-1- carboxylate (10 g, 44.4 mmol) (prepared substantially according to US2004013301 1A1 ) dissolved in dichloromethane (160 ml) was added oxalyl chloride (30 ml, 343 mmol) dropwise over 10 minutes. The resultant mixture was stirred at room temperature for 2hrs, concentrated in vacuo and then azetroped with toluene to give a yellow oil. The oil was dissolved in toluene (160 ml), 5-[2-(trifluoromethyl)phenyl]-1 H-tetrazole (10.46 g, 48.8 mmol) was added and the resultant solution was heated to 120 0C for 20 h. The reaction mixture was cooled and concentrated, partitioned between dichloromethane and saturated sodium bicarbonate solution. The layers were separated and the aqueous extracted twice more. The combined organics layers were washed with 2 x saturated sodium bicarbonate solution, brine and concentrated. The resultant solid was triturated in ether (~100ml) and collected by filtration to afford the title compound as an off-white solid: (3.7 g, 8.93 mmol, 20 % yield), LCMS - RT = 2.384min, M/Z (M+H) = 394
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.87 - 2.06 (m, 6 H) 2.07 - 2.37 (m, 6 H) 3.46 (s, 3 H) 3.71 (s, 3 H) 7.41 - 7.61 (m, 1 H) 7.69 (m, 2 H) 7.83 (s, 1 H).
Intermediate 2: 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- l}bicyclo[2.2.2]octane-1 -carboxylic acid
Figure imgf000021_0002
To a stirred solution of methyl 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]octane-1-carboxylate (350 mg, 0.890 mmol) dissolved in methanol (5 ml) and Water (0.500 ml) was added lithium hydroxide (107 mg, 4.45 mmol) and the resultant mixture heated to 60 0C for 4 hr. The reaction mixture was cooled and concentrated in vacuo to give a orange oil which was partitioned between ethyl acetate and water and the pH adjusted to -3 with 2N hydrochloric acid solution. The layers were separated and the aqueous extracted twice more.
Aqueous pH adjusted to -7 and sodium chloride was added. The saturated aqueous layer was extracted with 4 x ethyl acetate and the combined organics washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a white solid. (100 mg, 0.264 mmol, 30 % yield) LCMS - RT = 2.10min, M/Z (M+H) = 380
1 H NMR (400 MHz, DMSOd6) δ ppm 1.69 - 1.89 (m, 6 H) 1.93 - 2.15 (m, 6 H) 3.41 (s, 3 H) 7.53 - 7.69 (m, 1 H) 7.76 - 7.91 (m, 2 H) 7.91 - 8.10 (m, 1 H) 12.02 - 12.31 (m, 1 H)
Intermediate 3: 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]octane-1 -carboxamide
BOP
Figure imgf000022_0002
Figure imgf000022_0001
To a stirred solution of methyl 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]octane-1-carboxylate (0.8 g, 2.034 mmol) dissolved in methanol (10 ml) and water (1.000 ml) was added lithium hydroxide (0.195 g, 8.13 mmol) in 1 portion. The resultant mixture was heated to 60 0C for 18hrs. The reaction mixture was concentrated in vacuo and the resultant red/orange solid was suspended in N,N-Dimethylformamide (DMF) (20 ml). Triethylamine (1.134 ml, 8.13 mmol), ammonium chloride (0.544 g, 10.17 mmol) and finally Benzotriazol-1-yloxytris(dimethylamino)phosphonium
Hexafluorophosphate (1.079 g, 2.440 mmol) were added and the resultant mixture was stirred for 30 minutes. The reaction mixture was concentrated to 20% original volume and then partitioned between water and dichloromethane. The layers were separated and the aqueous extracted twice more. The combined organic layers were washed with 2 x water, brine and concentrated in vacuo to afford a red oil.
The oil was purified by 2 x 2Og SCX SPE. 4 Volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions combined and concentrated to afford the title compound as a light orange solid. (750mg, 1.982 mmol, 97 % yield)
LCMS - RT = 1.896 min, M/Z (M+H) = 379 (5 min run, TFA, Sunfire) 1 H NMR (400 MHz, MeOD) δ ppm 1.82 - 2.06 (m, 6 H) 2.08 - 2.32 (m, 6 H) 3.54 (s, 3 H)
7.53 - 7.69 (m, 1 H) 7.85 (s, 2 H) 7.92 - 8.06 (m, 1 H) Intermediate 4: 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]octane-1 -carbonitrile
Figure imgf000023_0001
To a stirred solution of 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]octane-1-carboxamide (750mg, 1.982 mmol) dissolved in Dichloromethane (10 ml) was added triethylamine (1.326 ml, 9.51 mmol) and the resultant yellow solution cooled to 0 0C. Trifluoroacetic anhydride (0.448 ml, 3.17 mmol) was added dropwise over 5 minutes and the resultant stirred 30 minutes. The crude reaction mixture was diluted with saturated sodium bicarbonate solution and further dichloromethane and the layers were separated. The aqueous layer was extracted twice more with dichloromethane and the combined organic layers then washed with saturated sodium bicarbonate solution, brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow solid.
(850mg, 2.359 mmol, 119 % yield)
LCMS - RT = 2.27 min, M/Z (M+H) = 361 (5 min run, TFA, Sunfire) 1 H NMR (400 MHz, MeOD) δ ppm 2.17 (m, 12 H) 3.54 (s, 3 H) 7.53 - 7.67 (m, 1 H) 7.85 (s, 2 H) 7.90 - 8.03 (m, 1 H)
Intermediate 5: [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine
Figure imgf000023_0002
The 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1 - carbonitrile (2.4g, 6.66 mmol) was dissolved in 2N ammonia in methanol (10ml) and hydrogenated on the H-Cube, 25oC, 20Bar, Raney Ni (50mm) 1.5ml/min for 30 minutes. The solvents were removed in vacuo to afford the title compound as a yellow solid: (2.3g, 6.31 mmol, 95 % yield) LCMS - RT = 1.79min, M/Z (M+H) = 365 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60 (m, 6 H) 2.15 (m, 6 H) 3.46 (s, 3 H) 7.41 - 7.61 (m, 1 H) 7.69 (m, 2 H) 7.77 - 7.89 (m, 1 H)
Intermediate 6: (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1 -yl)methanol
Figure imgf000024_0001
To a stirred suspension of methyl 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]octane-1-carboxylate (1 g, 2.54 mmol) in tetrahydrofuran (60 ml) was added lithium borohydride (1.107 g, 50.8 mmol) in 1 portion. The resultant was stirred at room temperature for 30 minutes and then heated to 60 0C for 3hrs. The reaction mixture was cooled in an ice bath and adjusted to pH1 with 6N hydrochloric acid solution. The acidic solution was stirred for 30 minutes and then basified to pH 10 with 3N sodium hydroxide solution. The basic aqueous layer was extracted with dichloromethane (3x 50ml) and the combined organic layers washed with water, saturated sodium bicarbonate solution, brine solution, dried over sodium sulphate and concentrated in vacuo to afford the title compound as a cream solid: (970 mg, 2.65 mmol, 104 % yield) LCMS - RT = 2.05min, M/Z (M+H) = 366
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 - 1.72 (m, 6 H) 2.07 - 2.25 (m, 6 H) 3.46 (s, 3 H) 3.77 (s, 2 H) 7.43 - 7.56 (m, 1 H) 7.69 (m , 2 H) 7.77 - 7.92 (m, 1 H).
Intermediate 7: (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1 -yl)methyl methanesulfonate
Figure imgf000024_0002
To a magnetically stirred solution of (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicycloP^^oct-i-yOmethanol (.809 g, 2.214 mmol) in dichloromethane
(DCM) (10 ml) at 25 0C was added DMAP (0.027 g, 0.221 mmol) and triethylamine (1.234 ml, 8.86 mmol). Methanesulfonyl chloride (0.190 ml, 2.435 mmol) was then added in one portion. The reaction stirred at 25 0C for 30 min. The reaction was quenched by the addition of sat. aq. NaHCO3. The layers were separated using a phase separator. The organic layer was concentrated under reduced pressure to give the title compound as a tan solid which was carried on without further purification.
(.918 g, 2.070 mmol, 93 % yield)
LCMS - RT = 2.31 min, M/Z (M+H) = 444
1H NMR (400 MHz. DMSOd6) δ ppm 7.94 (d, 1 H), 7.84 (m, 2 H), 7.60 (d, 1 H), 3.92 (s, 2
H), 3.41 (s, 3 H), 3.18 (s, 3 H), 2.02 (m, 6 H), 1.57 (m, 6 H).
Intermediate δ: (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)acetonitrile
Figure imgf000025_0001
A magnetically stirred solution of (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl methanesulfonate (.858 g, 1.935 mmol) and sodium cyanide (.907 g, 18.51 mmol) in dimethyl sulfoxide (DMSO) (4 ml) was heated to 160 0C in the microwave for 15 min. The reaction was poured onto sat. aq. NaHCO3 and then diluted with dichloromethane. The layers were separated and the organic layer was concentrated under reduced pressure. The crude material still contained DMSO. The excess DMSO was remove by lyophilization to give the title compound as a yellow solid. The product was carried on without further purification. (.68 g, 1.816 mmol, 94 % yield) LCMS - RT = 2.31 min, M/Z (M+H) = 375
1H NMR (400 MHz. DMSO-d6) δ ppm 7.97 (m, 1 H), 7.85 (m, 2 H), 7.63 (m, 1 H), 3.33 (s, 3 H), 2.50 (s, 2 H), 2.03 (m, 6 H), 1.61 (m, 6 H).
Intermediate 9: (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)acetic acid
Figure imgf000025_0002
A magnetically stirred solution of (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetonitrile (.22 g, 0.588 mmol) in HCI (6 ml, 197 mmol) was heated to 90 0C for 48 h. LCMS indicated that the reaction was complete. The excess HCI was removed under reduced pressure to give a crude solid. The solid material was taken up in MeCN and filtered. The organic layer was then concentrated under reduced pressure to give the title compound as a clear oil. The product was carried on without further purification. (.237 g, 0.551 mmol, 94 % yield) LCMS - RT = 2.15 min, M/Z (M+H) = 394
Example 1 :
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-(phenylmethyl)urea
Benzyl isocyanate
Figure imgf000026_0001
Figure imgf000026_0002
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (200 mg, 0.549 mmol) dissolved in dichloromethane (5 ml) was added (isocyanatomethyl)benzene (0.073 ml, 0.549 mmol). The resultant mixture was stirred for 18 hours and concentrated in vacuo. The crude oil was loaded onto a 5g SCX SPE and 3 volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions were combined and concentrated and the resultant oil purified by Waters reverse phase HPLC (20% to 60% Acetonitrile, 0.1 %TFA, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid. (32mg, 10% yield)
LCMS - RT = 2.39 min, M/Z (M+H) = 498
1 H NMR (400 MHz, DMSOd6) δ ppm 1.46 (m, 6 H) 1.97 (m, 6 H) 2.86 (d, 2 H) 3.45 (s, 3 H) 4.21 (m, 2 H) 5.94 (m, 1 H) 6.15 - 6.41 (m, 1 H) 7.13 - 7.43 (m, 5 H) 7.67 (m, 1 H) 7.86 (m, 2 H) 7.97 (m, 1 H) Example 2:
N-^^-dichlorophenylJmethyll-N'-^^-methyl-S-^-ttrifluoromethyOphenyll^H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000027_0001
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (200 mg, 0.549 mmol) dissolved in dichloromethane was added 2,4-dichloro-1-(isocyanatomethyl)benzene (133 mg, 0.659 mmol) in 1 portion.
The resultant was stirred for 1 hour and then concentrated in vacuo and the isolated crude purified by Waters reverse phase HPLC (30% to 70% acetonitrile, 0.1 %TFA, 16mins,
50ml/min, Sunfire column) to afford the title compound as a white solid
(70 mg, 0.103 mmol, 19 % yield)
LCMS - RT = 2.54 min, M/Z (M+H) = 566/568
1 H NMR (400 MHz, MeOD) δ ppm 1.63 (m, 6 H) 2.09 - 2.25 (m, 6 H) 3.00 (s, 2 H) 3.62 (s, 3 H) 4.40 (s, 2 H) 7.34 (s, 1 H) 7.38 (s, 1 H) 7.46 (d, J=2.01 Hz, 1 H) 7.60 - 7.75 (m, 1 H)
7.89 (m, 2 H) 7.95 - 8.06 (m, 1 H)
Example 3:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-phenylurea
Figure imgf000027_0002
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (80 mg, 0.220 mmol) dissolved in dichloromethane (5 ml) was added isocyanatobenzene (0.033 ml, 0.307 mmol) and the resultant mixture stirred for 60 minutes. The reaction mixture was concentrated in vacuo and purified by Waters reverse phase HPLC (20% to 70% Acetonitrile, 0.1%TFA, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid. (10 mg, 0.016 mmol, 7 % yield)
LCMS - RT = 2.4 min, M/Z (M+H) = 484 1 H NMR (400 MHz, MeOD) δ ppm 1.57 - 1.77 (m, 6 H) 2.17 (m, 6 H) 3.07 (s, 2 H) 3.67 (s, 3 H) 6.90 - 7.09 (m, 1 H) 7.27 (d, 2 H) 7.32 - 7.44 (m, 2 H) 7.63 - 7.81 (m, 1 H) 7.92 (d, 2 H) 7.98 - 8.13 (m, 1 H).
Example 4:
Λ/-(4-fluorophenyl)-Λ/l-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000028_0001
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (150 mg, 0.412 mmol) dissolved in dichloromethane (8 ml) was added 1-fluoro-4-isocyanatobenzene (70 mg, 0.535 mmol) in 1 portion. The resultant mixture was stirred for 36 hours, concentrated in vacuo and loaded onto a 5g SCX SPE. 3 volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions were combined and concentrated and the crude material purified by Waters reverse phase HPLC (20% to 80% Acetonitrile, 0.1% trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid. (23 mg, 0.037 mmol, 9 % yield)
LCMS - RT = 2.41 min, M/Z (M+H) = 502
1 H NMR (400 MHz, DMSOd6) δ ppm 1.51 (m , 6 H) 2.00 (m , 6 H) 2.92 (d, 2 H) 3.45 (s, 3 H) 6.16 (s, 1 H) 7.05 (m, 2 H) 7.39 (m, 2 H) 7.68 (m, 1 H) 7.85 (m, 1 H) 7.96 (m, 1 H) 8.44 (s, 1 H).
Example 5:
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000028_0002
Example 5 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ). (39 mg, 0.057 mmol, 14 % yield) LCMS - RT = 2.64 min, M/Z (M+H) = 570
1 H NMR (400 MHz, DMSOd6) δ ppm 1.51 (m, 6 H) 1.99 (m, 6 H) 2.93 (m, 2 H) 3.44 (s, 3 H) 6.32 (s, 1 H) 7.38 (m, 1 H) 7.44 - 7.58 (m, 1 H) 7.66 (m, 1 H) 7.85 (m, 1 H) 7.98 (m, 2 H) 8.80 (s, 1 H).
Example 6:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-[4-(trifluoromethyl)phenyl]urea
Figure imgf000029_0001
Example 6 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ).
(46 mg, 0.069 mmol, 17 % yield) LCMS - RT = 2.63 min, M/Z (M+H) = 552
1 H NMR (400 MHz, DMSOd6) δ ppm 1.50 (m, 6 H) 2.00 (m, 6 H) 2.94 (m, 2 H) 3.43 (s, 3 H) 7.48 - 7.62 (m, 3 H) 7.65 (m, 1 H) 7.84 (m, 2 H) 7.95 (m, 1 H) 8.85 (s, 1 H).
Example 7: N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000029_0002
Example 7 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ). (24 mg, 0.033 mmol, 8 % yield)
LCMS - RT = 2.83min, M/Z (M+H) = 620
1 H NMR (400 MHz, DMSOd6) δ ppm 1.52 (m, 6 H) 1.99 (m, 6 H) 2.96 (m, 2 H) 3.44 (s, 3
H) 6.53 (s, 1 H) 7.55 (s, 1 H) 7.66 (m, 1 H) 7.85 (m, 1 H) 7.96 (m, 1 H) 8.07 (s, 2 H) 9.20
(s, 1 H).
Example 8:
4-[({[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct- 1 -yl)methyl]amino}carbonyl)amino]benzoic acid
Figure imgf000030_0001
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- ylJbicycloβ^^oct-i-yOmethylJamine (80 mg, 0.220 mmol) dissolved in dichloromethane (5 ml) was added methyl 4-isocyanatobenzoate (46.3 mg, 0.263 mmol) and the resultant mixture stirred for 18 hours. The reaction mixture was concentrated in vacuo and then dissolved in methanol (5ml), water (1 ml) and lithium hydroxide (21 mg ,0.88 mmol) were added and the resultant mixture heated to 6O0C for 4 hours, concentrated in vacuo and purified by Waters reverse phase HPLC (20% to 70% Acetonitrile, 0.1 % trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid. (65mg, 0.096 mmol, 44 % yield) LCMS - RT = 2.21 min, M/Z (M+H) = 528
1 H NMR (400 MHz, MeOD) δ ppm 1.70 (m, 6 H) 2.09 - 2.28 (m, 6 H) 3.09 (s, 2 H) 3.66 (s, 3 H) 7.40 - 7.55 (m, 2 H) 7.66 - 7.81 (m, 1 H) 7.86 - 7.99 (m, 4 H) 7.98 - 8.08 (m, 1 H)
Example 9:
N-tS^-dichlorophenylJ-N'-^^-methyl-S-^-ttrifluoromethylJphenyll^H-i ^^-triazol-
3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000030_0002
Example 9 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
(41 mg, 0.058 mmol, 27 % yield) LCMS - RT = 2.70 min, M/Z (M+H) = 552/554
1 H NMR (400 MHz, MeOD) δ ppm 1.68 (m, 6 H) 2.09 - 2.24 (m, 6 H) 3.07 (s, 2 H) 3.65 (s, 3 H) 7.23 (s, 1 H) 7.37 (m, 1 H) 7.76 (m, 2 H) 7.91 (m, 2 H) 7.96 - 8.10 (m, 1 H)
Example 10: N-(3-cyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-tιϊazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000031_0001
Example 10 was prepared using the general procedure similar to that described above in
Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene
(Scheme 1 ).
(10 mg, 0.015 mmol, 7 % yield)
LCMS - RT = 2.45 min, M/Z (M+H) = 509 1 H NMR (400 MHz, MeOD) δ ppm 1.57 - 1.82 (m, 6 H) 2.06 - 2.28 (m, 6 H) 3.03 - 3.13 (m,
2 H) 3.66 (s, 3 H) 7.25 - 7.38 (m, 1 H) 7.39 - 7.51 (m, 1 H) 7.51 - 7.66 (m, 1 H) 7.68 - 7.81
(m, 1 H) 7.85 - 7.98 (m, 3 H) 8.05 (m, 1 H).
Example 11 : N^-cyanophenylJ-N'-^^-methyl-S-^-ttrifluoromethylJphenyll^H-i ^^-triazol-S- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000031_0002
Example 11 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ). (27mg, 0.041 mmol, 19 % yield)
LCMS - RT = 2.408 min, M/Z (M+H) = 509
1 H NMR (400 MHz, MeOD) δ ppm 1.67 (m., 6 H) 2.15 (m, 6 H) 3.08 (s, 2 H) 3.60 (s, 3 H)
7.58 (s, 2 H) 7.61 (s, 2 H) 7.64 - 7.72 (m, 1 H) 7.84 - 7.92 (m, 2 H) 7.94 - 8.06 (m, 1 H).
Example 12:
N-(4-chloro-3-nitrophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000032_0001
Example 12 was prepared using the general procedure similar to that described above in
Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene
(Scheme 1 ). (10 mg, 0.014 mmol, 6 % yield)
LCMS - RT = 2.67 min, M/Z (M+H) = 563
1 H NMR (400 MHz, MeOD) δ ppm 1.54 - 1.79 (m, 6 H) 2.00 - 2.26 (m, 6 H) 3.08 (s, 2 H)
3.64 (s, 3 H) 7.45 - 7.54 (m, 2 H) 7.66 - 7.75 (m, 1 H) 7.83 - 7.94 (m, 2 H) 7.96 - 8.04 (m, 1
H) 8.19 (m, 1 H).
Example 13:
N-(3-chloro-2-fluorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000032_0002
Example 13 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ). (58mg, 0.085 mmol, 39 % yield)
LCMS - RT = 2.60 min, M/Z (M+H) = 536 1 H NMR (400 MHz, MeOD) δ ppm 1.69 (m, 6 H) 2.18 (m, 6 H) 3.08 (s, 2 H) 3.62 (s, 3 H) 7.07 (m, 2 H) 7.53 - 7.77 (m, 1 H) 7.89 (m, 2 H) 8.00 (m, 2 H).
Example 14: N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000033_0001
Example 14 was prepared using the general procedure similar to that described above in
Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene
(Scheme 1 ).
(20mg, 0.027 mmol, 12 % yield)
LCMS - RT = 2.77 min, M/Z (M+H) = 586/588 1 H NMR (400 MHz, MeOD) δ ppm 1.54 - 1.78 (m, 6 H) 2.09 - 2.27 (m, 6 H) 3.07 (s, 2 H)
3.61 (s, 3 H) 7.37 - 7.51 (m, 1 H) 7.51 - 7.58 (m, 1 H) 7.63 - 7.72 (m, 1 H) 7.88 (m, 2 H)
7.98 (m, 2 H).
Example 15: N-tS.S-dichlorophenyO-N'-^^-methyl-S-^-ttrifluoromethyOphenyll^H-i ^^-triazol- 3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000033_0002
Example 15 was prepared using the general procedure similar to that described above in
Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene
(Scheme 1 ).
(1 1 mg, 0.016 mmol, 7 % yield)
LCMS - RT = 2.71 min, M/Z (M+H) = 552 1 H NMR (400 MHz, MeOD) δ ppm 1.56 - 1.79 (m, 6 H) 2.07 - 2.28 (m, 6 H) 3.06 (s, 2 H)
3.60 (s, 3 H) 6.87 - 7.10 (m, 1 H) 7.42 (m, 2 H) 7.59 - 7.74 (m, 1 H) 7.82 - 7.95 (m, 2 H)
7.94 - 8.05 (m, 1 H). Example 16:
N-[3-(methyloxy)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000034_0001
Example 16 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
(4mg, 6.06 μmol, 3 % yield)
LCMS - RT = 2.36 min, M/Z (M+H) = 514
1 H NMR (400 MHz, MeOD) δ ppm 1.68 (m, 6 H) 2.07 - 2.30 (m, 6 H) 3.07 (s, 2 H) 3.65 (s,
3 H) 3.79 (s, 3 H) 6.49 - 6.65 (m, 1 H) 6.76 - 6.91 (m, 1 H) 7.07 - 7.24 (m, 2 H) 7.58 - 7.78 (m, 1 H) 7.85 - 7.96 (m, 2 H) 7.97 - 8.12 (m, 1 H).
Example 17:
N-[4-(methyloxy)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000034_0002
Example 17 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
(18mg, 0.027 mmol, 13 % yield)
LCMS - RT = 2.31 min, M/Z (M+H) = 514
1 H NMR (400 MHz, MeOD) δ ppm 1.53 - 1.78 (m, 6 H) 2.10 - 2.29 (m, 6 H) 3.06 (s, 2 H)
3.66 (s, 3 H) 3.77 (s, 3 H) 6.86 (m, 2 H) 7.25 (m, 2 H) 7.66 - 7.82 (m, 1 H) 7.91 (m, 2 H) 8.03 (m, 1 H). Example 18:
N-(3,4-dicyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-
3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000035_0001
To a stirred solution of triphosgene (48.9 mg, 0.165 mmol) dissolved in dichloromethane (5 ml) at 00C was added a solution of 4-amino-1 ,2-benzenedicarbonitrile (79mg, 0.55mmol) and diisopropylethylamine (0.144 ml, 0.823 mmol) dissolved in dichloromethane (5 ml) dropwise over 30 minutes. The resultant mixture was stirred for 10 minutes and then a solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol- 3-yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (100 mg, 0.274 mmol) and diisopropylethylamine (0.144 ml, 0.823 mmol) dissolved in dichloromethane (5 ml) was added in 1 portion and the resultant mixture stirred for 30 minutes. The reaction mixture was concentrated and the isolated crude loaded onto a 10g SCX SPE. 3 volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions were combined and concentrated and the crude material purified by Waters reverse phase HPLC (20% to 70% Acetonitrile, 0.1% trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid. (9mg, 0.013 mmol, 5 % yield)
LCMS - RT = 2.45 min, M/Z (M+H) = 534
1 H NMR (400 MHz, MeOD) δ ppm 1.56 - 1.83 (m, 6 H) 2.10 - 2.30 (m, 6 H) 3.04 - 3.14 (m, 2 H) 3.68 (s, 3 H) 7.72 (none, 2 H) 7.78 - 7.87 (m, 1 H) 7.87 - 7.99 (m, 2 H) 7.99 - 8.10 (m, 1 H) 8.10 - 8.19 (m, 1 H).
Example 19:
N-[4-cyano-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000035_0002
Example 19 was prepared using the general procedure similar to that described above in Example 18 substituting the appropriate aniline in place of 4-amino-1 ,2- benzenedicarbonitrile (Scheme 2). (9mg, 0.012 mmol, 4 % yield) LCMS - RT = 2.58 min, M/Z (M+H) = 577
1 H NMR (400 MHz, MeOD) δ ppm 1.68 (m, 6 H) 2.05 - 2.32 (m, 6 H) 3.09 (s, 2 H) 3.60 (s, 3 H) 7.60 - 7.76 (m, 2 H) 7.77 - 7.87 (m, 1 H) 7.88 (m, 2 H) 7.92 - 8.06 (m, 1 H) 8.08 - 8.25 (m, 1 H).
Example 20:
N-[4-(methyloxy)-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2- (trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Figure imgf000036_0001
Example 20 was prepared using the general procedure similar to that described above in
Example 18 substituting the appropriate aniline in place of 4-amino-1 ,2- benzenedicarbonitrile (Scheme 2).
(9mg, 0.012 mmol, 4 % yield)
LCMS - RT = 2.54 min, M/Z (M+H) = 582
1 H NMR (400 MHz, MeOD) δ ppm 1.67 (m, 6 H) 2.07 - 2.28 (m, 6 H) 3.06 (s, 2 H) 3.61 (s,
3 H) 3.88 (s, 3 H) 6.97 - 7.19 (m, 1 H) 7.34 - 7.57 (m, 1 H) 7.58 - 7.75 (m, 2 H) 7.78 - 7.96
(m, 2 H) 7.96 - 8.12 (m, 1 H).
Example 21 :
N-(3-cyano-4-methylphenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000036_0002
Example 21 was prepared using the general procedure similar to that described above in Example 18 substituting the appropriate aniline in place of 4-amino-1 ,2- benzenedicarbonitrile (Scheme 2). (12mg, 0.018 mmol, 6 % yield) LCMS - RT = 2.43 min, M/Z (M+H) = 523
1 H NMR (400 MHz, MeOD) δ ppm 1.68 (m, 6 H) 2.16 (m 6 H) 3.07 (s, 2 H) 3.63 (s, 3 H) 7.22 - 7.39 (m, 1 H) 7.37 - 7.54 (m, 1 H) 7.62 - 7.77 (m, 1 H) 7.76 - 7.86 (m, 1 H) 7.84 - 7.97 (m, 2 H) 8.04 (m, 1 H).
Example 22:
N-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000037_0001
Example 22 was prepared using the general procedure similar to that described above in
Example 18 substituting the appropriate aniline in place of 4-amino-1 ,2- benzenedicarbonitrile (Scheme 2).
(15mg, 0.021 mmol, 8 % yield)
LCMS - RT = 2.55 min, M/Z (M+H) = 574
1 H NMR (400 MHz, MeOD) δ ppm 1.54 - 1.84 (m, 6 H) 2.06 - 2.27 (m, 6 H) 3.03 - 3.13 (m,
2 H) 3.59 - 3.67 (m, 3 H) 6.26 - 6.43 (m, 2 H) 7.00 - 7.1 1 (m, 2 H) 7.38 - 7.49 (m, 1 H) 7.59
- 7.75 (m, 2 H) 7.82 - 7.96 (m, 2 H) 8.02 (m, 2 H).
Example 23:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}urea
Et3N
Figure imgf000037_0002
Figure imgf000037_0003
To a stirred solution of triphosgene (148 mg, 0.500 mmol) dissolved in dichloromethane (8 ml) at O0C was added a solution of the {[2-(trifluoromethyl)phenyl]methyl}amine (250mg, 1.42mmol) and diisopropylethylamine (0.548 ml, 3.14 mmol) dissolved in dichloromethane (8 ml) over 45 minutes. The resultant mixture was stirred for 5 minutes and then a solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]amine (260 mg, 0.714 mmol) and diisopropylethylamine (0.548 ml, 3.14 mmol) in dichloromethane (8 ml) was added in 1 portion and the resultant mixture stirred for 18hrs. The crude reaction mixture was concentrated and loaded onto a 5g SCX SPE. 3 volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions were combined and concentrated and the resulting oil purified by Waters reverse phase HPLC (20% to 80% Acetonitrile, 0.1% trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid. (24 mg, 0.035 mmol, 6 % yield) LCMS - RT = 2.53 min, M/Z (M+H) = 566
1 H NMR (400 MHz, MeOD) δ ppm 1.51 - 1.74 (m, 6 H) 2.02 - 2.26 (m, 6 H) 2.94 - 3.09 (m, 2 H) 3.55 - 3.69 (m, 3 H) 4.49 - 4.64 (m, 2 H) 7.35 - 7.51 (m, 1 H) 7.55 - 7.65 (m, 2 H) 7.63 - 7.76 (m, 2 H) 7.83 - 7.95 (m, 2 H) 8.02 (m, 1 H).
Example 24:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-{[3-(trifluoromethyl)phenyl]methyl}urea
Figure imgf000038_0001
Example 24 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of {[2- (trifluoromethyl)phenyl]methyl}amine (Scheme 2). (12 mg, 0.018 mmol, 4 % yield) LCMS - RT = 2.51 min, M/Z (M+H) = 566
1 H NMR (400 MHz, MeOD) δ ppm 1.50 - 1.80 (m, 6 H) 1.99 - 2.28 (m, 6 H) 2.93 - 3.08 (m, 2 H) 3.60 (s, 3 H) 4.28 - 4.54 (m, 2 H) 7.47 - 7.61 (m, 3 H) 7.59 - 7.67 (m, 1 H) 7.65 - 7.76 (m, 1 H) 7.80 - 7.95 (m, 2 H) 7.95 - 8.08 (m, 1 H). Example 25:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-{[4-(trifluoromethyl)phenyl]methyl}urea
Figure imgf000039_0001
Example 25 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2). (13 mg, 0.019 mmol, 5 % yield)
LCMS - RT = 2.53min, M/Z (M+H) = 566
1 H NMR (400 MHz, MeOD) δ ppm 1.49 - 1.72 (m, 6 H) 2.01 - 2.25 (m, 6 H) 2.95 - 3.08 (m,
2 H) 3.62 (s, 3 H) 4.35 - 4.49 (m, 2 H) 7.42 - 7.55 (m, 2 H) 7.61 - 7.67 (m, 2 H) 7.67 - 7.75
(m, 1 H) 7.83 - 7.95 (m, 2 H) 8.02 (m, 1 H).
Example 26:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-({2-[(trifluoromethyl)oxy]phenyl}methyl)urea
Figure imgf000039_0002
Example 26 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2). (13 mg, 0.019 mmol, 5 % yield)
LCMS - RT = 2.56min, M/Z (M+H) = 582
1 H NMR (400 MHz, MeOD) δ ppm 1.54 - 1.68 (m, 6 H) 2.03 - 2.24 (m, 6 H) 2.93 - 3.07 (m,
2 H) 3.60 (s, 3 H) 4.37 - 4.49 (m, 2 H) 7.34 (none, 2 H) 7.44 - 7.54 (m, 1 H) 7.63 - 7.75 (m,
1 H) 7.83 - 7.95 (m, 2 H) 7.95 - 8.06 (m, 1 H). Example 27:
N-II^^-dichlorophenylJethyll-N'-^^-methyl-S-^-ttrifluoromethyOphenyll^H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000040_0001
Example 27 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(28 mg, 0.040 mmol, 4 % yield)
LCMS - RT = 2.60min, M/Z (M+H) = 580/582
1 H NMR (400 MHz, DMSOd6) δ ppm 1.43 (m, 6 H) 1.97 (m, 6 H) 2.79 (d, 2 H) 3.44 (s, 3
H) 4.98 (s, 1 H) 5.89 (s, 1 H) 6.51 (d, , 1 H) 7.33 - 7.52 (m, 2 H) 7.55 (d, 1 H) 7.66 (d, , 2
H) 7.76 - 7.92 (m, 2 H) 7.96 (d, , 1 H).
Example 28:
N-[(2-chlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea
Figure imgf000040_0002
Example 28 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(10 mg, 0.015 mmol, 5 % yield)
LCMS - RT = 2.447 min, M/Z (M+H) = 533
1 H NMR (400 MHz, MeOD) δ ppm 1.51 - 1.75 (m, 6 H) 2.01 - 2.24 (m, 6 H) 3.01 (s, 2 H)
3.65 (s, 3 H) 4.43 (s, 2 H) 7.17 - 7.34 (m, 2 H) 7.34 - 7.48 (m, 2 H) 7.64 - 7.79 (m, 1 H)
7.92 (m, 2 H) 7.97 - 8.12 (m, 1 H). Example 29:
N-{[4-chloro-2-(methylthio)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Figure imgf000041_0001
Example 29 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(17mg, 0.023 mmol, 8 % yield)
LCMS - RT = 2.51 min, M/Z (M+H) = 578
1 H NMR (400 MHz, MeOD) δ ppm 1.50 - 1.79 (m, 6 H) 2.14 (m, 6 H) 3.01 (s, 2 H) 3.67 (s,
3 H) 4.34 (s, 2 H) 7.04 - 7.20 (m, 1 H) 7.27 (d, 1 H) 7.66 - 7.82 (m, 1 H) 7.92 (d, 2 H) 8.04
(m, 1 H).
Example 30:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-{[4-(trifluoromethyl)-3-pyridinyl]methyl}urea
Figure imgf000041_0002
Example 30 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of {[2- (trifluoromethyl)phenyl]methyl}amine (Scheme 2). LCMS - RT = 2.2 min, M/Z (M+H) = 567
1 H NMR (400 MHz, MeOD) δ ppm 1.67 (m, 6 H) 2.17 (m, 6 H) 3.03 (s, 2 H) 3.72 (s, 3 H) 4.61 (s, 2 H) 7.68 - 7.85 (m, 2 H) 7.89 - 8.01 (m, 2 H) 8.01 - 8.13 (m, 1 H) 8.67 - 8.78 (m, 1 H) 8.85 (m, 1 H). Example 31 :
N-[(2,3-dichlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000042_0001
Example 31 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(4mg, 5.58 μmol, 2 % yield)
LCMS - RT = 2.50 min, M/Z (M+H) = 566
1 H NMR (400 MHz, MeOD) δ ppm 1.52 - 1.68 (m, 6 H) 1.99 - 2.29 (m, 6 H) 3.01 (s, 2 H)
3.61 (s, 3 H) 4.45 (s, 2 H) 7.20 - 7.41 (m, 2 H) 7.40 - 7.53 (m, 1 H) 7.61 - 7.76 (m, 1 H)
7.83 - 7.96 (m, 2 H) 8.01 (m, 1 H).
Example 32:
N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Figure imgf000042_0002
Example 32 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(14mg, 0.019 mmol, 7 % yield)
LCMS - RT = 2.583 min, M/Z (M+H) = 584
1 H NMR (400 MHz, MeOD) δ ppm 1.65 (m, 6 H) 2.17 (m, 6 H) 3.02 (s, 2 H) 3.67 (s, 3 H)
4.51 (s, 2 H) 7.30 - 7.42 (m, 1 H) 7.42 - 7.52 (m, 1 H) 7.57 - 7.69 (m, 1 H) 7.69 - 7.82 (m, 1
H) 7.85 - 7.98 (m, 2 H) 8.04 (m, 1 H). Example 33:
N-{[2-chloro-4-(methylsulfonyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Figure imgf000043_0001
Example 33 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(34mg, 0.045 mmol, 16 % yield)
LCMS - RT = 2.30 min, M/Z (M+H) = 610
1 H NMR (400 MHz, MeOD) δ ppm 1.65 (m, 6 H) 2.17 (m, 6 H) 3.02 (s, 2 H) 3.16 (s, 3 H)
3.69 (s, 3 H) 4.51 (s, 2 H) 7.66 (s, 1 H) 7.71 - 7.85 (m, 1 H) 7.94 (m, 2 H) 7.99 (d, 1 H)
8.01 - 8.09 (m, 1 H).
Example 34:
N-{[4-chloro-2-(methylsulfonyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Figure imgf000043_0002
Example 34 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of {[2- (trifluoromethyl)phenyl]methyl}amine (Scheme 2). (23mg, 0.030 mmol, 1 1 % yield)
LCMS - RT = 2.36 min, M/Z (M+H) = 610
1 H NMR (400 MHz, MeOD) δ ppm 1.63 (m, 6 H) 2.15 (m, 6 H) 2.99 (s, 2 H) 3.28 (s, 3 H)
3.65 (s, 3 H) 4.68 (s, 2 H) 7.66 (s, 1 H) 7.68 - 7.77 (m, 2 H) 7.93 (m, 2 H) 7.99 (m, 2 H). Example 35:
N-[(2-chloro-4-cyanophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000044_0001
Example 35 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of {[2- (trifluoromethyl)phenyl]methyl}amine (Scheme 2). (37mg, 0.052 mmol, 19 % yield)
LCMS - RT =2.4min, M/Z (M+H) = 558
1 H NMR (400 MHz, MeOD) δ ppm 1.65 (m, 6 H) 2.15 (m, 6 H) 3.01 (s, 2 H) 3.66 (s, 3 H)
4.48 (s, 2 H) 7.57 (s, 1 H) 7.68 (s, 2 H) 7.83 (d, 1 H) 7.92 (d, 2 H) 7.97 - 8.11 (m, 1 H).
Example 36:
N-[4-{[({[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amino}carbonyl)amino]methyl}-3-
(trifluoromethyl)phenyl]methanesulfonamide
Figure imgf000044_0002
Example 36 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(28mg, 0.034 mmol, 13 % yield)
LCMS - RT = 2.36min, M/Z (M+H) = 659
1 H NMR (400 MHz, MeOD) δ ppm 1.66 (m, 6 H) 2.17 (m, 6 H) 3.00 (s, 3 H) 3.02 (s, 2 H)
3.69 (s, 3 H) 4.49 (s, 2 H) 7.43 - 7.53 (m, 1 H) 7.55 (s, 2 H) 7.69 - 7.82 (m, 1 H) 7.86 -
8.00 (m, 2 H) 8.04 (m, 1 H). Example 37:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-(2-pyridinylmethyl)urea
Figure imgf000045_0001
Example 37 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(13mg, 0.017 mmol, 6 % yield)
LCMS - RT = 1.886 min, M/Z (M+H) = 499
1 H NMR (400 MHz, MeOD) δ ppm 1.66 (m, 6 H) 2.15 (m, 6 H) 3.01 (s, 2 H) 3.68 (s, 3 H)
4.68 (s, 2 H) 7.65 - 7.85 (m, 1 H) 7.94 (m, 3 H) 7.98 - 8.09 (m, 2 H) 8.48 - 8.66 (m, 1 H)
8.71 - 8.84 (m, 1 H).
Example 38:
N-(2-biphenylylmethyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-
3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000045_0002
Example 38 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2).
(28mg, 0.039 mmol, 14 % yield)
LCMS - RT = 2.61 min, M/Z (M+H) = 574
1 H NMR (400 MHz, MeOD) δ ppm 1.62 (m, 6 H) 2.16 (m, 6 H) 2.97 (s, 2 H) 3.66 (s, 3 H)
4.26 (s, 2 H) 7.19 - 7.28 (m, 1 H) 7.36 (m, 6 H) 7.45 (s, 3 H) 7.66 - 7.80 (m, 1 H) 7.84 -
7.97 (m, 2 H) 7.98 - 8.08 (m, 1 H). Example 39:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-{1-[3-(trifluoromethyl)phenyl]ethyl}urea
Figure imgf000046_0001
Example 39 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2). (57 mg, 0.078 mmol, 19 % yield)
LCMS - RT = 2.563 min, M/Z (M+H) = 580
1 H NMR (400 MHz, MeOD) δ ppm 1.46 (d, 3 H) 1.50 - 1.68 (m, 6 H) 2.12 (m, 6 H) 2.91 -
3.04 (m, 2 H) 3.64 (s, 3 H) 7.55 (d, 2 H) 7.57 - 7.63 (m, 1 H) 7.62 - 7.68 (m, 1 H) 7.69 -
7.78 (m, 1 H) 7.86 - 7.96 (m, 2 H) 7.97 - 8.08 (m, 1 H).
Example 40:
N-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-
(trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Figure imgf000046_0002
Example 40 was prepared using the general procedure similar to that described above in
Example 23 substituting the appropriate benzylamine in place of {[2-
(trifluoromethyl)phenyl]methyl}amine (Scheme 2). (19 mg, 0.025 mmol, 6 % yield)
LCMS - RT = 2.51 min, M/Z (M+H) = 596
1 H NMR (400 MHz, MeOD) δ ppm 1.53 - 1.73 (m, 6 H) 2.03 - 2.26 (m, 6 H) 2.93 - 3.09 (m,
2 H) 3.64 (s, 3 H) 3.85 (s, 3 H) 4.38 - 4.54 (m, 2 H) 7.08 - 7.27 (m, 2 H) 7.43 - 7.60 (m, 1
H) 7.64 - 7.78 (m, 1 H) 7.84 - 7.97 (m, 2 H) 8.02 (m, 1 H). Example 41 :
N-[2-(2,4-dichlorophenyl)ethyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea
Figure imgf000047_0001
To a stirred solution of the [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (100 mg, 0.274 mmol) dissolved in dichloromethane (5 ml) was added the 2,4-dichloro-1-(2-isocyanatoethyl)benzene (0.059 ml, 0.357 mmol) followed by diisopropylethylamine (0.105 ml, 0.604 mmol). The resultant solution was stirred 30 minutes, concentrated in vacuo and purified by Waters reverse phase HPLC (10% to 70% Acetonitrile, 0.1% trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a yellow solid. (47 mg, 0.064 mmol, 23 % yield) LCMS - RT = 2.55 min, M/Z (M+H) = 580/582
1 H NMR (400 MHz, MeOD) δ ppm 1.61 (m, 6 H) 2.14 (m, 6 H) 2.85 - 3.03 (m, 4 H) 3.42 (s, 2 H) 3.66 (s, 3 H) 7.31 (d, 2 H) 7.41 - 7.51 (m, 1 H) 7.66 - 7.81 (m, 1 H) 7.88 - 7.97 (m, 2 H) 7.97 - 8.10 (m, 1 H).
Example 42:
(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl {[2-(trifluoromethyl)phenyl]methyl}carbamate
DIPEA
Figure imgf000047_0002
Figure imgf000047_0003
To a stirred solution of triphosgene (42.6 mg, 0.144 mmol) dissolved in dichloromethane (3 ml) at room temperature was added a solution of (4-{4-methyl-5-[2- (trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethanol (150 mg, 0.411 mmol) and diisopropylethylamine (0.158 ml, 0.903 mmol) in dichloromethane (5.00 ml) dropwise over 30 minutes. The resultant mixture was stirred for 5 minutes and then a second solution of {[2-(trifluoromethyl)phenyl]methyl}amine (71.9 mg, 0.411 mmol) and diisopropylethylamine (0.158 ml, 0.903 mmol) dissolved in dichloromethane (5.00 ml) was added in 1 portion and the resultant mixture stirred for 18 hours. The reaction mixture was diluted with water, layers separated and the aqueous layer extracted twice more with dichloromethane. The combined organic layers were washed water, brine, dried over sodium sulphate and concentrated in vacuo and then purified by Waters Reverse Phase HPLC (20-80% Acetonitrile, 16mins, Sunfire) to afford the title compound as a white solid (28 mg, 0.049 mmol, 12 % yield) LCMS - RT = 2.7 min, M/Z (M+H) = 567
1 H NMR (400 MHz, MeOD) δ ppm 1.71 (m, 6 H) 2.14 (m, 6 H) 3.54 (s, 3 H) 3.85 (s, 2 H) 4.53 (s, 2 H) 7.36 - 7.53 (m, 1 H) 7.54 - 7.67 (m, 2 H) 7.66 - 7.77 (m, 2 H) 7.84 (m, 2 H) 7.91 - 8.04 (m, 1 H).
Example 43:
(2-chlorophenyl)methyl [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]carbamate
Figure imgf000048_0001
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (100 mg, 0.274 mmol) dissolved in dichloromethane (5 ml) was added triethylamine (0.115 ml, 0.823 mmol) followed by the (2- chlorophenyl)methyl chloridocarbonate (0.056 ml, 0.357 mmol). The resultant mixture was stirred for 10 minutes and then concentrated in vacuo to afford a yellow oil which was purified by Waters reverse phase HPLC (20% to 70% Acetonitrile, 0.1 % trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid : (5 mg, 7.34 μmol, 3 % yield) LCMS - RT = 2.53 min, M/Z (M+H) = 533
1 H NMR (400 MHz, MeOD) δ ppm 1.53 - 1.78 (m, 6 H) 2.07 - 2.23 (m, 6 H) 2.94 - 3.05 (m, 2 H) 3.66 (s, 3 H) 5.21 (s, 2 H) 7.29 - 7.38 (m, 2 H) 7.40 - 7.46 (m, 1 H) 7.46 - 7.56 (m, 1 H) 7.65 - 7.81 (m, 1 H) 7.85 - 7.98 (m, 2 H) 7.98 - 8.1 1 (m, 1 H). Example 44:
2-chlorophenyl [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]carbamate
Figure imgf000049_0001
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (80 mg, 0.220 mmol) dissolved in dichloromethane (5 ml) was added 2-chlorophenyl chloridocarbonate (0.049 ml, 0.307 mmol) and the resultant mixture stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and purified by Waters reverse phase HPLC (20% to 60% Acetonitrile, 0.1 % trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid : (37mg, 0.056 mmol, 25 % yield) LCMS - RT = 2.58min, M/Z (M+H) = 519/521
1 H NMR (400 MHz, MeOD) δ ppm 1.58 - 1.88 (m, 6 H) 2.18 (m, 6 H) 3.06 (m, 2 H) 3.63 (s, 3 H) 7.24 (m, 2 H) 7.35 (m, 1 H) 7.48 (m, 1 H) 7.66 - 7.77 (m, 1 H) 7.90 (m, 2 H) 7.96 - 8.09 (m, 1 H).
Example 45:
S^-chlorophenylJ-N-^^-methyl-S-^-ttrifluoromethylJphenyll^H-i^^-triazol-S- y^bicyclo^^^oct-i-yljmethyllpropanamide
Figure imgf000049_0002
To a stirred solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (100 mg, 0.274 mmol) dissolved in dichloromethane (5 ml) was added diisopropylethylamine (0.105 ml, 0.604 mmol), 3-(2- chlorophenyl)propanoic acid (60.8 mg, 0.329 mmol) followed by Benzotriazol-1- yloxytris(dimethylamino)phosphonium Hexafluorophosphate (146 mg, 0.329 mmol). The resultant solution was stirred for 1 hour, concentrated in vacuo and purified by Waters reverse phase HPLC (10% to 70% Acetonitrile, 0.1% trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid (30 mg, 0.044 mmol, 16 % yield) LCMS - RT = 2.54 min, M/Z (M+H) = 531 1 H NMR (400 MHz, MeOD) δ ppm 1.43 - 1.61 (m, 6 H) 1.99 - 2.18 (m, 6 H) 2.50 - 2.67 (m, 2 H) 2.96 - 3.04 (m, 2 H) 3.05 - 3.15 (m, 2 H) 3.65 (s, 3 H) 7.24 (m, 2 H) 7.32 - 7.37 (m, 1 H) 7.37 - 7.43 (m, 1 H) 7.68 - 7.78 (m, 1 H) 7.86 - 7.97 (m, 2 H) 7.99 - 8.10 (m, 1 H).
Example 46: N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}sulfamide
Figure imgf000050_0001
THF
Figure imgf000050_0002
To a stirred solution of sulfuryl chloride (0.280 ml, 3.43 mmol) dissolved in acetonitrile (5 ml) was added benzylamine (100 mg, 0.571 mmol). The resultant white suspension was heated to reflux (850C) for 18 hours and was then cooled and concentrated to afford a yellow oil which was dissolved in THF (5ml).
A second solution of [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]amine (187 mg, 0.514 mmol) dissolved in Tetrahydrofuran (5.00 ml) was prepared and cooled to -780C. The first solution was added to the second and the resultant suspension allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was concentrated to afford a yellow oil which loaded onto a 5g SCX SPE. 3 volumes of methanol were collected followed by 3 volumes of 2N ammonia in Methanol. The ammonia fractions were combined and concentrated and the residual oil purified by Waters reverse phase HPLC (30% to 70% Acetonitrile, 0.1 % trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a off-white solid : (20 mg, 0.027 mmol, 5 % yield) LCMS - RT = 2.55min, M/Z (M+H) = 602
1 H NMR (400 MHz, DMSOd6) δ ppm 1.51 (m, 6 H) 1.98 (m, 6 H) 2.65 (d, 2 H) 3.45 (s, 3 H) 4.23 (d, 2 H) 6.99 (s, 1 H) 7.44 - 7.56 (m, 2 H) 7.69 (m, 2 H) 7.80 (d, 1 H) 7.83 - 7.92 (m, 2 H) 7.97 (d, 1 H). Example 47:
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)-Λ/-phenylacetamide
Figure imgf000051_0001
To a magnetically stirred solution of (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetic acid (.015 g, 0.038 mmol) in N, N- dimethylformamide (DMF) (3 ml) at 25 0C was added aniline (3.48 μl, 0.038 mmol). Triethylamine (5.31 μl, 0.038 mmol) and BOP (0.017 g, 0.038 mmol) were added and the reaction stirred at 25 0C for 30 min. The mixture was then filtered and purified by HPLC (Sunfire 30x150mm column. A gradient of 20-60% MeCN/H2O (with 0.1% TFA) over 10 min. Flow Rate of 50 mL/min.) to afford the title compound as a white solid. (.012 g, 0.026 mmol, 67 % yield) LCMS - RT = 2.44min, M/Z (M+H) = 469
1H NMR (400 MHz. CDCI3) δ 7.89 (m, 1 H), 7.78 (m, 2 H), 7.64 (m, 1 H), 7.54 (m, 3 H), 7.34 (t, 2 H), 7.14 (t, 1 H), 3.59 (s, 3 H), 2.26 (s, 2 H), 2.17 (m, 6 H), 1.83 (m, 6 H).
Example 48: 2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)-Λ/-(phenylmethyl)acetamide
Figure imgf000051_0002
Example 48 was prepared using the general procedure similar to that described above in
Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
(20 mg, 0.034 mmol, 88 % yield)
LCMS - RT = 2.38 min, M/Z (M+H) = 483
1H NMR (400 MHz. CDCI3) δ 7.87 (t, 1 H), 7.76 (m, 2 H), 7.61 (d, 1 H), 7.35 (m, 2 H), 7.30 (m, 3 H), 6.17 (t, 1 H), 4.43 (d, 2 H), 3.56 (s, 3 H), 2.13 (m, 8 H), 1.74 (m, 6 H). Example 49:
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)-Λ/-{[2-(trifluoromethyl)phenyl]methyl}acetamide
Figure imgf000052_0001
Example 49 was prepared using the general procedure described above in Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
(13 mg, 0.024 mmol, 62 % yield)
LCMS - RT = 2.56 min, M/Z (M+H) = 551
1H NMR (400 MHz. CDCI3) δ 7.87 (t, 1 H), 7.76 (m, 2 H), 7.67 (d, 1 H), 7.53-7.62 (m, 3 H),
7.41 (t, 1 H), 6.01 (t, 1 H), 4.62 (d, 2 H), 3.54 (s, 3 H), 2.12 (m, 8 H), 1.72 (m, 6 H).
Example 50: 2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 ■ yl)-Λ/-{[3-(trifluoromethyl)phenyl]methyl}acetamide
Figure imgf000052_0002
Example 50 was prepared using the general procedure similar to that described above in
Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
(15 mg, 0.027 mmol, 72 % yield)
LCMS - RT = 2.55 min, M/Z (M+H) = 551
1H NMR (400 MHz. CDCI3) δ 7.87 (m, 1 H), 7.75 (m, 2 H), 7.55 (m, 3 H), 7.48 (m, 2 H), 6.30 (t, 1 H), 4.50 (d, 2 H), 3.53 (s, 3 H), 2.14 (m, 8 H), 1.75 (m, 6 H). Example 51 :
Λ/-{[2-chloro-4-(methylsulfonyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-
(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide
Figure imgf000053_0001
Example 51 was prepared using the general procedure similar to that described above in Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3). (39 mg, 0.055 mmol, 57 % yield) LCMS - RT = 2.32 min, M/Z (M+H) = 595
1H NMR (400 MHz. CDCI3) δ 7.95 (d, 1 H), 7.88 (m, 1 H), 7.79 (m, 3 H), 7.63 (m, 2 H), 6.72 (t, 1 H), 4.57 (d, 2 H), 3.56 (s, 3 H), 3.08 (s, 3 H), 2.17 (s, 2 H), 2.12 (m, 6 H), 1.75 (m, 6 H).
Example 52:
Λ/-[(2,4-dichlorophenyl)methyl]-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide
Figure imgf000053_0002
Example 52 was prepared using the general procedure similar to that described above in
Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
(31 mg, 0.047 mmol, 48 % yield)
LCMS - RT = 2.62 min, M/Z (M+H) = 552
1H NMR (400 MHz. CDCI3) δ 7.86 (m, 1 H), 7.74 (m, 2 H), 7.55 (s, 1 H), 7.40 (m, 2 H),
7.27 (m, 1 H), 6.09 (s, 1 H), 4.47 (m, 2 H), 3.50 (s, 3 H), 2.1 1 (m, 8 H), 1.73 (m, 6 H). Example 53:
Λ/-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-
(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide
Figure imgf000054_0001
Example 53 was prepared using the general procedure similar to that described above in Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3). (35 mg, 0.05 mmol, 38 % yield) LCMS - RT = 2.56 min, M/Z (M+H) = 581 1H NMR (400 MHz. DMSOd6) δ 8.30 (t, 1 H), 7.97 (m, 1 H), 7.86 (m, 2 H), 7.66 (d, 1 H), 7.45 (d, 1 H), 7.26 (dd, 1 H), 7.20 (d, 1 H), 4.36 (d, 2 H), 3.82 (s, 3 H), 2.08 (s, 3 H), 2.04 (s, 2 H), 2.00 (m, 8 H), 1.63 (m, 6 H).
Example 54: Λ/-[(2-chloro-4-cyanophenyl)methyl]-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide
Figure imgf000054_0002
Example 54 was prepared using the general procedure similar to that described above in
Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
(50 mg, 0.076 mmol, 54 % yield)
LCMS - RT = 2.50 min, M/Z (M+H) = 542
1H NMR (400 MHz. CDCI3) δ 7.87 (m, 1 H), 7.75 (m, 2 H), 7.66 (m, 1 H), 7.60 (m, 2 H), 7.54 (m, 1 H), 6.48 (t, 1 H), 4.45 (d, 2 H), 3.54 (s, 3 H), 2.1 1 (m, 8 H), 1.73 (m, 6 H).
Example 55:
Λ/-({2-chloro-4-[(methylsulfonyl)amino]phenyl}methyl)-2-(4-{4-methyl-5-[2-
(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide
Figure imgf000054_0003
Example 55 was prepared using the general procedure similar to that described above in Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3). (48 mg, 0.066 mmol, 47 % yield) LCMS - RT = 2.36 min, M/Z (M+H) = 610
1H NMR (400 MHz. DMSOd6) δ 8.28 (m, 1 H), 7.99 (m, 1 H), 7.88 (m, 1 H), 7.72 (m, 1 H), 7.33 (m, 1 H), 7.25 (m, 1 H), 7.17 (m, 1 H), 4.27 (d, 2 H), 3.50 (s, 3 H), 3.03 (s, 3 H), 2.08 (s, 2 H), 2.02 (m, 6 H), 1.63 (m, 6 H).
Example 56:
Λ/-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2- (trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide
Figure imgf000055_0001
Example 56 was prepared using the general procedure similar to that described above in
Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
(50 mg, 0.07 mmol, 52 % yield)
LCMS - RT = 2.58 min, M/Z (M+H) = 576
1H NMR (400 MHz. DMSOd6) δ 8.54 (t, 1 H), 8.27 (s, 1 H), 8.19 (d, 1 H), 7.97 (t, 1 H),
7.85 (m, 2 H), 7.68 (m, 2 H), 4.49 (d, 2 H), 3.44 (s, 3 H), 2.08 (s, 2 H), 2.00 (m, 6 H), 1.63
(m, 6 H).
Example 57: Λ/-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-
(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide
Figure imgf000055_0002
{4-[4-Methyl-5-(2-trifluoromethyl-phenyl)-4H-[1 ,2,4]triazol-3-yl]-bicyclo[2.2.2]oct-1-yl}- methylamine (80 mg, 0.220 mmol) and (3-Trifluoromethyl-phenyl)-acetic acid (45 mg, 220 mmol) were dissolved in N,N-dimethylformamide (4 ml_). Triethylamine (0.092 ml_, 0.659 mmol) was added and the reaction was stirred for 15 minutes. A solution of Benzotriazol- i-yloxytris(dimethylamino) phosphonium hexafluorophosphate (97 mg, 0.220 mmol) in N,N-dimethylformamide (1 ml.) was added. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate (50 ml.) and washed with a 1 :1 mixture of water and aqueous saturated sodium bicarbonate (40 ml_), water (2 x 25 ml.) and brine (25 ml_). The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure to give a crude solid. The crude material was purified by HPLC (Sunfire 30mm x 150 mm column, 30-60% MeCN/H2O (with 0.1 % TFA) over 15 min) to give the title compound as a pale yellow oil.
(42 mg, 0.076 mmol, 35% yield)
(M+H) = 551
1H NMR (400 MHz. DMSO) δ 7.90-7.83 (m, 2H), 7.80-7.72 (m, 2H), 7.61-7.46 (m, 4H),
3.69 (s, 2H), 3.18-3.04 (m, 5H), 2.19-2.10 (m, 6H), 1.57-1.50 (m, 6H).
Example 58:
2-(3-chlorophenyl)-Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]acetamide
Figure imgf000056_0001
{4-[4-Methyl-5-(2-trifluoromethyl-phenyl)-4H-[1 ,2,4]triazol-3-yl]-bicyclo[2.2.2]oct-1-yl}- methylamine (80 mg, 0.220 mmol) and (3-chlorophenyl)-acetic acid (37 mg, 220 mmol) were dissolved in N,N-dimethylformamide (4 ml_). Triethylamine (0.092 ml_, 0.659 mmol) was added and the reaction was stirred for 15 minutes. A solution of Benzotriazol-1- yloxytris(dimethylamino) phosphonium hexafluorophosphate (97 mg, 0.220 mmol) in N, N- dimethylformamide (1 ml.) was added. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate (50 ml.) and washed with a 1 :1 mixture of water and aqueous saturated sodium bicarbonate (40 ml_), water (2 x 25 ml.) and brine (25 ml_). The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure to give a crude solid. The crude material was purified by HPLC (Sunfire 30mm x 150 mm column, 30-60% MeCN/H2O (with 0.1 % TFA) over 15 min) to give the title compound as a light brown solid. (20 mg, 0.039 mmol, 18% yield) (M+H) = 517
1H NMR (400 MHz. DMSO) δ 8.02-7.96 (m, 2H), 7.89-7.82 (m, 2H), 7.65 (d, J = 6.53, 1 H), 7.37-7.33 (m, 2H), 7.31-7.29 (m, 1 H), 3.48 (s, 2H), 3.43 (s, 3H), 2.89 (d, J = 6.27, 2H), 1.99-1.95 (m, 6H), 1.48-1.44 (m, 6H).
Example 59:
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-2-[4-(trifluoromethyl)phenyl]acetamide
Figure imgf000057_0001
{4-[4-Methyl-5-(2-trifluoromethyl-phenyl)-4H-[1 ,2,4]triazol-3-yl]-bicyclo[2.2.2]oct-1-yl}- methylamine (75 mg, 0.206 mmol) and (4-Trifluoromethyl-phenyl)-acetic acid (42 mg, 206 mmol) were dissolved in N,N-dimethylformamide (4 ml_). Triethylamine (0.086 ml_, 0.617 mmol) was added and the reaction was stirred for 15 minutes. A solution of Benzotriazol- i-yloxytris(dimethylamino) phosphonium hexafluorophosphate (91 mg, 0.206 mmol) in N,N-dimethylformamide (1 ml.) was added. The reaction was stirred at room temperature for 20 hours. The reaction was diluted with ethyl acetate (50 ml.) and washed with a 1 :1 mixture of water and aqueous saturated sodium bicarbonate (40 ml_), water (2 x 25 ml.) and brine (25 ml_). The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure to give a crude solid. The crude material was purified by HPLC (Sunfire 30mm x 150 mm column, 30-60% MeCN/H2O (with 0.1 % TFA) over 15 min) to give the title compound as a pale yellow oil. (45 mg, 0.082 mmol, 40% yield)
(M+H) = 551
1H NMR (400 MHz. DMSO) δ 8.04-7.99 (m, 2H), 7.90-7.85 (m, 2H), 7.71 (d, J = 6.78, 1 H),
7.59-7.57 (m, 1 H), 7.40 (d, J = 1.00, 2H), 3.63 (s, 2H), 3.49 (s, 3H), 2.92 (d, J = 6.27, 2H),
2.03-1.96 (m, 6H), 1.53-1.46 (m, 6H). Example 60:
N'-[(2,4-dichlorophenyl)methyl]-N-methyl-N-[(4-{4-methyl-5-[2-
(trifluoromethylJphenyll^H-i ^^-triazol-S-y^bicyclo^^^loct-i-ylJmethyllurea
Methylamine
MsCl Ethanol
Figure imgf000058_0001
Pyridine
Figure imgf000058_0002
Figure imgf000058_0003
Figure imgf000058_0004
To a stirred solution of (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methanol (120mg, 0.328 mmol) dissolved in pyridine (5 ml) was added methanesulfonyl chloride (0.031 ml, 0.394 mmol) and dimethylaminopyridine (5mg) and the resultant was stirred at room temp for 1 hour. The solvents were removed in vacuo and the resultant oil dissolved in 33% w/v methylamine in ethanol (5 ml, 10.00 mmol) and irradiated in the microwave (300W, 14O0C) for 20mins. -50% conversion. Solvents removed in vacuo and the material was used crude in the next step. To a stirred solution of N-methyl-1-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicycloP^^oct-i-yOmethanamine (250mg, 0.330 mmol) suspended in dichloromethane (5 ml) was added 2,4-dichloro-1-(isocyanatomethyl)benzene (0.048 ml, 0.330 mmol) in 1 portion and the resultant was stirred for 30 minutes. The reaction mixture was concentrated and loaded onto a 10g SCX SPE. 3 volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions were combined and concentrated and the crude material purified by Waters reverse phase HPLC (30% to 70% acetonitrile, 0.1 % trifluoroacetic acid, 16mins, 50ml/min, Sunfire column) to afford the title compound as a white solid : (25 mg, 0.034 mmol, 10 % yield) LCMS - RT = 2.60 min, M/Z (M+H) = 580/582
1 H NMR (400 MHz, MeOD) δ ppm 1.61 - 1.82 (m, 6 H) 2.06 - 2.25 (m, 6 H) 3.06 (s, 3 H) 3.22 (d, 2 H) 3.65 (s, 3 H) 4.37 - 4.48 (m, 2 H) 7.27 - 7.42 (m, 2 H) 7.41 - 7.53 (m, 1 H) 7.67 - 7.81 (m, 1 H) 7.88 - 7.98 (m, 2 H) 8.04 (m, 1 H). Example 61 :
4-fluoro-Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]benzamide
Figure imgf000059_0001
[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]amine (30 mg, 0.08 mmol) was dissolved in dichloromethane (2 ml_). Triethylamine (0.024 ml_, 0.17 mmol) and 4-fluorobenzoyl chloride (20 mg, 0.12 mmol) were added and the reaction was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the crude material was purified by HPLC (Sepax 21.2 mm x 250 mm column, 10-80% MeCN/H2O (with 0.07% TFA) over 21 min) to give the title compound as a white solid. (18 mg, 0.03 mmol, 37% yield) LCMS - RT = 1.83 min, IWZ (M+H) = 487
1H NMR (400 MHz. DMSOd6) δ ppm 7.99 (m, 1 H), 7.88 (m, 2 H), 7.82 (m, 2 H), 7.67 (m, 1 H), 7.17 (m, 2 H), 3.62 (s, 3 H), 3.32 (s, 3 H), 2.27 (m, 12 H).
Example 62: Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-W-[2-(trifluoromethyl)phenyl]urea
Figure imgf000059_0002
[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]amine (40 mg, 0.13 mmol) was dissolved in tetrahydrofuran (3 mL).
Triethylamine (0.095 mL, 0.68 mmol) and i-isocyanato-2-trifluoromethyl benzene (38 mg,
0.2 mmol) were added and the reaction was stirred for 10 hours at room temperature.
The reaction was diluted with water and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by HPLC (Sepax 21.2 mm x
250 mm column, 10-80% MeCN/H2O (with 0.07% TFA) over 21 min) to give the title compound as a white solid. (51 mg, 0.09 mmol, 67% yield) LCMS - RT = 1.94 min, M/Z (M+H) = 552
1H NMR (400 MHz. DMSOd6) δ ppm 7.99 (m, 1 H), 7.87 (m, 2 H), 7.82 (d, 1 H), 7.67 (m, 1 H), 7.62 (d, 1 H), 7.56 (t, 1 H), 7.23 (t, 1 H), 3.60 (s, 3 H), 3.06 (s, 2 H), 2.15 (m, 6 H), 1.68 (m, 6 H).
Example 63:
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 - yl)methyl]-2-(trifluoromethyl)benzamide
Figure imgf000060_0001
2-Trifluoromethyl benzoic acid (1 g, 5.26 mmols) was dissolved in dichloromethane (15 ml_). Oxalyl dichloride (1.67 g, 13.15 mmols) was added dropwise and stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give 2-trifluoromethyl benzoyl chloride as a crude intermediate (1.1 g). [(4-{4-methyl-5-[2- (trifluoromethyl)phenyl]-4H-1 ^^-triazol-S-ylJbicycloP^^Joct-i-y^methylJamine (50 mg, 0.13 mmol) was dissolved in dichloromethane (3 ml.) and triethylamine (0.075 ml_, 0.54 mmol) was added. The crude 2-trifluoromethyl benzoyl chloride (57 mg, 0.27 mmol) was added to the solution and the reaction was stirred for 2 hours at room temperature. The reaction was diluted with water and extracted with dichloromethane (3 x 5 ml_). The combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by HPLC (Sepax 21.2 mm x 250 mm column, 10-80% MeCN/H2O (with 0.07% TFA) over 21 min) to give the title compound as a white solid.
(44 mg, 0.08 mmol, 60% yield).
LCMS - RT = 1.86 min, M/Z (M+H) = 537
1H NMR (400 MHz. DMSOd6) δ ppm 7.99 (m, 1 H), 7.88 (m, 2 H), 7.79 (m, 1 H), 7.69 (m,
2 H), 7.62 (m, 1 H), 7.54 (d, 1 H), 3.63 (s, 3 H), 3.21 (s, 2 H), 2.15 (m, 6 H), 1.72 (m, 6 H).
Biological Activity
The compounds according to Formula I are sEH inhibitors and 11 β-HSD1 inhibitors. The compounds according to Formula I, therefore, are useful in the treatment of conditions involving sEH activity and/or 1 1 β-HSD1 activity. The biological activity of the compounds according to Formula I against sEH, mEH, 1 1 β-HSD1 and / or 11 β-HSD2 can be determined using any suitable assay for determining the relevant activity of a candidate compound, as well as suitable tissue and / or in vivo models. Suitable assays for determining sEH, mEH, 1 1 β-HSD1 and 1 1 β-HSD2 inhibitory activity are provided below.
As stated above, the compounds according to Formula I are sEH inhibitors and 11 β-HSD1 inhibitors. In one embodiment the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 0,000 nM and an IC50 against 1 1 β-HSD1 from 0.1 nM to 10,000 nM. In another embodiment the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 1 ,000 nM and an IC50 against 1 1 β- HSD1 from 0.1 nM to 1 ,000 nM. In another embodiment the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 100 nM and an IC50 against 11 β-HSD1 from 0.1 nM to 100 nM. In another embodiment the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 10 nM and an IC50 against 1 1 β-HSD1 from 0.1 nM to 10 nM.
As stated above, mEH provides an important detoxification pathway in mammals. Compounds that exhibit pharmacological selectivity for sEH over mEH therefore are desirable in the methods of treatment described below. Accordingly, in another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 10:1 for sEH over mEH. In another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 100:1 for sEH over mEH. In another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 1000:1 for sEH over mEH.
Also, as stated above, 1 1 β-HSD2 catalyzes the conversion of active glucocorticoids to an inactive form in mammals. Compounds that exhibit pharmacological selectivity for 11 β-HSD1 over 11 β-HSD2 therefore are desirable in the methods of treatment described below. Accordingly, in another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 10:1 for 11 β-HSD1 over 11 β-HSD2. In another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 100:1 for 11 β-HSD1 over 11 β-HSD2. In another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 1000:1 for 11 β-HSD1 over 11 β-HSD2.
In vitro sEH or mEH fluorescence assay
Inhibition of sEH or mEH activity can be measured in a fluorescent assay based upon the format described by Wolf et al. (Analytical Biochemistry Vol. 355 (2006) pp. 71- 80). In the presence of sEH or mEH, PHOME ((3-Phenyl-oxiranyl)-acetic acid cyano-(6- methoxy-naphthalen-2-yl)-methyl ester), is hydrolyzed to a diol which goes through an intramolecular cyclization and the release and decomposition of cyanohydrin (products = cyanide and 6-methoxy-2-naphthaldehyde). Production of 6-methoxy-2-naphthaldehyde is monitored at excitation of 360 nm and an emission of 465 nm.
The assay is used in a quenched assay format by sequentially adding enzyme (5 μL; 200 pM sEH or 150 nM mEH in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v); 10 minute ambient pre-incubation after addition) then PHOME substrate (5 μL; 10 uM PHOME substrate in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v)) to a 384 well assay plate (Greiner 784076) pre-stamped with 25-100 nl_ compound at the desired concentration. The reaction is incubated for 30 minutes (sEH assay) or 60 minutes (mEH assay) at room temperature, then quenched by the addition of stop solution (5 μL; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water. Microtiter plates are centrifuged after each addition for 30 seconds at 500 rpm. The fluorescence is measured on an EnVision plate reader platform (Perkin Elmer) using a 360 nm excitation filter, 460 nm emission filter, and 400 nm dichroic filter.
Compounds are first prepared in neat DMSO at a concentration of 10 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 50 μM-0.8 nM or 25 μM-0.42 nM or 2.5 μM to 42 pM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values. Cell-based sEH inhibitor assay Cell based sEH inhibition is measured using the 14,15-DHET immunoassay ELISA kit available from Detroit R&D (Cat. No. DH1 ), according to the following procedure:
• HEK293 cells are transduced by sEH BacMam virus to increase sEH expression
(other cell lines may be suitable) as follows: One day before the experiment, 1.5 million HEK293 cells (BioCat ID 80556) are seated in 3 mL of DMEM/F12 {with L- Glutamine, 15 mM HEPES, pH 7.30), with 10% fetal bovine serum {from SAFC
Biosciences, Cat. No.12176-1000M), no antibiotic, in a 25 cm2 flask {from Corning Incorporated, Cat. No.430639) and 30 μl_ sEH BacMam virus is added. The cells are gently mixed then incubated at 37 0C, 5% CO2, for 24 hours.
• The cells are trypsinized to release them from the growth flask, washed once with PBS, then re-suspended in 5 ml. DMEM/F12 without phenol red. Cell density should be approximately 3 * 10 5 cells/mL (= 300 cells/μL), counted using the Cedex AS20
(from Innovatis).
• The cells are then diluted in DMEM/F12 to 5.1 cells/ L, and 98 L/well (= 500 cells/well) of this cell suspension is transferred to an assay plate (96 well, clear polystyrene, flat bottom, from Whatman, Cat. No.7701-1350). • 2 L of the diluted test compound is then added to the cells in the assay plate. The reaction plate is shaken gently and incubated at room temperature for 30 min, after which 10 L of substrate solution is added (substrate solution is prepared by diluting 1.24 L of 14,15-EET from Cayman Chemical, Cat. No. 50651 with 8.24 L DMEM/F12). The assay plate is then incubated for one hour at room temperature. • After the 1 hour reaction, the reaction mixture is diluted 3-fold with provided sample dilution buffer (ex. Add 220 μl_ to the 110 μl_ reaction mixture), mixed well, and spun for 5 min at 500 rpm.
• 100 μL of the diluted reaction mixture is then transferred from the reaction plates to the ELISA plates, and the ELISA is performed according to the instructions provided in the kit. Concentrations of 14,15-DHET are determined relative to a standard curve.
• The IC50 value is calculated directly using the derived 14, 15-DHET concentration or derived from a dose-respone curve using the % inhibition [% inhibition = 100*(1- (sample DHET - 0 cell DHET) / (500 cells DHET - O cell DHET)].
• Compounds are first prepared in neat DMSO at a concentration of 0.5 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 9 concentrations (e.g. 10 μM-1.5 nM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
In vitro 1 1 B-HSD1 scintillation proximity assay
Inhibition of 1 1 β-HSD1 activity can be measured in a scintillation proximity assay (SPA) based format described by Mundt et al. (ASSAY and Drug Development Technologies Vol. 3 No. 4 (2005) pp. 367-375). The assay measures the β-NADPH dependent reductase activity of Human 1 1 β-HSD1 upon cortisone substrate to yield the active glucocorticoid Cortisol. Microsomal membranes are prepared from frozen cell pellets of Super 9 (in-house generated variant of Sf9 insect cells) infected for approximately 72 hours with baculovirus encoding for human 11 B-HSD1. Ten volumes of ice-cold, lysis solution (2OmM sodium phosphate buffer pH7.0, 5% glycerol, 1 mM EDTA, and Protease Inhibitor Cocktail III at 1 :500 [Calbiochem, San Diego, CA]) is added per gram of cell pellet, and the pellet kept on ice until it can be loosened from the tube. The slurry is transferred to a glass Waring blender, and the following process repeated four times: homogenization for 15 seconds on high followed by a 5 minute incubation on ice. After transfer to tubes, the homogenate is centrifuged at 600xg for 10 minutes at 40C; the supernatant from this spin is transferred to ultracentrifuge tubes which are spun at 100000xg for one hour at 40C. The cell pellet is resuspended in ice-cold 4OmM phosphate buffer, pH7.5 with 5% glycerol and 1 mM EDTA, aliquoted, and stored at -8O0C. The total protein recovered is determined with commercial protein assay kit using bovine albumin as the standard. Assays are initiated by incubating 0.5 μl_ of compound sample in the presence of 15 ugs/mL of Sf9 microsomes, 1 mM β-NADPH, and 16 nM [3H]cortisone ([S]/Km < 10) in buffer containing 50 mM HEPES, 100 mM KCI, 5 mM NaCI, 2 mM MgCI2, 0.02% Brij-35 (w/v) pH 7.4 in a reaction volume of 50 μl_. The assay is incubated for 3 hours at 37 °C before quenching the reaction with 25 μl_ of 10 μM 18β-glycyrrhetinic acid, a potent natural product inhibitor of 1 1 β-HSD1 , and 8 mg/ml_ Protein-A-coated Yttrium silicate SPA beads pre-absorbed with 2.1 ug/mL monoclonal Cortisol antibody in the presence of Superblock® Blocking Buffer (Pierce, Rockford, IL). Microtiter plates are sealed and incubated overnight before detection of scintillation on a ViewLux Plate Imager for 10 minutes using a clear filter.
Compounds are first prepared in neat DMSO at a concentration of 10 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 50 μM-0.8 nM or 25 μM-0.42 nM or 2.5 μM to 42 pM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
In vitro 1 1 B-HSD2 scintillation proximity assay
Compounds (0 - 100 μM) are pre-incubated with recombinant microsomal human 11 β-HSD2 (10 μg/ml) and 1 mM NAD+ in assay buffer (50 mM Hepes, pH 7.4, 100 mM KCI, 5 mM NaCI, 0.2 mM MgCI2, and 2% DMSO) at ambient temperature for 20 min. Wells containing 10 μM glycyrrhetinic acid, a potent natural product 11 β-HSD2 inhibitor, serves as background control. Reactions are initiated with the addition of 10 nM [3H]- cortisol (36.5 nCi; [cortisol]/Km ~ 1 ), incubated at ambient temperature for 60 min (which is within the linear response time of the assay), and quenched with the addition of 20 μM glycyrrhetinic acid. Remaining [3H]-cortisol is assayed by addition of 0.7 mg (to a final concentration of 0.6 mg/ml) Protein A-YSi SPA beads (GE Healthcare) pre-complexed with a murine anti-cortisol monoclonal antibody (East Coast Bio, East Berwick, ME). Reaction mixtures are incubated with SPA beads for at least 16 hours at ambient temperature, and cpm is measured on a Microbeta Trilux scintillation plate counter (PerkinElmer, Waltham, MA). Percent inhibition (%/) is calculated at each compound concentration using Equation 1 :
Figure imgf000065_0001
where cpm, min, and max refer to counts per minute of reaction in presence of compound,
10 μM glycyrrhetinic acid, and 2% DMSO, respectively. IC50 values (the concentration of compound that yields 50% enzyme inhibition) are calculated by plotting %/ versus logarithm of the compound concentration, and fitting the data to a four-parameter Hill equation (Equation 2): n / T 1 top - bottom %/ = bottom + F ,. τr.n λ .... (2) where bottom and top are the lower and upper asymptotes of the sigmoidal curve, respectively, and Hill refers to the Hill slope of the curve. Fits are constrained by fixing bottom and top as 0% and 100%l, respectively.
Biological Activity Results
All of the compounds exemplified above were tested for activity as sEH inhibitors.
Where the assay for a particular compound had been performed two or more times, the following conclusion regarding their activities is based on the average of individual experiments: All of the tested compounds, except Example 44, were found to have an IC50 against sEH from 0.1 nM to 2,512 nM. Example 44 was found to have an IC50 greater than 3,981 nM. It is not known whether or not Example 44 would inhibit sEH activity at concentrations above 3,981 nM.
All of the compounds exemplified above were tested for activity as 11 β-HSD1 inhibitors. Where the assay for a particular compound had been performed two or more times, the following conclusion regarding their activities is based on the average of individual experiments: All exemplified compounds were found to have an IC50 against
11 β-HSD1 from 2.5 nM to 40 nM. Methods of Use
The compounds of the invention inhibit the sEH enzyme and the 11 β-HSD1 enzyme and can be useful in the treatment of conditions wherein the underlying pathology is (at least in part) attributable to sEH and/or 1 1 β-HSD1 involvement or in conditions wherein sEH and/or 11 β-HSD1 inhibition offers some clinical benefit even though the underlying pathology is not (even in part) attributable to sEH and/or 11 β-HSD1 involvement. Examples of such conditions include hypertension, organ failure / damage (including heart failure, renal failure, and liver failure), peripheral vascular disease (including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g. retinopathy), atherosclerosis, atherothrombotic disorders (including coronary artery disease, coronary vasospasm, angina, stroke, myocardial ischemia, myocardial infarction, and hyperlipidemia), metabolic disorders (including diabetes, metabolic syndrome, hyperglycemia, and obesity), inflammation, inflammatory disorders (including arthritis, inflammatory pain, overactive bladder, asthma, and COPD), cognitive disorders (including cognitive impairment, dementia, and depression), glaucoma, osteoporosis, and polycystic ovary syndrome. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
Essential hypertension is commonly associated with the development of significant end organ damage such as renal, endothelial, myocardial, and erectile dysfunction. Such conditions occur "secondary" to the elevated systemic arterial blood pressure. Secondary conditions may be prevented by treatment of the underlying ("primary") cause. Accordingly, in another aspect the invention is directed to methods of preventing such secondary conditions. In addition, sEH is indirectly involved in the regulation of platelet function through its effect on EETs. Drugs that inhibit platelet aggregation are believed to decrease the risk of atherthrombotic events, such as myocardial infarction and stroke, in patients with established cardiovascular atherosclerotic disease. Accordingly, in another aspect the invention is directed to methods of preventing atherothrombotic events, such as myocardial infarction and stroke in patients with a history of recent myocardial infarction, stroke, transient ischemic attacks, unstable angina, or atherosclerosis.
The methods of treating and the methods of preventing described above comprise administering a safe and effective amount of a compound of the invention to a patient in need thereof. As used herein, "treatment" in reference to a condition means: (1 ) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound of the invention will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient being treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan.
As used herein, "patient" refers to a human or other animal. The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration. The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 mg.
Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
The compounds of this invention may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective β-adrenoceptor and α-|- adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.
Compositions The compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically- acceptable. The compound of the invention and the pharmaceutically-acceptable excepient or excepients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance. Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

Claims

What is claimed is:
1. A compound of Formula (I):
Figure imgf000072_0001
(I) wherein:
A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four
Ri is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc,
C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, S(O2)NRcRc, piperdinyl, pyrrolidinyl, morpholinyl, and phenyl;
R2 and R3 are independently hydrogen or C1-3 alkyl;
m is O, 1 or 2; X is
Figure imgf000072_0002
R4 and R5 are independently hydrogen or C i-6 alkyl;
R6 is hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl; n is 1 or 2; x is O - 5;
Rγ is phenyl unsubstituted or substituted by one to five substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O2)Ra, SRb, S(O2)Ra, and S(O2)NRcRc;
R8 and R9 are hydrogen or methyl, provided only one may be methyl; each Ra is independently Ci-6 alkyl or Ci-6 haloalkyl; each Rb is independently H, Ci-6 alkyl or Ci-6 haloalkyl; and each Rc is independently H or C1-6 alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of Formula (I) of claim 1 wherein:
A is phenyl which is or substituted by one or two Ri groups;
Ri is selected from the group consisting of: halo, Ra, and ORb;
R2 and R3 are hydrogen; m is 0 or 1 ;
X is
Figure imgf000073_0001
R4 and R5 are hydrogen;
R6 is Ci-6 alkyl; n is 1 ;
R7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb,
NRcS(O2)Ra, SRb, S(O2)Ra, and S(O2)NRcRc;
R8 and R9 are hydrogen; each Ra is independently C1-6 alkyl or C1-6 haloalkyl; each Rb is independently H, C1-6 alkyl or C1-6 haloalkyl; and each Rc is independently H or C1-6 alkyl; or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 selected from:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-(phenylmethyl)urea;
N-[(2,4-dichlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^Joct-i-y^methylJurea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-phenylurea; ^(^fluorophenyO-yV-^^-methyl-S-p-^rifluoromethyOphenyll^H-i ^^-triazol-S- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-[4-(trifluoromethyl)phenyl]urea;
N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-y^methyllurea;
4-[({[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]amino}carbonyl)amino]benzoic acid;
N-(3,4-dichlorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(3-cyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(4-cyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(4-chloro-3-nitrophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(3-chloro-2-fluorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-
3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-(3,5-dichlorophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[3-(methyloxy)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[4-(methyloxy)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-(3,4-dicyanophenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[4-cyano-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-
1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[4-(methyloxy)-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-
4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-(3-cyano-4-methylphenyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-
3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea; N-[3-cyano-4-(1 H-pyrrol-1-yl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[3-(trifluoromethyl)phenyl]methyl}urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[4-(trifluoromethyl)phenyl]methyl}urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-({2-[(trifluoromethyl)oxy]phenyl}methyl)urea;
N-[1-(2,4-dichlorophenyl)ethyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-y^methyllurea;
N-[(2-chlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-{[4-chloro-2-(methylthio)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[4-(trifluoromethyl)-3-pyridinyl]methyl}urea;
N-[(2,3-dichlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^loct-i-y^methyllurea;
N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea; N-{[2-chloro-4-(methylsulfonyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2- (trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethyOurea; N-{[4-chloro-2-(methylsulfonyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2- (trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethyOurea; N-[(2-chloro-4-cyanophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^loct-i-yOmethyOurea;
N-[4-{[({[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]amino}carbonyl)amino]methyl}-3-(trifluoromethyl)phenyl]methanesulfonamide; N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-(2-pyridinylmethyl)urea;
N-(2-biphenylylmethyl)-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]urea;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{1-[3-(trifluoromethyl)phenyl]ethyl}urea; N-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2- (trifluoromethyOphenyO^H-i ^^-triazol-S-ylJbicycloP^^loct-i-yOmethyOurea; N-[2-(2,4-dichlorophenyl)ethyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-y^methyllurea;
(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl {[2-(trifluoromethyl)phenyl]methyl}carbamate;
(2-chlorophenyl)methyl [(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]carbamate;
2-chlorophenyl[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]carbamate;
3-(2-chlorophenyl)-N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- ylJbicycloβ^^oct-i-yOmethyllpropanamide;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}sulfamide;
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/- phenylacetamide;
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/- (phenylmethyl)acetamide;
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/- {[2-(trifluoromethyl)phenyl]methyl}acetamide;
2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-Λ/- {[3-(trifluoromethyl)phenyl]methyl}acetamide;
Λ/-{[2-chloro-4-(methylsulfonyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide;
Λ/-[(2,4-dichlorophenyl)methyl]-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide;
Λ/-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2- (trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide; Λ/-[(2-chloro-4-cyanophenyl)methyl]-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide;
Λ/-({2-chloro-4-[(methylsulfonyl)amino]phenyl}methyl)-2-(4-{4-methyl-5-[2- (trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)acetamide; Λ/-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide;
Λ/-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-2-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)acetamide; 2-(3-chlorophenyl)-Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)methyl]acetamide;
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-2-[4-(trifluoromethyl)phenyl]acetamide;
N'-[(2,4-dichlorophenyl)methyl]-N-methyl-N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea;
4-fluoro-Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4/-/-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct- 1 -yl)methyl]benzamide;
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-Λ/'-[2-(trifluoromethyl)phenyl]urea; and
Λ/-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-2-(trifluoromethyl)benzamide.
4. A compound of claim 1 selected from:
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-(2-pyridinylmethyl)urea trifluoroacetate;
N-[(2,4-dichlorophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-S-ylJbicyclop^^oct-i-y^methyllurea trifluoroacetate;
N-{[4-chloro-2-(methylthio)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea trifluoroacetate;
N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]- 4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea trifluoroacetate; N-[(2-chloro-4-cyanophenyl)methyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-1-yl)methyl]urea trifluoroacetate;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1 -yl)methyl]urea trifluoroacetate; N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-[4-(trifluoromethyl)phenyl]urea trifluoroacetate;
N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-{[2-(trifluoromethyl)phenyl]methyl}urea trifluoroacetate; and N-[(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1- yl)methyl]-N'-({2-[(trifluoromethyl)oxy]phenyl}methyl)urea trifluoroacetate.
5. A pharmaceutical composition comprising a compound of Formula (I) of claims 1-4 and a pharmaceutically acceptable carrier or excipient.
6. A method of treating hypertension, heart failure, renal failure, liver failure, peripheral vascular disease, coronary artery disease, myocardial ischemia, angina, hyperlipidemia, diabetes, hypergylcemia, metabolic syndrome, obesity, myocardial infarction, diabetic nephropathy, diabetic heart failure, dyslipidemia, and stroke which comprises administering to a human in need thereof, a compound of Formula I of claims 1-4.
7. A method according to claim 6 wherein the compound of Formula I is administered orally.
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