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WO2009070497A1 - SEH AND 11 β-HSD1 INHIBITORS AND THEIR USE - Google Patents

SEH AND 11 β-HSD1 INHIBITORS AND THEIR USE Download PDF

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Publication number
WO2009070497A1
WO2009070497A1 PCT/US2008/084289 US2008084289W WO2009070497A1 WO 2009070497 A1 WO2009070497 A1 WO 2009070497A1 US 2008084289 W US2008084289 W US 2008084289W WO 2009070497 A1 WO2009070497 A1 WO 2009070497A1
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Prior art keywords
tricyclo
sulfonyl
dec
methyl
carboxamide
Prior art date
Application number
PCT/US2008/084289
Other languages
French (fr)
Inventor
Joseph Paul Jr. Marino
John Jeffrey Mcatee
David G. Washburn
Original Assignee
Smithkline Beecham Corporation
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Publication of WO2009070497A1 publication Critical patent/WO2009070497A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention is directed to sEH and 1 1 ⁇ -HSD1 inhibitors and their use in the treatment of a variety of conditions mediated by the sEH enzyme or the 11 ⁇ -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 Biophvs.. 47, 87-98, 2007], heart failure [Xu et al., Proc. Natl Acad. Sci. I/. S. A, 103, 18733-18738, 2006], renal dysfunction / end organ damage [Zhao et al., J. Am. Soc. Nephrol.. 15, 1244-1253, 2004; Imi ⁇ et al.. Hypertension. 46, 975-981 , 2005], stroke [Koerner et al., J. Neurosci..
  • 11 beta-hvdroxysteroid dehydrogenase type 1 11 beta-hydroxysteroid dehydrogenase type 1 (“1 1 ⁇ -HSD1 ") is an intracellular enzyme that converts inactive glucocorticoids (e.g. cortisone) to active glucocorticoids (e.g. Cortisol).
  • inactive glucocorticoids e.g. cortisone
  • active glucocorticoids e.g. Cortisol
  • 11 ⁇ -HSD1 can lead to cardiovascular and metabolic disorders.
  • liver-specific overexpression of 11 ⁇ -HSD1 in mice leads to insulin resistance, dyslipidemia and hypertension [Paterson et al., Proc Natl Acad U.S.A., 101 , 7088-7093, 2004].
  • 11 beta-hydroxysteroid dehydrogenase type 2 (“11 ⁇ -HSD2”) catalyzes the pre-receptor dehydrogenation of active glucocorticoids to an inactive form.
  • 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 1 1 ⁇ -HSD2 cause a decrease in 1 1 ⁇ -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 novel sEH and 11 ⁇ -HSD1 inhibitors and their use in the treatment of diseases mediated by the sEH enzyme or the 1 1 ⁇ -HSD1 enzyme. Specifically, the invention is directed to compounds according to Formula I:
  • A, W, and n are defined below, and to pharmaceutically-acceptable salts thereof.
  • this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of hypertension, organ failure / damage (including heart failure, renal failure, cardiac and renal fibrosis, and liver failure), peripheral vascular disease (including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g.
  • organ failure / damage including heart failure, renal failure, cardiac and renal fibrosis, and liver failure
  • peripheral vascular disease including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g.
  • Atherosclerosis 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 including osteoporosis, and polycystic ovary syndrome.
  • 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 ⁇ -
  • agents being selected from the group consisting of may be administered alone or
  • the invention is directed to compounds according to Formula I:
  • A is A1 , A2, or A3 wherein
  • W is S(O 2 )R2 or C(O)NR2R2;
  • X, Y, and Z are each selected from the group consisting of: Rc, Rd, Rg, or Rh; or two of X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycyclic ring having from 5 to 15 member atoms wherein said ring optionally contains one to four heteroatoms as member atoms in the ring and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa, and the other of X, Y and Z is selected from the group consisting of: H, Rc, Rd, Rg, or Rh; or X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycycl
  • 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 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.
  • 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.
  • 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 I.
  • 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.
  • 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.
  • Aryl refers to a monovalent aromatic hydrocarbon ring.
  • Aryl groups are monocyclic ring systems or bicyclic ring systems.
  • Monocyclic aryl ring refers to phenyl.
  • Bicyclic aryl ring refers to napthyl, biphenyl, and to rings wherein phenyl is fused to a cycloalkyl ring having 5, 6, or 7 member atoms.
  • Aryl groups may be optionally substituted with one or more substituents as defined herein.
  • Cycloalkyl refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms.
  • C3-C6 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 groups having from 3 to 7 member atoms or less are monocyclic ring systems. Cycloalkyl groups having at least 7 member atoms may be monocyclic, bridged or fused bicyclic ring systems. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, and cycloheptenyl.
  • 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.
  • Heteroaryl refers to a monovalent aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Unless otherwise specified, heteroaryl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms.
  • Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system.
  • Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, iso
  • Heteroatom refers to a nitrogen, sulphur, or oxygen atom.
  • Heterocycloalkyl refers to a saturated or unsaturated ring containing from 1 to
  • heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Unless otherwise specified, heterocycloalkyl groups are monocyclic, bridged, or fused ring systems. Monocyclic heterocycloalkyl rings have from 4 to 7 member atoms. Bridged or bicyclic heterocycloalkyl rings have from 7 to 11 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic.
  • Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1 ,3-dioxolanyl, 1 ,3- dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azetidinyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3
  • 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.
  • Optionally substituted indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted or substituted with one or more substituents as defined herein.
  • “Substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. 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.
  • a single atom 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.
  • A is A 1 , A 2 , or A 3 ;
  • W is S(O 2 )R 2 or C(O)NR 2 R 2 ;
  • p is 1 or 2;
  • X, Y, Z together form adamantyl which may be substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa;
  • Ri is hydrogen;
  • One R 2 is hydrogen; and the other R 2 is phenyl, pyridyl, furyl, thienyl, benzofuryl, benzothienyl, benzothiazolyl, cyclohexyl, pyrido-oxazinyl, phenyl-ethyl, napthyl, or C 2-6 alkyl; all of which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C 1-6 alkyl, NRbRb, C(O)NRbRb
  • A is A 2 , or A 3 ; W iS S(O 2 )R 2 Or C(O)NR 2 R 2 ; p is 1 or 2;
  • R 1 is hydrogen
  • R 2 is H 1 ; and the other R 2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C 1-6 alkyl, NH 2 , NHC(O)CH 3 , CF 3 , OCF 3 , phenyl, C 1-6 alkoxy, OH, CN, , NO 2 ,
  • n 1 or 2; or a pharmaceutically acceptable salt thereof.
  • A is A 2 ;
  • W is S(O 2 )R 2 ;
  • p is 1 ;
  • X, Y, Z together form unsubstituted adamantyl;
  • R 1 is hydrogen;
  • One R 2 is H 1 ; and the other R 2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C 1-6 alkyl, NH 2 , NHC(O)CH 3 , CF 3 , OCF 3 , phenyl, C 1-6 alkoxy, OH, CN; -NRbRb, and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • Compounds of Formula (I) include:
  • 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.
  • 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).
  • 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 1.4).
  • a reagent W which may be a sulfonyl chloride (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a base (such as NaOH) in a solvent (such as THF and water) at temperatures between O 0 C to 8O 0 C provides intermediate 1.2.
  • Scheme 2 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.5).
  • Intermediate 2.1 commercially available or made from commercially available starting materials using methods known to those skilled in the art
  • an amine 2.2 commercially available or made from commercially available starting materials using methods known to those skilled in the art
  • a coupling reagent such as HATU
  • a base such as triethylamine
  • a solvent such as methylene chloride
  • Treatment of intermediate 2.3 with an acid (such as HCI) in a solvent (such as dioxane) provides intermediate 2.4.
  • reagent W which may be a sulfonyl chloride or an isocyanate (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a base (such as triethylamine) in a solvent (such as methylene chloride) at temperatures between -1O 0 C to 8O 0 C provides compounds according to Formula I wherein A is A1 (depicted as compound 2.5).
  • Scheme 3 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A2 (depicted as compound 3.5), and PG is a protecting group such as a Boc or Cbz group.
  • Scheme 4 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A3 (depicted as compound 4.5).
  • Scheme 5 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A3 (depicted as compound 4.5).
  • Scheme 5 represents a reaction scheme for the synthesis of certain compounds according to Formula I (depicted as compounds 5.2 and 5.4).
  • Treatment of compound 5.1 with BBr 3 in a solvent (such as methylene chloride) provides 5.2.
  • a solvent such as methylene chloride
  • treatment of compound 5.3 with Pd/C, and H 2 in a solvent such as ethanol
  • MS and liquid chromatography MS were recorded on a MDS Sciex liquid chromatography / mass spectroscopy system. All mass spectra were performed under electrospray ionization (ESI), chemical ionization (Cl), electron impact (El) or by fast atom bombardment (FAB) methods.
  • HPLC data was recorded on an Agilent 1 100 series HPLC system with C-18 reverse phase column (Eclipse XDB-C18, 4.6 x 250 mm, 5 micron) running a gradient of 1-99% MeCN/H2O (+0.1% TFA) over 12 minutes.
  • BOP is an abbreviation for (Benzotriazol-i-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate
  • DMF is an abbreviation for dimethylformamide
  • DMSO is an abbreviation for Dimethylsulfoxide
  • HATU is an abbreviation for 2-(1 H-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium
  • 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
  • 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
  • Step 1 Preparation of ⁇ (2/?)-1-r(3-methylphenyl)sulfonyll-2-pyrrolidinyl ⁇ acetic acid
  • a 100 mL round bottom flask was equipped with a magnetic stir bar and charged with a solution of (2/?)-2-pyrrolidinylacetic acid (875 mg, 5.3 mmol) dissolved in 3.2M NaOH (6.2 mL, 19.8 mmol) and THF (15 mL).
  • the solution was cooled to 0 0 C in an ice bath, and then a solution of 3-methylbenzenesulfonyl chloride (1.4 mL, 9.5 mmol) in THF (15 mL) was added slowly.
  • the reaction was allowed to stir at 0 0 C and monitored by LC/MS until the reaction was complete (5 h).
  • the solution was acidified with 1 N HCI to reach a pH of 6 to 7 and THF was removed under reduced pressure.
  • Step 2 Preparation of 2- ⁇ (2R)-1-r(3-methylphenyl)sulfonyll-2-pyrrolidinyl ⁇ -N-tricvclo
  • reaction mixture was filtered and purified by reverse-phase HPLC (SunfireTM Prep
  • Step 1 Preparation of 1 ,1-dimethylethyl 2-r2-oxo-2-(tricvclor3.3.1.1 3 ' 7 1dec-2-ylamino) ethyli-1-pyrrolidinecarboxylate
  • Step 2 Preparation of 2-(2-pyrrolidinyl)- ⁇ /-tricvclor3.3.1.1 3 ' 7 ldec-1-ylacetamide 1 ,1-dimethylethyl-2-[2-oxo-2-(tricyclo[3.3.1.1 3 ' 7 ]dec-2-ylamino)ethyl]-1 -pyrrolidine carboxylate (165 mg) was dissolved in dioxane (2 ml.) and treated with 4M HCI (2 ml.) in dioxane at RT. The reaction was stirred at RT for 30 minutes. The reaction mixture was then concentrated and extracted with CH 2 CI 2 . The organics were collected and washed with aqueous Na 2 CO 3 and brine.
  • Step 3 Preparation of N-tricvclora.S.i .i ⁇ ldec-i-yl-2-d- ⁇ -ftrifluoromethvnphenyll sulfonyl ⁇ -2-pyrrolidinyl)acetamide
  • Step 1 Preparation of 2-(2-pyrrolidinyl)-/ ⁇ /-tricvclor3.3.1.1 3 ' 7 ldec-1-ylacetamide hydrochloride salt
  • Step 2 Preparation of N-r(2.4-dichlorophenvnmethyll-2-r2-oxo-2-(tricvclor3.3.1.1 3 ' 7 ldec-1- ylamino)ethyll-1-pyrrolidinecarboxamide
  • Step 1 Preparation of 1 ,1-dimethylethyl 2- ⁇ [(tricvclo[3.3.1.13,71dec-1- ylcarbonyl)aminolmethyl ⁇ -1-piperidinecarboxylate
  • Step 2 Preparation of N-(2-piperidinylmethyl)tricvclor3.3.1.13,7ldecane-1-carboxamide Hydrochloride Salt 1 ,1-dimethylethyl 2- ⁇ [(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl ⁇ -1- piperidinecarboxylate (9.1 g, 24.2 mmol) was dissolved in CH 2 CI 2 (25 ml.) and 4M HCI in dioxane (30.2 ml_). Solution stirred over night. Solid precipitate was filtered to give a tacky solid which was redissolved, stirred and sonicated in MeOH/hexanes and chilled. Solid precipitate was filtered to yield white solid as hydrochloride salt (5.0 g, 14.4 mmol, 59.5%). MS (ES+): m/e 277 [M + H] + .
  • Step 3 Preparation of N-[[1-[(3-chloro-4-hvdroxyphenyl)sulfonyl1-2-piperidinyl1methyl1- tricvclo[3.3.1.13,71decane-1-carboxamide N-(2-piperidinylmethyl)tricyclo[3.3.1.13,7]decane-1-carboxamide (200 mg, 0.64 mmol) was dissolved in CH 2 CI 2 (1 ml.) in a 13 x 100 mm test tube. Et 3 N (270 uL, 1.9 mmol) was added followed by 3-chloro-4-(methyloxy)benzenesulfonyl chloride (154 mg, 0.64 mmol).
  • Step 1 Preparation of 1 ,1-dimethylethyl 4-( ⁇ r(tricvclo[3.3.1.1 3 ' 7 ldec-1- ylamino)carbonyl1amino ⁇ methyl)-1-piperidinecarboxylate
  • Step 2 Preparation of ⁇ /-(4-piperidinylmethyl)- ⁇ /'-tricvclor3.3.1.1 3 ' 7 ldec-1-ylurea
  • reaction mixture was concentrated, diluted with water and CH2CI2 (30 ml.) and washed with NaHCO3 (saturated solution). The organics were collected, dried over
  • Step 3 Preparation of ⁇ /1-r(3-chloro-2-methylphenyl)sulfonyll-N-r(tricvclor3.3.1.13,7ldec- 1-ylamino)carbonyl1-4-piperidinemethanamine
  • N-( ⁇ 1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2- piperidinyl ⁇ methyl)tricyclo[3.3.1.13,7]decane-1-carboxamide (125 mg, 0.25 mmol) was dissolved in CH 2 CI 2 (2 ml.) and 1 M BBr 3 in CH 2 CI 2 (2.08 ml_, 2.08 mmol) was added under a N 2 atmosphere into a 4 ml. capped vial. The solution stirred 3 h. H 2 O (0.25 ml.) was added dropwise (vigorous exotherm) and the mixture stirred 1 h.
  • 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, 11 ⁇ -HSD1 and / or 1 1 ⁇ -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, 11 ⁇ -HSD1 and 11 ⁇ -HSD2 inhibitory activity are provided below.
  • the compounds according to Formula I are sEH inhibitors and 1 1 ⁇ -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 10,000 nM and an IC50 against 11 ⁇ -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 IC50 against sEH from 0.1 nM to 1 ,000 nM and an IC50 against 11 ⁇ - 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 IC50 against sEH from 0.1 nM to 100 nM and an IC50 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 n M to 10 nM and an IC50 against 1 1 ⁇ - HSD1 from 0.1 nM to 1 O nM.
  • mEH provides an important detoxification pathway in mammals.
  • 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.
  • 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.
  • 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.
  • 1 1 ⁇ -HSD2 catalyzes the conversion of active glucocorticoids to an inactive form in mammals.
  • Compounds that exhibit pharmacological selectivity for 1 1 ⁇ -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 IC50) equal to or greater than 10:1 for 1 1 ⁇ -HSD1 over 11 ⁇ -HSD2.
  • 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 ⁇ -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 IC50) 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
  • the assay is used in a quenched assay format by sequentially adding enzyme (5 uL; 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 ul; 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 uL; 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 ul; 10 uM P
  • 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 uL; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water.
  • Stop solution 5 uL; 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.
  • 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
  • reaction mixture is diluted 3-fold with provided sample dilution buffer (ex. Add 220 ⁇ L to the 1 10 ⁇ L reaction mixture), mixed well, and spun for 5 min at 500 rpm.
  • 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 ⁇ M-1.5 nM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
  • the assay measures the ⁇ -NADPH dependent reductase activity of Human 11 ⁇ -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.
  • 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 uL 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 uL.
  • the assay is incubated for 3 hours at 37 °C before quenching the reaction with 25 uL of 10 uM 18 ⁇ -glycyrrhetinic acid, a potent natural product inhibitor of 11 ⁇ -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 : n) where cpm, min, and max refer to counts per minute of reaction in presence of compound, 10 ⁇ M 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 i t°P - bottom . _.
  • Example 24 All of the compounds exemplified above except Example 24 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 3 and Example 5 were found to have an IC50 against sEH from 0.1 nM to 10,000 nM. Example 3 was found to have an IC50 of 19,953 nM. Example 5 was to have an IC50 greater than 25,119 nM. It is not known whether or not Example 5 would inhibit sEH activity at concentrations above 25,119 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 1 1 ⁇ -HSD1 inhibition offers some clinical benefit even though the underlying pathology is not (even in part) attributable to sEH and/or 11 ⁇ - HSD1 involvement.
  • organ failure / damage including heart failure, renal failure, cardiac and renal fibrosis, 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.
  • Heart failure is a complex heterogenous disorder characterized by reduced cardiac output, resulting in the inability of the heart to meet perfusion demands of the body. Cardiac proinflammatory cytokine recruitment and maladaptive cardiac hypertrophy, fibrosis and apoptosis/necrosis are factors associated with the progression of heart failure. Compounds of the invention are directed to methods of treating such conditions.
  • 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.
  • 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 ⁇ -
  • ACE angiotensin converting enzyme
  • 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.
  • 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.
  • 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. 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.

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Abstract

The invention is directed to novel sEH and 11 β-HSD1 inhibitors and their use in the treatment of diseases mediated by the sEH enzyme or the 1 1 β-HSD1 enzyme. Specifically, the invention is directed to compounds according to Formula I: wherein A, W, and n are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH and 11 β-HSD1 inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme or the 11 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 the 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.

Description

sEH AND 11 β-HSD1 INHIBITORS AND THEIR USE
FIELD OF THE INVENTION
The invention is directed to sEH and 1 1 β-HSD1 inhibitors and their use in the treatment of a variety of conditions mediated by the sEH enzyme or the 11 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. 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 Biophvs.. 47, 87-98, 2007], heart failure [Xu et al., Proc. Natl Acad. Sci. I/. S. A, 103, 18733-18738, 2006], renal dysfunction / end organ damage [Zhao et al., J. Am. Soc. Nephrol.. 15, 1244-1253, 2004; Imiα 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 ("1 1 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. Dallman et al, Endocrinol 145, 2633-2638, 2004; Stulnig et al., Diabetol 47, 1-11 , 2004; Wang, Nutrit Metabol 2, 1-14, 2005; Young et al., CHn Sci 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, 11 beta-hydroxysteroid dehydrogenase type 2 ("11 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 1 1 β-HSD2 cause a decrease in 1 1 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 [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, hypertension, and heart failure. [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, 1 179-1184, 1999; Krozowski et al. Endo J, 50, 485- 489, 2003, Walker, Eur J Endocrinol, 157. 545-59, 2007]; cognitive disorders including cognitive impairment, dementia, and depression [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 [Chrousos, Proc Nat Acad Sci, 101, 6329-6330, 2004]; and polycystic ovary syndrome [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 11 β-HSD1 plays in the conversion of inactive glucocorticiods to active glucocorticoids, it is desirable to prepare compounds that inhibit sEH activity and 1 1 β-HSD1 activity. Thus, there is a need to identify compounds that inhibit sEH activity and 1 1 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 novel sEH and 11 β-HSD1 inhibitors and their use in the treatment of diseases mediated by the sEH enzyme or the 1 1 β-HSD1 enzyme. Specifically, the invention is directed to compounds according to Formula I:
Figure imgf000004_0001
Formula I
wherein A, W, and n are defined below, and to pharmaceutically-acceptable salts thereof.
In yet another aspect, this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of hypertension, organ failure / damage (including heart failure, renal failure, cardiac and renal fibrosis, 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.
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 Compounds
The invention is directed to compounds according to Formula I:
Figure imgf000005_0001
Formula wherein:
A is A1 , A2, or A3 wherein
A1 is
Figure imgf000005_0002
A2 is
Figure imgf000005_0003
Figure imgf000006_0001
p is 1 or 2; W is S(O2)R2 or C(O)NR2R2;
X, Y, and Z are each selected from the group consisting of: Rc, Rd, Rg, or Rh; or two of X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycyclic ring having from 5 to 15 member atoms wherein said ring optionally contains one to four heteroatoms as member atoms in the ring and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa, and the other of X, Y and Z is selected from the group consisting of: H, Rc, Rd, Rg, or Rh; or X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycyclic ring having from 5 to 15 member atoms wherein said ring optionally contains one to four heteroatoms as member atoms in the ring and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa; when W is C(O)NR2R2, R1 is H, Rc, or Rd; when W is S(O2)R2, R1 is H; when W is C(O)NR2R2, each R2 is independently H, CH3, Re, Rf, Rg, Rh, or Rm; when W is S(O2)R2, R2 is independently CH3, Re, Rf, Rg, Rh, or Rm; each Ra is independently H, C1-C3 alkyl, or C1-C3 haloalkyl provided that when Ra is C1-C3 haloalkyl and is attached to a nitrogen atom, the carbon atom immediately adjacent to the nitrogen atom is not substituted with halo; each Rb is independently H, C1-C3 alkyl or both Rb groups, independently in each instance, taken together with the nitrogen atom to which they are attached form a saturated monocyclic ring having from 5 to 7 member atoms wherein said ring optionally contains one additional heteroatom as a member atom and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C3 alkyl, ORa, and NRaRa; each Rc is independently C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of: Ri, Rj, Rk, Rl, ORa, SRa, NRbRb, C(O)ORa, C(O)NRbRb, and C3-C6 cycloalkyl; each Rd is independently C3-C6 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: ORa, SRa, NRbRb, C(O)ORa, C(O)NRbRb, C1-C3 alkyl, and C1-C3 haloalkyl; each Re is independently C2-C10 alkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -SRa, -NRbRb, -C(O)ORa, - C(O)NRbRb, and C3-C6 cycloalkyl; each Rf is independently C3-C12 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -SRa, -NRbRb, - C(O)ORa, -C(O)NRbRb, C1-C3 alkyl, and C1-C3 haloalkyl; each Rg is independently aryl optionally substituted with one or more substituents selected from the group consisting of: -CN, -NO2, halo, Rc, Rd, C1-C3 haloalkyl, -CORa, -ORa, -SRa, -NRbRb, -S(O2)Ra, -S(O2)NRbRb, C(O)ORa, C(O)NRbRb, and - NRaC(O)NRbRb; each Rh is independently heteroaryl optionally substituted with one or more substituents selected from the group consisting of: -CN, -NO2, halo, Rc, Rd, C1-C3 haloalkyl, -CORa, -ORa, -SRa, -NRbRb, -S(O2)Ra, -S(O2)NRbRb, C(O)ORa, C(O)NRbRb, and -NRaC(O)NRbRb; each Ri is independently C3-C6 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -NRbRb, C1-C3 alkyl, and C1- C3 haloalkyl; each Rj is independently monocyclic heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -NRbRb, C1-C3 alkyl, and C1-C3 haloalkyl; each Rk is independently aryl optionally substituted with one or more substituents selected from the group consisting of: -CN, halo, -ORa, C1-C3 alkyl, C1-C3 haloalkyl, and -NRbRb; each Rl is independently heteroaryl optionally substituted with one or more substituents selected from the group consisting of: -CN, halo, -ORa, C1-C3 alkyl, C1-C3 haloalkyl, and -NRbRb; each Rm is independently C1-C3 alkyl substituted with Rg or Rh; and n is O, 1 or 2; or a pharmaceutically acceptable salt thereof. 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.
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 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.
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. 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 I.
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. Terms and Definitions
"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.
"Aryl" refers to a monovalent aromatic hydrocarbon ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl ring refers to napthyl, biphenyl, and to rings wherein phenyl is fused to a cycloalkyl ring having 5, 6, or 7 member atoms. Aryl groups may be optionally substituted with one or more substituents as defined herein.
"Cycloalkyl" refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms. For example, C3-C6 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 groups having from 3 to 7 member atoms or less are monocyclic ring systems. Cycloalkyl groups having at least 7 member atoms may be monocyclic, bridged or fused bicyclic ring systems. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, and cycloheptenyl.
"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.
"Heteroaryl" refers to a monovalent aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Unless otherwise specified, heteroaryl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms. Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzothienyl, furopyridinyl, and napthyridinyl.
"Heteroatom" refers to a nitrogen, sulphur, or oxygen atom. "Heterocycloalkyl" refers to a saturated or unsaturated ring containing from 1 to
4 heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Unless otherwise specified, heterocycloalkyl groups are monocyclic, bridged, or fused ring systems. Monocyclic heterocycloalkyl rings have from 4 to 7 member atoms. Bridged or bicyclic heterocycloalkyl rings have from 7 to 11 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1 ,3-dioxolanyl, 1 ,3- dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azetidinyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, and pthalimidyl. "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.
"Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted or substituted with one or more substituents as defined herein. "Substituted" in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. 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). In certain embodiments, a single atom 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.
"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. Representative Embodiments In one embodiment: A is A1, A2, or A3 ; W is S(O2)R2 or C(O)NR2R2; p is 1 or 2;
X, Y, Z together form adamantyl which may be substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa; Ri is hydrogen; One R2 is hydrogen; and the other R2 is phenyl, pyridyl, furyl, thienyl, benzofuryl, benzothienyl, benzothiazolyl, cyclohexyl, pyrido-oxazinyl, phenyl-ethyl, napthyl, or C2-6alkyl; all of which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C1-6alkyl, NRbRb, C(O)NRbRb, CF3, OCF3, phenyl, C1-6 alkoxy, ORa, CN, NO2, C(O)ORa, or morpholinyl; Ra is hydrogen or C1-3alkyl; Rb is hydrogen or C1-3alkyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
In another embodiment:
A is A2, or A3; W iS S(O2)R2 Or C(O)NR2R2; p is 1 or 2;
X, Y, Z together form unsubstituted adamantyl;
R1 is hydrogen;
One R2 is H1; and the other R2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C1-6alkyl, NH2, NHC(O)CH3, CF3, OCF3, phenyl, C1-6 alkoxy, OH, CN, , NO2,
-NRbRb, CO2CH3, or morpholinyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
In yet another embodiment:
A is A2; W is S(O2)R2; p is 1 ;
X, Y, Z together form unsubstituted adamantyl; R1 is hydrogen; One R2 is H1; and the other R2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C1-6alkyl, NH2, NHC(O)CH3, CF3, OCF3, phenyl, C1-6 alkoxy, OH, CN; -NRbRb, and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
It is to be understood that the present invention covers all combinations of particular groups described hereinabove.
Compounds of Formula (I) include:
2-{(2R)-1-[(3-methylphenyl)sulfonyl]-2-pyrrolidinyl}-N-tricyclo[3.3.1.13'7]dec-2- ylacetamide;
N-tricyclo[3.3.1.13'7]dec-1-yl-2-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}-2-pyrrolidinyl) acetamide;
N-[(2,4-dichlorophenyl)methyl]-2-[2-oxo-2-(tricyclo[3.3.1.13'7]dec-1-ylamino)ethyl]-1- pyrrolidinecarboxamide;
N-[[1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide; 1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
N-^i-^S-nitrophenyl)sulfonyl]-2-piperidinylJmethyOtricyclo[3.3.1.13,7]decane-i- carboxamide;
N-({1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2- piperidinyl}methyl)tricyclo[3.3.1.13,7]decane-1-carboxamide;
(2R)-1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
N-[[(2R)-1-[(4-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-^R^I-p-fluorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(2-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidineacetamide; 1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; 1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidineacetamide;
1-(3-pyridinylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide trif I u oroacetate (1 :1 ;)
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
2-[1 -(4-biphenylylsulfonyl)-2-pyrrolidinyl]-N-tricyclo[3.3.1.13'7]dec-1 -ylacetamide;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; 1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide;
1-[(2-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(cyclohexylamino)carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
N-(2-chlorophenyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
N-(2,4-dichlorophenyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide; 4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2-
(trifluoromethoxy)phenyl]-1 -piperidinecarboxamide;
N-cyclohexyl-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine; i-φhenylsulfonyl)-N-^tricycloβ.S.I .I SJJdec-i-ylamino^arbonyl]^- piperidinemethanamine; i-φutylsulfonyO-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonylH- piperidinemethanamine; 1-([1 ,1'-biphenyl]-4-ylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2-
(trifluoromethyl)phenyl]-1-piperidinecarboxamide; N-(phenylmethyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide; i^methylsulfonyO-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonylH- piperidinemethanamine;
N-butyl^-tt^tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]aminolmethyl]-!- piperidinecarboxamide;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine ;
1-[(2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine; N-phenyl^-ftt(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyllaminolmethyl]-!- piperidinecarboxamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-(butylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; 1-(cyclohexylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide;
1-[(2-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; i-φhenylsulfonyO-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine; 1-[(4-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine ;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide ;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide ; ^(phenylsulfonyO-N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- pyrrolidinemethanamine;
1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; 1-[(4-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine ;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(2-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[(3-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide ;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide; 1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide;
1-[(3-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide; 1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide ;
1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide; 1-[(2,4-dimethoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
N-[4-(dimethylamino)phenyl]-4-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide trifluoroacetate (1 :1 ); i-φhenylsulfonyO-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- piperidinemethanamine; i-φhenylsulfonyO-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- piperidinemethanamine;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1 -([1 , 1 '-biphenyl]-4-ylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1 -yl-3-pyrrolidineacetamide;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tfS-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidinemethanamine;
1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidinemethanamine;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
1-[(2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; i-^S-methylphenyl)sulfony^-N-^tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine; i-[(4-methoxyphenyl)sulfony^-N-f(tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine;
N-f(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-t^-(trifluoromethyl)pheny^sulfonyl]-2- pyrrolidinemethanamine;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; i-[(4-methylphenyl)sulfony^-N-^tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine;
N-(2,4-dichlorophenyl)-2-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide; N-[(2,4-dichlorophenyl)methyl]-2-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-pyrrolidinecarboxamide ; i-^^-dimethoxyphenyl)sulfonyl]-N-t(tricyclofS.S.I .I SJldec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine; 1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
N-f(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tP-(trifluoromethyl)phenyl]sulfonyl]-3- piperidinemethanamine ; i-[(2-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- piperidinemethanamine ;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tfS-(trifluoromethyl)phenyl]sulfonyl]-3- piperidinemethanamine; 1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
1-[(3-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
1-[(4-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine ;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine; 1-[(4-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
N-(2,4-dichlorophenyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide ;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
N-[(2,4-dichlorophenyl)methyl]-4-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide;
1-(cyclohexylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine; N-(1-phenylethyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide; 1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; 1-[(2,4-dimethoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-4- piperidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine; N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-i-^-(trifluoromethyl)phenyl]sulfonyl]-2- piperidinemethanamine; i-[(2-methylphenyl)sulfonyl]-N-^tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- piperidinemethanamine;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-ttS-(trifluoromethyl)pheny^sulfonyl]-2- piperidinemethanamine;
1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(3-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine ; i-[(4-methoxyphenyl)sulfony^-N-t(tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- piperidinemethanamine;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; 1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3- piperidineacetamide;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3- piperidineacetamide;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3- piperidineacetamide; 1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide; 1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-4- piperidineacetamide; 1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-4- piperidineacetamide;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide;
1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide; 1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-[[1-tP-(trifluoromethyl)phenyl]sulfonyl]-3-piperidinyl]methyl]-tricyclotS.S.I .I S.yjdecane-
1-carboxamide; N-[[1-[(2-chlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^^-dimethoxyphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-ffi-[(4-methoxyphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2- piperidinemethanamine;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(4-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
N-[(2,4-dichlorophenyl)methyl]-2-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide; N-(2,4-dichlorophenyl)-2-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine; i-^^-dimethoxyphenyl)sulfonyl]-N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- piperidinemethanamine;
N-f(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-t^-(trifluoromethyl)phenyl]sulfonyl]-3- piperidinemethanamine;
N-[(2,4-dichlorophenyl)methyl]-3-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1 -piperidinecarboxamide;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
N-(2,4-dichlorophenyl)-3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide;
N-[[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide; N-[[1-(phenylsulfonyl)-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1-carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; N-[[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-methylphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methylphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[(2,4-dichlorophenyl)methyl]-4-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide; N-[[1-(phenylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1-carboxamide;
N-[[1-^S-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-(phenylsulfonyl)-2-piperidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
1-(cyclohexylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(cyclohexylamino)carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[[2-(trifluoromethoxy)phenyl]amino]carbonyl]-3- pyrrolidineacetamide;
N-[[1-(phenylsulfonyl)-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide; N-[[1-[(2-methylphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methyl phenyl )sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide; N-ffi-[[4-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]methyll-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methyl phenyl )sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide; N-[[1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2,4-dimethoxyphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; 1-(butylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^S-(trifluoromethyl)phenyl]sulfonyl]^-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-[(3-chlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2,4-dimethoxyphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-phenyl-3-ftt(tricyclofS.S.I .ISJldec-i-ylamino^arbonyllaminolmethyl]-!- pyrrolidinecarboxamide;
N-(2-chlorophenyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide; N-[4-(dimethylamino)phenyl]-3-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-pyrrolidinecarboxamide trifluoroacetate (1 :1 ) ;
N-[(2,4-dichlorophenyl)methyl]-3-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-pyrrolidinecarboxamide;
3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2- (trifluoromethyl)phenyl]-1 -pyrrolidinecarboxamide;
3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2-
(trifluoromethoxy)phenyl]-1 -pyrrolidinecarboxamide;
1-[(4-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidinemethanamine;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; i-[(4-fluorophenyl)sulfonyl]-N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- pyrrolidinemethanamine;
1-([1 ,1'-biphenyl]-4-ylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; N-butyl-3-tt^tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]aminolmethyl]-!- pyrrolidinecarboxamide;
N-(1-phenylethyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide; i-^S-methoxyphenyl)sulfonyll-N-f(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyll-3- pyrrolidinemethanamine;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tfS-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidinemethanamine;
1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; 1-[(3-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(3-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-cyclohexyl-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-(phenylmethyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-(2,4-dichlorophenyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide; N-[(2,4-dichlorophenyl)methyl]-2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- pyrrolidinecarboxamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1 -carboxamide;
N-[[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide ; N-[(2,4-dichlorophenyl)methyl]-3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; N-ffi-p-(trifluoromethyl)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclotS.S.I .I SJldecane-
1-carboxamide;
N-[(2,4-dichlorophenyl)methyl]-3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- pyrrolidinecarboxamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; N-[[1-[(2-chlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-methyl phenyl )sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methyl phenyl )sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclotS.S.I .IS^Jdecane-i- carboxamide;
N-[[1-[(4-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]methy^-tricyclofS.S.I .ISJldecane-
1 -carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methyl phenyl )sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclotS.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(2-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^S-(trifluoromethyl)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclotS.S.I .I S.yjdecane-
1 -carboxamide; N-[[1-[(3-chlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^S-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide ; N-[[1-[(4-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2,4-dimethoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[(2,4-dichlorophenyl)methyl]-2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide ;
1-[(2-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; 1-[(2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(2-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-[[1-[(5-chloro-2-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1 -carboxamide;
N-[[1-[(3-chloro-4-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(2-fluoro-5-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-[(3-chloro-2-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[[4-(acetylamino)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^phenylmethyl)sulfonyl]-2-piperidinyl]methyll-tricyclotS.S.I .I SJldecane-i- carboxamide;
N-[[1-^S^-dimethoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-^S-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(2,3-dihydro-1-methyl-1 H-pyrido[2,3-b][1 ,4]oxazin-6-yl)sulfonyl]-2- piperidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
4-methoxy-5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinyl]sulfonyl]-3-thiophenecarboxylic acid methyl ester; N-[[1-[(3-methoxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1 ,4-oxazin-7-yl)sulfonyl]-3- pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
4-methoxy-5-[[3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- pyrrolidinyl]sulfonyl]-3-thiophenecarboxylic acid methyl ester;
N-[[1-[(4-cyanophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-cyanophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-tfi-[(4-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclofS.S.I .I SJldecane-i- carboxamide;
N-[[1-(6-benzothiazolylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide ;
N-[[1-(benzo[b]thien-3-ylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[[4-[(benzoylamino)methyl]-2-thienyl]sulfonyl]-3-pyrrolidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2-cyanophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(4-chloro-3-nitrophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^S-nitrophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclotS.3.1.13,7]decane-1- carboxamide; N-tfi-[(4-nitrophenyl)sulfonyl]-2-piperidinyl]methyll-tricyclotS.S.I .I SJldecane-i- carboxamide ;
3-methyl-5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1-piperidinyl]sulfonyl]-
2-furancarboxylic acid methyl ester;
N-[[1-[(4-chloro-3-nitrophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-nitrophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-nitrophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(2-chloro-4-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3,5-dichlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[[4-(2-oxo-1-pyrrolidinyl)phenyl]sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1-piperidinyl]sulfonyl]-2- furancarboxylic acid methyl ester; 2-methyl-5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1-piperidinyl]sulfonyl]-
3-furancarboxylic acid methyl ester;
N-[2-[1-[(4-chlorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(4-fluorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(3-chlorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[2-[1-[(3-methylphenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; N-[2-[1-[(2-chlorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-EP-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[2-[1-(phenylsulfonyl)-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1-carboxamide; N-[[1-[(3-cyanophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-hydroxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-^-hydroxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-3-azetidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-3-azetidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-chloro-2-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2-methoxy-4-methylphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(4-fluoro-3-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(3-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(5-chloro-2-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(4-hydroxy-3-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2-chloro-4-cyanophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1-carboxamide; N-III-ICS-aminophenyl)sulfonyl]-3-pyrrolidinyl]methy^-tricycloIS.S.1.13,7]decane-1- carboxamide;
N-[[1-[(4-aminophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclotS.S.I .I S.yjdecane-i- carboxamide; N-fti-[(4-aminophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(2-hydroxy-4-methylphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-methylbenzo[b]thien-2-yl)sulfonyl]-3-pyrrolidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-methylbenzo[b]thien-2-yl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-(benzo[b]thien-2-ylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-φenzo^thien-2-ylsulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(5-chloro-3-methylbenzo[b]thien-2-yl)sulfonyl]-3-pyrrolidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-chloro-3-methylbenzo[b]thien-2-yl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-(2-benzofuranylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-(2-benzofuranylsulfonyl)-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[2-[1-[(4-chlorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane- 1 -carboxamide;
N-[2-[1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[2-[1-[(3-chlorophenyl)sulfonyl]-2-pyrτolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(3-methylphenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[2-[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[2-[1-[(2-chlorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methoxy-1-naphthalenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
Λ/-({1-[(4-chloro-2,5-dimethylphenyl)sulfonyl]-3- pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1 -carboxamide;
Λ/-({1-[(2,5-dichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide; Λ/-[(1 -{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3- pyrrolidinyl)methyl]tricyclo[3.3.1.13'7]decane-1 -carboxamide;
Λ/-({1-[(2,5-dimethylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
Λ/-({1-[(4-bromo-2-chlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane- 1 -carboxamide;
Λ/-({1-[(2,3-dichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
Λ/-({1-[(2,3,4-trichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide; Λ/-({1-[(2-chloro-6-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide;
Λ/-({1-[(2,6-dichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
Λ/-({1-[(5-bromo-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane- 1 -carboxamide;
Λ/-({1-[(5-fluoro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide; and
Λ/-({1-[(3-fluoro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide; or a pharmaceutically acceptable salt thereof. 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.
Scheme 1
Figure imgf000035_0001
1.1 1.2 1.3 1.4
Scheme 1 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 1.4). Treatment of intermediate 1.1 with a reagent W which may be a sulfonyl chloride (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a base (such as NaOH) in a solvent (such as THF and water) at temperatures between O0C to 8O0C provides intermediate 1.2. Treatment of intermediate 1.2 with an amine 1.3 (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a coupling reagent (such as 1 H-1 ,2,3-benzotriazol-1-yloxy-tris(dimethylamino)- phosphonium hexafluorophosphate (BOP) reagent) and a base (such as triethylamine) in a solvent (such as DMF) at temperatures between 00C to 800C provides compounds according to Formula I wherein A is A1 (depicted as compound 1.4).
Scheme 2
Figure imgf000036_0001
2.1 2.2 2.3 2.4
W W base KTΉPfN-J- Y R1 Z
2.5
Scheme 2 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.5). Treatment of intermediate 2.1 (commercially available or made from commercially available starting materials using methods known to those skilled in the art) with an amine 2.2 (commercially available or made from commercially available starting materials using methods known to those skilled in the art) with a coupling reagent (such as HATU) and a base (such as triethylamine) in a solvent (such as methylene chloride) at temperatures between 0 to 8O0C provides intermediate 2.3. Treatment of intermediate 2.3 with an acid (such as HCI) in a solvent (such as dioxane) provides intermediate 2.4. Treatment of intermediate 2.4 with a reagent W which may be a sulfonyl chloride or an isocyanate (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a base (such as triethylamine) in a solvent (such as methylene chloride) at temperatures between -1O0C to 8O0C provides compounds according to Formula I wherein A is A1 (depicted as compound 2.5). Scheme 3
Figure imgf000037_0001
O Zh
3.1 3.2 3.3 3.4
Figure imgf000037_0002
3.5
Scheme 3 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A2 (depicted as compound 3.5), and PG is a protecting group such as a Boc or Cbz group.
Scheme 4
Figure imgf000037_0003
4.1 4.2 4.3 4.4
Figure imgf000037_0004
4.5
Scheme 4 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A3 (depicted as compound 4.5). Scheme 5
Figure imgf000038_0001
.1 5.2
5.3 5.4
Scheme 5 represents a reaction scheme for the synthesis of certain compounds according to Formula I (depicted as compounds 5.2 and 5.4). Treatment of compound 5.1 with BBr3 in a solvent (such as methylene chloride) provides 5.2. In addition, treatment of compound 5.3 with Pd/C, and H2 in a solvent (such as ethanol) yields compound 5.4. 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.
1 H NMR spectra were recorded on a Bruker Avance 400 megahertz NMR spectrometer. 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).
MS and liquid chromatography MS were recorded on a MDS Sciex liquid chromatography / mass spectroscopy system. All mass spectra were performed under electrospray ionization (ESI), chemical ionization (Cl), electron impact (El) or by fast atom bombardment (FAB) methods. HPLC data was recorded on an Agilent 1 100 series HPLC system with C-18 reverse phase column (Eclipse XDB-C18, 4.6 x 250 mm, 5 micron) running a gradient of 1-99% MeCN/H2O (+0.1% TFA) over 12 minutes.
All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, p-anisaldehyde solution, aqueous potassium permanganate or potassium iodide / platinum chloride solution in water.
Flash column chromatography was performed on silica gel.
The naming program used is ACD Name Pro 6.02. 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. For example, the following abbreviations are used herein: "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 "DMSO" is an abbreviation for Dimethylsulfoxide
"equiv" is an abbreviation for equivalent
"HATU" is an abbreviation for 2-(1 H-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium
"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
Example 1 2-{(2R)-1-[(3-methylphenyl)sulfonyl]-2-pyrrolidinyl}-N-tricyclo[3.3.1.13'7]dec-2-ylacetamide
Figure imgf000040_0001
Step 1 : Preparation of {(2/?)-1-r(3-methylphenyl)sulfonyll-2-pyrrolidinyl}acetic acid
A 100 mL round bottom flask was equipped with a magnetic stir bar and charged with a solution of (2/?)-2-pyrrolidinylacetic acid (875 mg, 5.3 mmol) dissolved in 3.2M NaOH (6.2 mL, 19.8 mmol) and THF (15 mL). The solution was cooled to 00C in an ice bath, and then a solution of 3-methylbenzenesulfonyl chloride (1.4 mL, 9.5 mmol) in THF (15 mL) was added slowly. The reaction was allowed to stir at 00C and monitored by LC/MS until the reaction was complete (5 h). The solution was acidified with 1 N HCI to reach a pH of 6 to 7 and THF was removed under reduced pressure. The aqueous residue was further acidified to a pH of 3 with additional 1 N HCI, diluted with water, and extracted with EtOAc (1 x 100 mL). The organic layer was dried over Mg2SO4, filtered, and concentrated to dryness to give {(2/?)-1-[(3-methylphenyl)sulfonyl]-2- py rrol id i ny l}acetic acid as a brown oil which was used without further purification in the next step. MS (ES) m/e 284 [M+H]+.
Step 2: Preparation of 2-{(2R)-1-r(3-methylphenyl)sulfonyll-2-pyrrolidinyl}-N-tricvclo
[3.3.1.13'7ldec-2-ylacetamide
{(2/?)-1-[(3-methylphenyl)sulfonyl]-2-pyrrolidinyl}acetic acid (113 mg, 0.4 mmol), tricyclo[3.3.1.13'7]dec-2-ylamine (60.5 mg, 0.4 mmol), Et3N (0.1 mL, 0.8 mmol), and 1 H-
1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP,
177 mg, 0.4 mmol) were combined together in DMF (1.5 mL) and stirred at RT for 18 h.
The reaction mixture was filtered and purified by reverse-phase HPLC (Sunfire™ Prep
C18 (OBD™ 5 Dm 30 x 150 mm), A: acetonitrile (0.1% TFA) B: water (0.1% TFA), A: 40 to 70%) to provide the title compound (71.5 mg, 0.17 mmol, 43 %) as a pale orange oil.
MS (ES) m/e 417 [M+H]+. Example 2
N-tricyclo[3.3.1.13'7]dec-1-yl-2-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}-2-pyrrolidinyl) acetamide
Figure imgf000041_0001
Step 1 : Preparation of 1 ,1-dimethylethyl 2-r2-oxo-2-(tricvclor3.3.1.13'71dec-2-ylamino) ethyli-1-pyrrolidinecarboxylate
(^{[(I J-dimethylethyOoxylcarbonyl]-2-pyrrolidinyOacetic acid (100 mg, 0.436 mmol) was dissolved in CH2CI2 (1 ml.) and the mixture was treated with HATU (182 mg, 0.480 mmol), Et3N (0.12 ml_, 0.872 mmol), and 1-adamantyl amine (90 mg, 0.479 mmol) at RTe. The reaction was stirred for two h. The reaction mixture was washed with 1 M HCI, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (gradient elution from 50:1 to 10:1 methylene chloride:methanol) to yield 1 ,1-dimethylethyl 2-[2-oxo-2- (tricyclo[3.3.1.13'7]dec-2-ylamino)ethyl]-1-pyrrolidinecarboxylate (165 mg) as a pale yellow solid. MS (ES) m/e 363 [M+H]+.
Step 2: Preparation of 2-(2-pyrrolidinyl)-Λ/-tricvclor3.3.1.13'7ldec-1-ylacetamide 1 ,1-dimethylethyl-2-[2-oxo-2-(tricyclo[3.3.1.13'7]dec-2-ylamino)ethyl]-1 -pyrrolidine carboxylate (165 mg) was dissolved in dioxane (2 ml.) and treated with 4M HCI (2 ml.) in dioxane at RT. The reaction was stirred at RT for 30 minutes. The reaction mixture was then concentrated and extracted with CH2CI2. The organics were collected and washed with aqueous Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give 2-(2-pyrrolidinyl)-Λ/-tricyclo[3.3.1.13'7]dec-1-ylacetamide as a brown oil which was used without further purification in the next step. MS (ES) m/e 263 [M+H]+.
Step 3: Preparation of N-tricvclora.S.i .i^ldec-i-yl-2-d-^-ftrifluoromethvnphenyll sulfonyl}-2-pyrrolidinyl)acetamide
2-(2-pyrrolidinyl)-Λ/-tricyclo[3.3.1.13'7]dec-1-ylacetamide (73 mg, 0.279 mmol) was dissolved in of CH2CI2 (3 ml.) and treated with Et3N (0.12 ml_, 0.837 mmol) followed by 4- trifluoromethylbenzenesulfonyl chloride (75 mg, 0.307 mmol) at RT. The reaction was stirred for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to provide the title compound (35 mg, 0.074 mmol, 27%) as a white solid. MS (ES) m/e 471 [M+H]+.
Example 3
N-[(2,4-dichlorophenyl)methyl]-2-[2-oxo-2-(tricyclo[3.3.1.13'7]dec-1-ylamino)ethyl]-1- pyrrolidinecarboxamide
Figure imgf000042_0001
Step 1 : Preparation of 2-(2-pyrrolidinyl)-/\/-tricvclor3.3.1.13'7ldec-1-ylacetamide hydrochloride salt
1 ,1-dimethylethyl-2-[2-oxo-2-(tricyclo[3.3.1.13'7]dec-2-ylamino)ethyl]-1 -pyrrolidine carboxylate (12.8 g, 35.3 mmol) was dissolved in dioxane (30 ml.) and treated with 4M HCI in dioxane (30 ml.) at RT. The reaction was stirred at RT for 30 min. The reaction mixture was concentrated to give the hydrochloride salt of 2-(2-pyrrolidinyl)-Λ/- tricyclo[3.3.1.13'7]dec-1-ylacetamide (9.76 g, 92 %) which was used without further purification in the next step. MS (ES) m/e 263 [M+H]+.
Step 2: Preparation of N-r(2.4-dichlorophenvnmethyll-2-r2-oxo-2-(tricvclor3.3.1.13'7ldec-1- ylamino)ethyll-1-pyrrolidinecarboxamide
Crude 2-(2-pyrrolidinyl)-Λ/-tricyclo[3.3.1.13'7]dec-1-ylacetamide, hydrochloride salt (300 mg, estimated 30 % purity, 0.3 mmol) was dissolved in 3 ml. of methylene chloride and treated with Et3N (0.17 ml_, 1.28 mmol) and cooled to 00C. 2,4-dichloro-1- (isocyanatomethyl)benzene (0.043 ml_, 0.33 mmol) was added dropwise and stirred for 10 min at 00C. The reaction mixture was warmed to RT and stirred for 3 h. The solvent was evaporated and the crude mixture was purified by preparative HPLC to provide N- [(2,4-dichlorophenyl)methyl]-2-[2-oxo-2-(tricyclo[3.3.1.13'7]dec-1-ylamino)ethyl] -1- pyrrolidinecarboxamide (63 mg, 0.14 mmol, 45 %). MS (ES) m/e 464 [M+H]+.
Example 4
N-[[1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000043_0001
Step 1 : Preparation of 1 ,1-dimethylethyl 2-{[(tricvclo[3.3.1.13,71dec-1- ylcarbonyl)aminolmethyl}-1-piperidinecarboxylate
The (3s,5s,7s)-tricyclo[3.3.1.13,7]decane-1-carboxylic acid (4.7 g, 26.1 mmol) and BOP (1 1.5 g. 26.1 mmol) were dissolved in CH2CI2 (25 ml.) in a 2-neck round bottom flask. A mixture of 1 ,1-dimethylethyl 2-(aminomethyl)-1-piperidinecarboxylate (5.6 g, 26.1 mmol) in CH2CI2 (25 ml.) with Et3N (10.9 ml_, 78 mmol) was slowly (exotherm) added to the solution via pipet. The mixture stirred overnight, and the non-UV active product was seen by LCMS ionization. Concentrated down solvent, added 30 ml EtOAc, let stir 3 h, the white solid precipitate was filtered and dried in vacuum oven to yield a white solid
(9.0 g, 21.5 mmol, 82%). MS (ES+): m/e 377 [M + H]+.
Step 2: Preparation of N-(2-piperidinylmethyl)tricvclor3.3.1.13,7ldecane-1-carboxamide Hydrochloride Salt 1 ,1-dimethylethyl 2-{[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl}-1- piperidinecarboxylate (9.1 g, 24.2 mmol) was dissolved in CH2CI2 (25 ml.) and 4M HCI in dioxane (30.2 ml_). Solution stirred over night. Solid precipitate was filtered to give a tacky solid which was redissolved, stirred and sonicated in MeOH/hexanes and chilled. Solid precipitate was filtered to yield white solid as hydrochloride salt (5.0 g, 14.4 mmol, 59.5%). MS (ES+): m/e 277 [M + H]+.
Step 3: Preparation of N-[[1-[(3-chloro-4-hvdroxyphenyl)sulfonyl1-2-piperidinyl1methyl1- tricvclo[3.3.1.13,71decane-1-carboxamide N-(2-piperidinylmethyl)tricyclo[3.3.1.13,7]decane-1-carboxamide (200 mg, 0.64 mmol) was dissolved in CH2CI2 (1 ml.) in a 13 x 100 mm test tube. Et3N (270 uL, 1.9 mmol) was added followed by 3-chloro-4-(methyloxy)benzenesulfonyl chloride (154 mg, 0.64 mmol). The mixture was agitated a few seconds until homogeneous, sat 10 minutes, and solid precipitate was filtered to give the title compound as a white solid (125 mg, 0.25 mmol). To provide a sample for testing, the filtrate was concentrated to dryness and dissolved in MeOH (1 ml.) for reversed-phase HPLC purification: (Sunfire™ Prep C18 (OBD™ 5 um 30 x 150 mm), A: acetonitrile (0.1%TFA) B: water (0.1% TFA), A: 30 to 90%). MS (ES) m/e 481 [M+H]+.
Example 5 1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine
Figure imgf000044_0001
Step 1 : Preparation of 1 ,1-dimethylethyl 4-({r(tricvclo[3.3.1.13'7ldec-1- ylamino)carbonyl1amino}methyl)-1-piperidinecarboxylate
To a stirring solution of 1-adamantanine hydrochloride (3.09 g, 16.5 mmol), DIEA (4.2 g, 33.0 mmol), and CH2CI2 (40 ml.) was added a solution of triphosgene (1.62 g, 5.4 mmol) and CH2CI2 (40 ml_). The resulting solution was stirred at RT for 10 min and then a solution of 1-boc-4-(aminomethyl)piperdine (3.44 g, 16.0 mmol) and CH2CI2 (10 ml.) was added. The solution was stirred at RT for 40 min. The reaction mixture was washed with 1 M HCI, NaHCO3 (saturated solution), and brine. The organics were collected, dried over Na2SO4, filtered, and concentrated to yield the desired product (6.2 g).
Step 2: Preparation of Λ/-(4-piperidinylmethyl)-Λ/'-tricvclor3.3.1.13'7ldec-1-ylurea
To a solution of 1 ,1-dimethylethyl 4-({[(tricyclo[3.3.1.13'7]dec-1- ylamino)carbonyl]amino}methyl)-1-piperidinecarboxylate (3 .0 g, 75 mmol) in dioxane (20 ml.) was added 4 N HCI in dioxane (20 ml.) and the reaction mixture was stirred for 1 h.
The reaction mixture was concentrated, diluted with water and CH2CI2 (30 ml.) and washed with NaHCO3 (saturated solution). The organics were collected, dried over
Na2SO4, filtered, and concentrated to yield the desired product (0.98 g). Step 3: Preparation of Λ/1-r(3-chloro-2-methylphenyl)sulfonyll-N-r(tricvclor3.3.1.13,7ldec- 1-ylamino)carbonyl1-4-piperidinemethanamine
To a solution of Λ/-^-piperidinylmethyl)-Λ/'-tricycloβ.S.i .i^dec-i-ylurea (50 mg,
0.2 mmol), Et3N (34.7 g, 0.3 mmol), and CH2CI2 (5 ml.) was added 3-chloro-2- methylbenzenesulfonyl chloride (46 mg, 0.2 mmol) and the reaction mixture was stirred for 6 h. The crude mixture was purified by preparative HPLC to provide the desired product (50 mg). MS (ES) m/e 500.1 [M+H]+.
Example 6 N-({1-[(3-nitrophenyl)sulfonyl]-2-piperidinyl}methyl)tricyclo[3.3.1.13,7]decane-1- carboxamide
Figure imgf000045_0001
10% Pd-C (35 mg) was placed in a N2 filled 250 ml. Parr bottle, followed by a solution of N-({1-[(3-nitrophenyl)sulfonyl]-2-piperidinyl}methyl)tricyclo[3.3.1.13,7]decane- 1-carboxamide (306 mg, 0.66 mmol) and EtOH (8 ml_). This mixture was placed on Parr shaker at 55 psi of H2 for 1 h after which N2 was bubbled through mixture 10 min. The reaction mixture was filtered and the filtrate was collected and evaporated to dryness. The crude product was redissolved in CH2CI2 (3 ml.) and filtered again. The filtrate was collected and concentrated under high vacuum to yield the desired product as a light brown solid (218 mg, 0.4 mmol, 68.6%). MS (ES+): m/e 432 [M + H]+.
Example 7
N-({1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2- piperidinyl}methyl)tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000046_0001
N-({1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2- piperidinyl}methyl)tricyclo[3.3.1.13,7]decane-1-carboxamide (125 mg, 0.25 mmol) was dissolved in CH2CI2 (2 ml.) and 1 M BBr3 in CH2CI2 (2.08 ml_, 2.08 mmol) was added under a N2 atmosphere into a 4 ml. capped vial. The solution stirred 3 h. H2O (0.25 ml.) was added dropwise (vigorous exotherm) and the mixture stirred 1 h. The mixture was concentrated to near dryness, MeOH (1 ml_), and was purified by reversed-phase HPLC: (Sunfire™ Prep C18 (OBD™ 5 urn 30 x 150 mm), A: acetonitrile (0.1 %TFA) B: water (0.1% TFA), A: 30 to 90%). The title compound resulted as a white solid (7.9 mg, 0.16 mmol, 6.2%). MS (ES) m/e 467 [M+H]+.
The following table illustrates compounds that were prepared in using the general procedure described above. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure.
exp # structure m/z name
(2R)-1-[(3-methylphenyl)sulfonyl]-N-
417 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
Figure imgf000046_0002
N-[[(2R)-1-[(4-chlorophenyl)sulfonyl]-2-
437.2 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000047_0001
N-[[(2R)-1-[(3-fluorophenyl)sulfonyl]-2-
421.3 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000047_0002
1 -[(3-methylphenyl)sulfonyl]-N-
417 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
Figure imgf000047_0003
1-[(2-methoxyphenyl)sulfonyl]-N-
433 tricyclo[3.3.1.13,7]dec-1-yl-2-
Figure imgf000047_0004
pyrrolidineacetamide
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-
471 (trifluoromethyl)phenyl]sulfonyl]-2-
Figure imgf000047_0005
pyrrolidineacetamide
1-[(2-chlorophenyl)sulfonyl]-N-
437 tricyclo[3.3.1.13,7]dec-1-yl-2-
Figure imgf000047_0006
pyrrolidineacetamide 1 -[(2-methylphenyl)sulfonyl]-N-
417 tricyclo[3.3.1.13,7]dec-1-yl-2-
Figure imgf000048_0001
pyrrolidineacetamide
A
N-tricyclo[3.3.1.13,7]deo-1-yl-1-[[3-
471 (trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidineacetamide
Figure imgf000048_0002
1-(3-pyridinylsulfonyl)-N-
404 tricyclo[3.3.1.13,7]dec-1-yl-2-
Figure imgf000048_0003
pyrrolidineacetamide trifluoroacetate (1 :1 )
1 -[(4-methylphenyl)sulfonyl]-N-
417 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
Figure imgf000048_0004
2-[1-(4-biphenylylsulfonyl)-2-pyrrolidinyl]-N-
479 tricyclo[3.3.1.13'7]dec-1-ylacetamide
Figure imgf000048_0005
CUs 1-(phenylsulfonyl)-N-
Figure imgf000049_0001
403 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
1-[(2,4-dichlorophenyl)sulfonyl]-N-
471 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
Figure imgf000049_0002
1-[(3-chlorophenyl)sulfonyl]-N-
437 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
Figure imgf000049_0003
1-[(3-fluorophenyl)sulfonyl]-N-
421 tricyclo[3.3.1.13,7]dec-1-yl-2-
Figure imgf000049_0004
pyrrolidineacetamide
1-[(4-methoxyphenyl)sulfonyl]-N-
433 tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide
Figure imgf000049_0005
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-
68 465.1 tricyclo[3.3.1.13,7]dec-1-yl-2-
Figure imgf000056_0001
piperidineacetamide
1-[(3-fluorophenyl)sulfonyl]-N-
69 b?-crr!20- 421.3 tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide
1-[(4-methoxyphenyl)sulfonyl]-N-
70
Figure imgf000056_0002
433.3 tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-
71 'K>?-"Cnr"^- 471.3 (trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide
1-[(4-chlorophenyl)sulfonyl]-N-
72 437.3 tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-
73 485.3 (trifluoromethyl)phenyl]sulfonyl]-2-
Figure imgf000056_0003
piperidineacetamide
1-[(2-chlorophenyl)sulfonyl]-N-
74 451.3 tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide
Figure imgf000056_0004
1-[(2-methylphenyl)sulfonyl]-N-
75 431.3 tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide
Figure imgf000057_0001
1-[(3-chlorophenyl)sulfonyl]-N-
76 451.3 tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide
Figure imgf000057_0002
1-[(3-methylphenyl)sulfonyl]-N-
77 431.3 tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide
Figure imgf000057_0003
1-[(4-methoxyphenyl)sulfonyl]-N-
78 447.3 tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide
Figure imgf000057_0004
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-
79 485.3 (trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide
Figure imgf000057_0005
Figure imgf000058_0001
)
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
1-[(3-methylphenyl)sulfonyl]-N-
127 431.1 tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide
1-[(4-chlorophenyl)sulfonyl]-N-
128 451.3 tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide
1-[(4-methylphenyl)sulfonyl]-N-
129 431.1 tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-
130 477.3 tricyclo[3.3.1.13,7]dec-1-yl-3-
Figure imgf000065_0001
piperidineacetamide
1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-
131
Figure imgf000065_0002
464.3 tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide
1-[(2-methylphenyl)sulfonyl]-N-
132 431.1 tricyclo[3.3.1.13,7]dec-1-yl-4-
Figure imgf000065_0003
piperidineacetamide
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-
133 485.1 (trifluoromethyl)phenyl]sulfonyl]-4-
Figure imgf000065_0004
piperidineacetamide
1-[(2,4-dichlorophenyl)sulfonyl]-N-
134 500.2 [(tricyclo[3.3.1.13,7]dec-1-
Figure imgf000065_0005
ylamino)carbonyl]-2-piperidinemethanamine
Figure imgf000066_0001
Figure imgf000067_0001
1-[(4-fluorophenyl)sulfonyl]-N-
150
Figure imgf000068_0001
435.5 tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide
1-[(2,4-dichlorophenyl)sulfonyl]-N-
151 485.0 tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-
152 465.1 tricyclo[3.3.1.13,7]dec-1-yl-4-
Figure imgf000068_0002
piperidineacetamide
1-[(2-chlorophenyl)sulfonyl]-N-
153 451.1 tricyclo[3.3.1.13,7]dec-1-yl-4-
Figure imgf000068_0003
piperidineacetamide
1-[(3-chlorophenyl)sulfonyl]-N-
154 451.1 tricyclo[3.3.1.13,7]dec-1-yl-4-
Figure imgf000068_0004
piperidineacetamide
1-[(3-methylphenyl)sulfonyl]-N-
155 431.1 tricyclo[3.3.1.13,7]dec-1-yl-4-
Figure imgf000068_0005
piperidineacetamide
1-[(4-methoxyphenyl)sulfonyl]-N-
156 447.1 tricyclo[3.3.1.13,7]dec-1-yl-4-
Figure imgf000068_0006
piperidineacetamide
Figure imgf000069_0001
Figure imgf000070_0001
N-[[1-[(3-methylphenyl)sulfonyl]-3-
171 431.1 pipeιϊdinyl]methyl]-
Figure imgf000071_0001
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[(4-methoxyphenyl)sulfonyl]-3-
172 447.1 piperidinyl]methyl]-
Figure imgf000071_0002
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3-
173 485.1 piperidinyl]methyl]-
Figure imgf000071_0003
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[(4-chlorophenyl)sulfonyl]-3-
174 451.1 piperidinyl]methyl]-
Figure imgf000071_0004
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[(4-methylphenyl)sulfonyl]-3-
175 431.1 piperidinyl]methyl]-
Figure imgf000071_0005
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[(4-fluorophenyl)sulfonyl]-3-
176 435.1 piperidinyl]methyl]-
Figure imgf000071_0006
tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
)
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
-
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-3-
260 451.1 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000085_0001
N-[[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3-
261 471.1 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000085_0002
N-[[1-[(2-chlorophenyl)sulfonyl]-3-
262 437.1 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000085_0003
N-[[1-[(2-methylphenyl)sulfonyl]-3-
263 417.1 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000085_0004
N-[[1-[(3-chlorophenyl)sulfonyl]-3-
264 437.0 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000085_0005
Figure imgf000086_0001
N-[[1-[(4-fluorophenyl)sulfonyl]-3-
270 421.1 pyrrolidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000087_0001
N-[[1-[(2-chlorophenyl)sulfonyl]-2-
271 451.1 pipeιϊdinyl]methyl]-
Figure imgf000087_0002
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[(2-methylphenyl)sulfonyl]-2-
272 431.1 piperidinyl]methyl]-
Figure imgf000087_0003
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2-
273 485.1 piperidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000087_0004
N-[[1-[(3-chlorophenyl)sulfonyl]-2-
274 451.1 piperidinyl]methyl]-
Figure imgf000087_0005
tricyclo[3.3.1.13,7]decane-1-carboxamide
N-[[1-[(3-methylphenyl)sulfonyl]-2-
275 431.1 piperidinyl]methyl]-
Figure imgf000087_0006
tricyclo[3.3.1.13,7]decane-1-carboxamide
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
As used above, the phrase "using the general procedure described above" indicates that the procedure used employs similar, but not necessarily identical, reaction conditions to those referred to.
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, 11 β-HSD1 and / or 1 1 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, 11 β-HSD1 and 11 β-HSD2 inhibitory activity are provided below.
As stated above, the compounds according to Formula I are sEH inhibitors and 1 1 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 10,000 nM and an IC50 against 11 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 11 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 n M to 10 nM and an IC50 against 1 1 β- HSD1 from 0.1 nM to 1 O 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 1 1 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 1 1 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 uL; 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 ul; 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 uL; 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/DL, and 98 DL/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 DL 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 DL of substrate solution is added (substrate solution is prepared by diluting 1.24 DL of 14,15-EET from Cayman Chemical, Cat. No. 50651 with 8.24 DL 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 1 10 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 11 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 uL 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 uL. The assay is incubated for 3 hours at 37 °C before quenching the reaction with 25 uL of 10 uM 18β-glycyrrhetinic acid, a potent natural product inhibitor of 11 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 : n) 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 i t°P - bottom . _.
%/ = bottom + 1 ι 1 y r\( ,.iogI τrC5.n0-x λ)'H ..iU.. ( v2) ' 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 except Example 24 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 3 and Example 5 were found to have an IC50 against sEH from 0.1 nM to 10,000 nM. Example 3 was found to have an IC50 of 19,953 nM. Example 5 was to have an IC50 greater than 25,119 nM. It is not known whether or not Example 5 would inhibit sEH activity at concentrations above 25,119 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 0.1 nM to 10,000 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 1 1 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, cardiac and renal fibrosis, 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.
Heart failure is a complex heterogenous disorder characterized by reduced cardiac output, resulting in the inability of the heart to meet perfusion demands of the body. Cardiac proinflammatory cytokine recruitment and maladaptive cardiac hypertrophy, fibrosis and apoptosis/necrosis are factors associated with the progression of heart failure. Compounds of the invention are directed to methods of treating such 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 according to Formula I:
Figure imgf000116_0001
Formula I wherein:
A is A1 , A2, or A3;
A1 is
Figure imgf000116_0002
Figure imgf000116_0003
Figure imgf000116_0004
p is 1 or 2;
W is S(O2)R2 or C(O)NR2R2; X, Y, and Z are each selected from the group consisting of: Rc, Rd, Rg, or Rh; or two of X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycyclic ring having from 5 to 15 member atoms wherein said ring optionally contains one to four heteroatoms as member atoms in the ring and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa, and the other of X, Y and Z is selected from the group consisting of: H, Rc, Rd, Rg, or Rh; or X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycyclic ring having from 5 to 15 member atoms wherein said ring optionally contains one to four heteroatoms as member atoms in the ring and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa; when W is C(O)NR2R2, R1 is H, Rc, or Rd; when W is S(O2)R2, R1 is H; when W is C(O)NR2R2, each R2 is independently H, CH3, Re, Rf, Rg, Rh, or Rm; when W is S(O2)R2, R2 is independently CH3, Re, Rf, Rg, Rh, or Rm; each Ra is independently H, C1-C3 alkyl, or C1-C3 haloalkyl provided that when Ra is C1-C3 haloalkyl and is attached to a nitrogen atom, the carbon atom immediately adjacent to the nitrogen atom is not substituted with halo; each Rb is independently H, C1-C3 alkyl or both Rb groups, independently in each instance, taken together with the nitrogen atom to which they are attached form a saturated monocyclic ring having from 5 to 7 member atoms wherein said ring optionally contains one additional heteroatom as a member atom and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C3 alkyl, ORa, and NRaRa; each Rc is independently C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of: Ri, Rj, Rk, Rl, ORa, SRa, NRbRb, C(O)ORa, C(O)NRbRb, and C3-C6 cycloalkyl; each Rd is independently C3-C6 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: ORa, SRa, NRbRb, C(O)ORa, C(O)NRbRb, C1-C3 alkyl, and C1-C3 haloalkyl; each Re is independently C2-C10 alkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -SRa, -NRbRb, -C(O)ORa, - C(O)NRbRb, and C3-C6 cycloalkyl; each Rf is independently C3-C12 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -SRa, -NRbRb, - C(O)ORa, -C(O)NRbRb, C1-C3 alkyl, and C1-C3 haloalkyl; each Rg is independently aryl optionally substituted with one or more substituents selected from the group consisting of: -CN, -NO2, halo, Rc, Rd, C1-C3 haloalkyl, -CORa, -ORa, -SRa, -NRbRb, -S(O2)Ra, -S(O2)NRbRb, C(O)ORa, C(O)NRbRb, and - NRaC(O)NRbRb; each Rh is independently heteroaryl optionally substituted with one or more substituents selected from the group consisting of: -CN, -NO2, halo, Rc, Rd, C1-C3 haloalkyl, -CORa, -ORa, -SRa, -NRbRb, -S(O2)Ra, -S(O2)NRbRb, C(O)ORa, C(O)NRbRb, and -NRaC(O)NRbRb; each Ri is independently C3-C6 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -NRbRb, C1-C3 alkyl, and C1- C3 haloalkyl; each Rj is independently monocyclic heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of: -ORa, -NRbRb, C1-C3 alkyl, and C1-C3 haloalkyl; each Rk is independently aryl optionally substituted with one or more substituents selected from the group consisting of: -CN, halo, -ORa, C1-C3 alkyl, C1-C3 haloalkyl, and -NRbRb; each Rl is independently heteroaryl optionally substituted with one or more substituents selected from the group consisting of: -CN, halo, -ORa, C1-C3 alkyl, C1-C3 haloalkyl, and -NRbRb; each Rm is independently C1-C3 alkyl substituted with Rg or Rh; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein: A is A1, A2, or A3; W is S(O2)R2 or C(O)NR2R2; p is 1 or 2; X, Y, Z together form adamantyl which may be substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa; Ri is hydrogen; One R2 is hydrogen; and the other R2 is phenyl, pyridyl, furyl, thienyl, benzofuryl, benzothienyl, benzothiazolyl, cyclohexyl, pyrido-oxazinyl, phenyl-ethyl, napthyl, or C2-6alkyl; all of which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C1-6alkyl, NRbRb, C(O)NRbRb, CF3, OCF3, phenyl, C1-6 alkoxy, ORa, CN, NO2, C(O)ORa, or morpholinyl; Ra is hydrogen or C1-3alkyl; Rb is hydrogen or C1-3alkyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 wherein:
A is A2, or A3;
W is S(O2)R2 or C(O)NR2R2; p is 1 or 2; X, Y, Z together form unsubstituted adamantyl;
Ri is hydrogen;
One R2 is H1; and the other R2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C1-6alkyl, NH2, NHC(O)CH3, CF3, OCF3, phenyl, C1-6 alkoxy, OH, CN, , NO2,
-NRbRb, CO2CH3, or morpholinyl; and n is 1 or 2;
or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 wherein:
A is A2;
W is S(O2)R2;
P is 1 ; X, Y, Z together form unsubstituted adamantyl;
Ri is hydrogen;
One R2 is H1; and the other R2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C1-6alkyl, NH2, NHC(O)CH3, CF3, OCF3, phenyl, C1-6 alkoxy, OH, CN; and n is 1 ; or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 chosen from:
2-{(2R)-1-[(3-methylphenyl)sulfonyl]-2-pyrrolidinyl}-N-tricyclo[3.3.1.13'7]dec-2- ylacetamide;
N-tricyclo[3.3.1.13'7]dec-1-yl-2-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}-2-pyrrolidinyl) acetamide;
N-[(2,4-dichlorophenyl)methyl]-2-[2-oxo-2-(tricyclo[3.3.1.13'7]dec-1-ylamino)ethyl]-1- pyrrolidinecarboxamide; N-[[1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
N-^i-^-nitrophenyl)sulfonyl]-2-piperidinylJmethyl)tricyclotS.3.1.13,7]decane-1- carboxamide;
N-({1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2- piperidinyl}methyl)tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
(2R)-1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
N-[[(2R)-1-[(4-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[(2R)-1-[(3-fluorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(2-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidineacetamide;
1-(3-pyridinylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide trifluoroacetate (1 :1 ;)
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
2-[1 -(4-biphenylylsulfonyl)-2-pyrrolidinyl]-N-tricyclo[3.3.1.13'7]dec-1 -ylacetamide; 1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; 1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; 1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2- pyrrolidineacetamide;
1-[(2-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; 1-[(cyclohexylamino)carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
N-(2-chlorophenyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide; N-(2,4-dichlorophenyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2-
(trifluoromethoxy)phenyl]-1 -piperidinecarboxamide;
N-cyclohexyl-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine; i-φhenylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]^- piperidinemethanamine; 1-(butylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
1-([1 ,1'-biphenyl]-4-ylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine;
4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2- (trifluoromethyl)phenyl]-1 -piperidinecarboxamide;
N-(phenylmethyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
^(methylsulfonyl^N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]^- piperidinemethanamine; N-butyl^-tt^tricyclotS.S.I .I SJldec-i-ylamino^arbony^aminolmethyl]-!- piperidinecarboxamide; i-[(4-methylphenyl)sulfonyl]-N-^tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]^- piperidinemethanamine ; i-[(2-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]^- piperidinemethanamine;
N-phenyl-^ttt(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]aminolmethyl]-i- piperidinecarboxamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-pyrrolidineacetamide; 1-(butylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-(cyclohexylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide;
1-[(2-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-(phenylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; i-[(4-fluorophenyl)sulfonyO-N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine ;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide ;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide ;
^(phenylsulfonyO-N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- pyrrolidinemethanamine;
1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(4-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine ;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(2-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[(3-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide ; 1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide;
1-[(3-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide; 1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide ; 1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2- piperidineacetamide;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-2-piperidineacetamide;
N-[4-(dimethylamino)phenyl]-4-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide trifluoroacetate (1 :1 ); 1-(phenylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
^(phenylsulfonyO-N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- piperidinemethanamine;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-([1 ,1'-biphenyl]-4-ylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tfS-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidinemethanamine;
1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2- pyrrolidinemethanamine;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; 1-[(2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
1-[(3-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; i-[(4-methoxyphenyl)sulfony^-N-f(tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine;
N-f(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-t^-(trifluoromethyl)pheny^sulfonyl]-2- pyrrolidinemethanamine; 1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; i-[(4-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine;
N-(2,4-dichlorophenyl)-2-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-[(2,4-dichlorophenyl)methyl]-2-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1 -pyrrolidinecarboxamide ; i-^^-dimethoxyphenyl)sulfonyl]-N-f(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine; 1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
N-t(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-i-fP-(trifluoromethyl)phenyl]sulfonyl]-3- piperidinemethanamine ; i-[(2-methylphenyl)sulfonyl]-N-^tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-3- piperidinemethanamine ;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tfS-(trifluoromethyl)phenyl]sulfonyl]-3- piperidinemethanamine; 1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine; i-^S-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- piperidinemethanamine; i-^-methoxyphenyl)sulfonyll-N-f(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyll-3- piperidinemethanamine;
1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine ;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine; 1-[(4-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
N-(2,4-dichlorophenyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide ;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine;
N-[(2,4-dichlorophenyl)methyl]-4-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide;
1-(cyclohexylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-4- piperidinemethanamine; N-(1-phenylethyl)-4-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2- piperidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; 1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; 1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; 1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-4- piperidineacetamide; 1-[(2,4-dichlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-tP-(trifluoromethyl)pheny^sulfonyl]-2- piperidinemethanamine; i-[(2-methylphenyl)sulfonyl]-N-^tricyclofS.S.I .ISJldec-i-ylamino^arbonyl]-2- piperidinemethanamine;
N-t(tricyclotS.S.I .I SJldec-i-ylamino^arbonyl]-i-ttS-(trifluoromethyl)pheny^sulfonyl]-2- piperidinemethanamine; 1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(3-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine ;
1-[(4-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-(phenylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3- piperidineacetamide;
1-[(2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3- piperidineacetamide; 1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3- piperidineacetamide;
1-[(4-fluorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide;
1-[(2,4-dichlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide; 1-[(3-chloro-2-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(3-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(3-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide; 1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-4- piperidineacetamide;
1-[(4-chlorophenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide;
1-[(4-methylphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide; 1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[2-(trifluoromethyl)phenyl]sulfonyl]-4- piperidineacetamide;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4-piperidineacetamide; 1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-4- piperidineacetamide;
1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- piperidineacetamide;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-[[1-P-(trifluoromethyl)phenyl]sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-p-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo^.3.1.13,7]decane-1- carboxamide;
N-[[1-^^-dimethoxyphenyl)sulfonyl]-3-piperidinyl]methylJ-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(3-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-ffi-[[4-(trifluoromethyl)phenyl]sulfonyl]-3-piperidinyl]methyl]-tricyclotS.S.I .I SJldecane-
1 -carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2- piperidinemethanamine; 1-[(4-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(4-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
N-[(2,4-dichlorophenyl)methyl]-2-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide;
N-(2,4-dichlorophenyl)-2-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- piperidinecarboxamide; 1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- piperidinemethanamine;
N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3- piperidinemethanamine;
N-[(2,4-dichlorophenyl)methyl]-3-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1-piperidinecarboxamide;
1-[(2,4-dimethoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine; 1-[(4-methoxyphenyl)sulfonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-piperidineacetamide; N-(2,4-dichlorophenyl)-3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide;
N-[[1-P-(trifluoromethyl)phenyl]sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; 1-[[[(2,4-dichlorophenyl)methyl]amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide;
N-[[1-(phenylsulfonyl)-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1-carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]^-piperidinyl]methyl]-tricyclotS.S.I .IS^Jdecane-i- carboxamide; N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-tP-(trifluoromethyl)phenyl]sulfonyl]^-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-methylphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methylphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(4-methoxyphenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[(2,4-dichlorophenyl)methyl]-4-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide;
N-[[1-(phenylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-3-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1-carboxamide;
N-[[1-(phenylsulfonyl)-2-piperidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
1-(cyclohexylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[(cyclohexylamino)carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide; 1-[[(2,4-dichlorophenyl)amino]carbonyl]-N-tricyclo[3.3.1.13,7]dec-1-yl-3- pyrrolidineacetamide;
N-tricyclo[3.3.1.13,7]dec-1-yl-1-[[[2-(trifluoromethoxy)phenyl]amino]carbonyl]-3- pyrrolidineacetamide; N-[[1-(phenylsulfonyl)-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1-carboxamide;
N-[[1-[(2-methyl phenyl )sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-^S-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-[(3-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methyl phenyl )sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclotS.S.I .IS^Jdecane-i- carboxamide;
N-[[1-[(4-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(4-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[[4-methylphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclotS.3.1.13,7]decane-1- carboxamide;
N-[[1-^^-dimethoxyphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclotS.S.I .IS^Jdecane-i- carboxamide;
1-(butylsulfonyl)-N-tricyclo[3.3.1.13,7]dec-1-yl-3-pyrrolidineacetamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^S-(trifluoromethyl)phenyl]sulfonyl]^-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1 -carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-4-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-^^-dimethoxyphenyl)sulfonyl]^-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide; N-III-^^-dimethoxyphenyl)sulfonyll-3-pyrTolidinyl]methyll-tricyclop.S.I .ISJldecane-i- carboxamide;
N-phenyl-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide; N-(2-chlorophenyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-μ^dimethylaminoJphenyll-3-HKtricycloβ.S.I .IS^dec-i- ylamino)carbonyl]amino]methyl]-1-pyrrolidinecarboxamide trifluoroacetate (1 :1 ) ;
N-[(2,4-dichlorophenyl)methyl]-3-[[[(tricyclo[3.3.1.13,7]dec-1- ylamino)carbonyl]amino]methyl]-1 -pyrrolidinecarboxamide;
3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2-
(trifluoromethyl)phenyl]-1 -pyrrolidinecarboxamide;
3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-N-[2-
(trifluoromethoxy)phenyl]-1-pyrrolidinecarboxamide; 1-[(4-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-[(tricyclo[3.3.1.1 S^Jdec-i-ylaminoJcarbonyl]-i-t^trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidinemethanamine; i-[(4-chlorophenyl)sulfonyll-N-[(tricycloβ.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(4-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(4-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-butyl-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-(1-phenylethyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
1-[(3-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3- pyrrolidinemethanamine; 1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; i-^S-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-3- pyrrolidinemethanamine; 1-[(3-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-cyclohexyl-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-(phenylmethyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-(2,4-dichlorophenyl)-3-[[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]methyl]-1- pyrrolidinecarboxamide;
N-[(2,4-dichlorophenyl)methyl]-2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- pyrrolidinecarboxamide; N-[[1-[(2,4-dichlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-tP-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1 -carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-2-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide ;
N-[(2,4-dichlorophenyl)methyl]-3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide; N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-tP-(trifluoromethyl)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[(2,4-dichlorophenyl)methyl]-3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- pyrrolidinecarboxamide;
N-[[1-[(2,4-dichlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-chloro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-methylphenyl)sulfonyll-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methyl phenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; N-[[1-[(4-chlorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methyl phenyl )sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-chlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[[3-(trifluoromethyl]phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-[(4-chlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide ;
N-[[1-[(4-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(4-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(2,4-dimethoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[(2,4-dichlorophenyl)methyl]-2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinecarboxamide ;
1-[(2-methoxyphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
1-[(2-methylphenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine; 1-[(2-fluorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- pyrrolidinemethanamine;
N-[[1-[(5-chloro-2-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3-chloro-4-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane- 1 -carboxamide;
N-[[1-[(2-fluoro-5-methylphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3-chloro-2-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide; N-[[1-[[4-(acetylamino)phenyl]sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(phenylmethyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3,4-dimethoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2,3-dihydro-1-methyl-1 H-pyrido[2,3-b][1 ,4]oxazin-6-yl)sulfonyl]-2- piperidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide; 4-methoxy-5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- piperidinyl]sulfonyl]-3-thiophenecarboxylic acid methyl ester;
N-[[1-[(3-methoxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1 ,4-oxazin-7-yl)sulfonyl]-3- pyrrolidinyl]methyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
4-methoxy-5-[[3-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1- pyrrolidinyl]sulfonyl]-3-thiophenecarboxylic acid methyl ester;
N-[[1-[(4-cyanophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-cyanophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide; N-[[1-(6-benzothiazolylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide ;
N-[[1-(benzo[b]thien-3-ylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[[4-[(benzoylamino)methyl]-2-thienyl]sulfonyl]-3-pyrrolidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2-cyanophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-chloro-3-nitrophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(3-nitrophenyl)sulfonyl]-2-piperidinyl]methyll-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(4-nitrophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide ;
3-methyl-5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1-piperidinyl]sulfonyl]- 2-furancarboxylic acid methyl ester;
N-[[1-[(4-chloro-3-nitrophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-nitrophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide; N-[[1-[(^nitrophenyl)sulfony^-3-pyrrolidiny^methy^-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-chloro-4-fluorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide; N-[[1-[(3,5-dichlorophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[[4-(2-oxo-1-pyrrolidinyl)phenyl]sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide;
N-[[1-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13,7]decane-1-carboxamide;
5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1-piperidinyl]sulfonyl]-2- furancarboxylic acid methyl ester;
2-methyl-5-[[2-[[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl]-1-piperidinyl]sulfonyl]-
3-furancarboxylic acid methyl ester; N-[2-[1-[(4-chlorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(4-fluorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[2-[1-[(3-chlorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(3-methylphenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[2-[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1-carboxamide;
N-[2-[1-[(2-chlorophenyl)sulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(2-(trifluoromethyl)phenyOsulfonyl]-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane- 1-carboxamide;
N-[2-[1-(phenylsulfonyl)-3-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(3-cyanophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-hydroxyphenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide; N-[[1-[(2-hydroxyphenylJsulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-i- carboxamide;
N-[[1-[(3-chlorophenyl)sulfonyl]-3-azetidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(2-chlorophenyl)sulfonyl]-3-azetidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-chloro-2-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2-methoxy-4-methylphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(4-fluoro-3-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide; N-[[1-[(3-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(5-chloro-2-hydroxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(4-hydroxy-3-methoxyphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(2-chloro-4-cyanophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[[1-[(3-aminophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(4-aminophenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-aminophenyl)sulfonyl]-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(2-hydroxy-4-methylphenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-methylbenzo[b]thien-2-yl)sulfonyl]-3-pyrrolidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-methylbenzo[b]thien-2-yl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide; N-[[1-(benzo[b]thien-2-ylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-(benzo[b]thien-2-ylsulfonyl)-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[[1-[(5-chloro-3-methylbenzo[b]thien-2-yl)sulfonyl]-3-pyrrolidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-[(5-chloro-3-methylbenzo[b]thien-2-yl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
N-[[1-(2-benzofuranylsulfonyl)-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-(2-benzofuranylsulfonyl)-2-piperidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[(4-chlorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[2-[1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[[4-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[2-[1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[[2-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[2-[1-[(3-chlorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; N-[2-[1-[(3-methylphenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[2-[1-[[3-(trifluoromethyl)phenyl]sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-
1 -carboxamide;
N-[2-[1-[(2-chlorophenyl)sulfonyl]-2-pyrrolidinyl]ethyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide;
N-[[1-[(4-methoxy-1-naphthalenyl)sulfonyl]-2-piperidinyl]methyl]- tricyclo[3.3.1.13, 7]decane-1 -carboxamide;
Λ/-({1-[(4-chloro-2,5-dimethylphenyl)sulfonyl]-3- pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1 -carboxamide; A/-({1-[(2,5-dichlorophenyl)sulfonyl]-3-pyrrolidinyl}rnethyl)tricyclo[3.3.1.137]decane-1- carboxamide;
Λ/-[(1-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3- pyrrolidinyl)methyl]tricyclo[3.3.1.13'7]decane-1 -carboxamide; Λ/-({1-[(2,5-dimethylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
/\/-({1-[(4-bromo-2-chlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide;
Λ/-({1-[(2,3-dichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
Λ/-({1-[(2,3,4-trichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
Λ/-({1-[(2-chloro-6-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide; Λ/-({1-[(2,6-dichlorophenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-1- carboxamide;
Λ/-({1-[(5-bromo-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide;
Λ/-({1-[(5-fluoro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane- 1 -carboxamide; and
Λ/-({1-[(3-fluoro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane-
1 -carboxamide; or a pharmaceutically acceptable salt thereof.
6. A compound chosen from:
Λ/-({1 -[(4-bromo-2-chlorophenyl)sulfonyll-3-pyrrolidinylJmethyOtricyclo^.3.1.13'7]decane-
1 -carboxamide;
1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-3- piperidinemethanamine; 1-[(2-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; i-[(2-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine;
1-[(3-chlorophenyl)sulfonyl]-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]-2- pyrrolidinemethanamine; 1-[(3-methylphenyl)sulfonyll-N-[(tricyclo[3.3.1.13,7]dec-1-ylamino^arbonyl]-2- pyrrolidinemethanamine;
Λ/-^i-[(2-chloro-B-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane- 1-carboxamide; i-[(4-methylphenyl)sulfonyl]-N-^tricyclo[3.3.1.13,7]dec-i-ylamino)carbonyl]-2- piperidinemethanamine;
Λ/-({1-[(3-fluoro-2-methylphenyl)sulfonyl]-3-pyrrolidinyl}methyl)tricyclo[3.3.1.13'7]decane- 1-carboxamide; i-φhenylsulfonyO-N-[(tricyclo[3.3.1.13,7]dec-i-ylamino^arbonyl]-2- pyrrolidinemethanamine; and
N-[[1-[(2-methyl phenyl)sulfonyl]-3-pyrrolidinyl]methyl]-tricyclo[3.3.1.13,7]decane-1- carboxamide; or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of Formula (I) of claims 1- 6 and a pharmaceutically acceptable carrier or excipient.
8. 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 1-6.
9. A method according to claim 8 wherein the compound of Formula I is administered orally.
PCT/US2008/084289 2007-11-28 2008-11-21 SEH AND 11 β-HSD1 INHIBITORS AND THEIR USE WO2009070497A1 (en)

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